Official Journal of the International Society of Nephrology

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management ofChronic Kidney Disease
volume 3 | issue 1 | JANUARY 2013
http://www.kidney-international.org

KDIGO 2012 Clinical Practice Guideline
for the Evaluation and Management ofChronic Kidney Disease

KDIGO gratefully acknowledges the following consortium of sponsors that make our initiatives possible: Abbott, Amgen,
Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole Food
Company, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, JC Penney, Kyowa Hakko Kirin, NATCO—The
Organization for Transplant Professionals, NKF-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical,
Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma,and Wyeth.
Sponsorship Statement: KDIGO is supported by a consortium of sponsors and no funding is accepted for the developmentof specific guidelines.

contents

http://www.kidney-international.org& 2013 KDIGO

VOL 3 | ISSUE 1 | JANUARY (1) 2013

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Managementof Chronic Kidney Diseasev

Tables and Figures

vii

KDIGO Board Members

viii

Reference Keysx

CKD Nomenclaturexi

Conversion Factors & HbA1c Conversionxii

Abbreviations and Acronyms

1

Notice2

Foreword

3

Work Group Membership

4

Abstract5

Summary of Recommendation Statements

15

Introduction:

19

Chapter 1:

Definition, and classification of CKD

63Chapter 2:

Definition, identification, and prediction of CKD progression

73

Chapter 3:

Management of progression and complications of CKD

91Chapter 4:

Other complications of CKD: CVD, medication dosage, patient safety, infections,
hospitalizations, and caveats for investigating complications of CKD

112

Chapter 5:

Referral to specialists and models of care

120

Methods for Guideline Development

128

Biographic and Disclosure Information

134

Acknowledgments

136

References

The case for updating and context

This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics(COPE) www.publicationethics.org

http://www.kidney-international.org

contents& 2013 KDIGOTABLES
18

Table 1.

KDIGO nomenclature and description for grading recommendations

20

Table 2.

Criteria for CKD

20Table 3.

Criteria for definition of CKD

27

Table 4.

Classification of CKD based on presence or absence of systemic disease and location within the kidney ofpathologic-anatomic findings

27

Table 5.

GFR categories in CKD

28Table 6.

Albuminuria categories in CKD

31

Table 7.

Relationship among categories for albuminuria and proteinuria

32

Table 8.

CGA staging of CKD: examples of nomenclature and comments

33

Table 9.

Prognosis of CKD: Relationship of outcomes and strength of relationship to Cause (C), GFR (G), Albuminuria (A)and other measures

35

Table 10.

Annual percentage change in GFR across diagnosis categories

39

Table 11.

Sources of error in GFR estimating using creatinine

41

Table 12.

Equations based on serum creatinine assays in adults that are traceable to the standard reference material

44

Table 13.

Performance comparison of creatinine-based GFR estimating equations in North America, Europe, and Australia

48

Table 14.

Performance comparison of creatinine-based GFR estimating equations outside of North America, Europe, and Australia

50

Table 15.

Sources of error in GFR estimating using cystatin C

52

Table 16.

Equations based on IDMS traceable creatinine and IFCC traceable cystatin C assays

54

Table 17.

Performance comparison of cystatin C-based estimating equations in North American and European populations

55

Table 18.

Strengths and limitations of GFR measurement methods and markers

59

Table 19.

Factors affecting urinary ACR

64

Table 20.

Decline in kidney function in various populations (longitudinal studies only)

65

Table 21.

Decline in kidney function in CKD populations

67

Table 22.

Studies evaluating rapid progression (general population studies only)

68

Table 23.

CKD progression and risk of all-cause mortality and ESRD using baseline (first) eGFR

68

Table 24.

Association between absolute and percentage change in kidney function and risk of ESRD, based on adjustment
for eGFR at the first and last measurement

77

Table 25.

Intensive versus normal glycemic control and albuminuria outcome

78

Table 26.

Recommended Daily Intake of sodium for healthy children

81

Table 27.

Prevalence of CKD complications by GFR category derived from CKD cohorts

81

Table 28.

Hemoglobin cutoffs for people living at sea level

87

Table 29.

Phosphate binding agents in routine clinical practice and their ranked cost

89

Table 30.

Summary data for bisphosphonates and CKD

100

Table 31.

Peripheral arterial disease and CKD

103Table 32.

Cautionary notes for prescribing in people with CKD

107

Table 33.

Risk factors for infection in people with CKD

110Table 34.

Components of community CKD management programs

114

Table 35.

Early versus late referral: consequences and benefits

114

Table 36.

Outcomes of early versus late referral

122

Table 37.

Topics of interest for the management of CKD guideline

123

Table 38.

Literature yield of primary articles for all topics

123

Table 39.

Classification of study quality

124

Table 40.

GRADE system for grading quality of evidence

124

Table 41.

Final grade for overall quality of evidence

124

Table 42.

Balance of benefits and harm

125

Table 43.

KDIGO nomenclature and description for grading recommendations

125

Table 44.

Determinants of strength of recommendation

125

Table 45.

The Conference on Guideline Standardization checklist for reporting clinical practice guidelines

Kidney International Supplements (2013) 3, v

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contents

http://www.kidney-international.org& 2013 KDIGOFIGURES
16

Figure 1.

Conceptual model of CKD

22

Figure 2.

Normal values for GFR by age

23

Figure 3.

Relationship of eGFR with mortality

23

Figure 4.

Relationship of albuminuria with mortality

28

Figure 5.

Age-standardized rates of death from any cause, cardiovascular events, and hospitalization, according to theeGFR among 1,120,295 ambulatory adults

29

Figure 6.

Summary of continuous meta-analysis for general population cohorts with ACR

30

Figure 7.

Summary of categorical meta-analysis for general population cohorts with ACR

31

Figure 8.

Prevalence of CKD in the USA by GFR and albuminuria

34

Figure 9.

Prognosis of CKD by GFR and albuminuria category

39

Figure 10. Determinants of the serum level of endogenous filtration markers

43

Figure 11. Performance of the CKD-EPI and MDRD Study equations in estimating measured GFR in the external validation
data set

46

Figure 12. Comparison of distribution of GFR and CKD prevalence by age (NHANES 1999-2004)

47

Figure 13. Meta-analysis of NRI for all-cause mortality, CVD mortality, and ESRD

50

Figure 14. Association of CKD definitions with all-cause mortality and ESRD

53

Figure 15. Performance of three equations for estimating GFR

57

Figure 16. Suggested protocol for the further investigation of an individual demonstrating a positive reagent strip test foralbuminuria/proteinuria or quantitative albuminuria/proteinuria test

63

Figure 17. GFR and albuminuria grid to reflect the risk of progression

69

Figure 18. Distribution of the probability of nonlinearity with three example trajectories demonstrating different probabilities
of nonlinearity

86

Figure 19. Summary estimates for risks of all-cause mortality and cardiovascular mortality associated with levels of serum
phosphorus, PTH, and calcium

88

Figure 20. Prevalence of deficiency of 1,25(OH)2D3, 25(OH)D3, and secondary hyperparathyroidism by GFR intervals

113

Figure 21. Referral decision making by GFR and albuminuria

116

Figure 22. The CKD chronic care model

Additional information in the form of supplementary materials can be found online at http://www.kdigo.org/clinical_practice_guidelines/ckd.php

vi

Kidney International Supplements (2013) 3, vi

http://www.kidney-international.org& 2013 KDIGOKDIGO Board Members
Garabed Eknoyan, MD
Norbert Lameire, MD, PhD
Founding KDIGO Co-Chairs
Kai-Uwe Eckardt, MD
Immediate Past Co-Chair

Bertram L Kasiske, MD
KDIGO Co-ChairDavid C Wheeler, MD, FRCPKDIGO Co-Chair

Omar I Abboud, MD, FRCP
Sharon Adler, MD, FASN
Rajiv Agarwal, MD
Sharon P Andreoli, MD
Gavin J Becker, MD, FRACPFred Brown, MBA, FACHE
Daniel C Cattran, MD, FRCPC
Allan J Collins, MD, FACP
Rosanna Coppo, MD
Josef Coresh, MD, PhD
Ricardo Correa-Rotter, MD
Adrian Covic, MD, PhD
Jonathan C Craig, MBChB, MM (Clin Epi), DCH, FRACP, PhD
Angel LM de Francisco, MD
Paul E de Jong, MD, PhD
Ana Figueiredo, RN, MSc, PhD
Mohammed Benghanem Gharbi, MD
Gordon Guyatt, MD, MSc, BSc, FRCPCDavid Harris, MD
Lai Seong Hooi, MD
Enyu Imai, MD, PhD
Lesley A Inker, MD, MS, FRCP

Michel Jadoul, MD
Simon Jenkins, MBE, FRCGP
Suhnggwon Kim, MD, PhD
Martin K Kuhlmann, MD
Nathan W Levin, MD, FACP
Philip K-T Li, MD, FRCP, FACP
Zhi-Hong Liu, MD
Pablo Massari, MD
Peter A McCullough, MD, MPH, FACC, FACP
Rafique Moosa, MD
Miguel C Riella, MD
Adibul Hasan Rizvi, MBBS, FRCP
Bernardo Rodriquez-Iturbe, MD
Robert Schrier, MD
Justin Silver, MD, PhD
Marcello Tonelli, MD, SM, FRCPCYusuke Tsukamoto, MD
Theodor Vogels, MSW
Angela Yee-Moon Wang, MD, PhD, FRCP
Christoph Wanner, MD
Elena Zakharova, MD, PhD

NKF-KDIGO GUIDELINE DEVELOPMENT STAFF

Kerry Willis, PhD, Senior Vice-President for Scientific Activities
Michael Cheung, MA, Guideline Development Director
Sean Slifer, BA, Guideline Development Manager

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http://www.kidney-international.org& 2013 KDIGO

Reference KeysNOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS
Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the
supporting evidence is shown as A, B, C, or D.

Implications
Grade*

Patients

Clinicians

PolicyLevel 1
‘We recommend’

Most people in your situation would want
the recommended course of action and onlya small proportion would not.

Most patients should receive therecommended course of action.

The recommendation can be evaluated as a
candidate for developing a policy or aperformance measure.

Level 2‘We suggest’

The majority of people in your situation
would want the recommended course ofaction, but many would not.

Different choices will be appropriate fordifferent patients. Each patient needs help toarrive at a management decision consistent
with her or his values and preferences.

The recommendation is likely to require
substantial debate and involvement of
stakeholders before policy can be
determined.

*The additional category ‘Not Graded’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence.
The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations
are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Grade

Quality of evidence

Meaning

A
B
C
D

High
Moderate
Low
Very low

We are confident that the true effect lies close to that of the estimate of the effect.
The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
The true effect may be substantially different from the estimate of the effect.
The estimate of effect is very uncertain, and often will be far from the truth.

ADULT GFR ESTIMATING EQUATIONS
2009 CKD-EPI creatinine equation: 141  min(SCr/k, 1)a  max(SCr/k, 1) 1.209  0.993Age [  1.018 if female] [  1.159 if black], where
SCr is serum creatinine (in mg/dl), k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is theminimum of SCr/k or 1, and max is the maximum of SCr/k or 1.

Equations expressed for specified sex and serum creatinine level
GenderSerum creatinine

Equation for estimating GFRFemaleFemaleMale
Malep0.7 mg/dl (p62 mmol/l)
40.7 mg/dl (462 mmol/l)
p0.9 mg/dl (p80 mmol/l)
40.9 mg/dl (480 mmol/l)

144  (SCr/0.7) 0.329  0.993Age [  1.159 if black]144  (SCr/0.7) 1.209  0.993Age [  1.159 if black]141  (SCr/0.9) 0.411  0.993Age [  1.159 if black]141  (SCr/0.9) 1.209  0.993Age [  1.159 if black]2012 CKD-EPI cystatin C equation: 133  min(SCysC/0.8, 1) 0.499  max(SCysC/0.8, 1) 1.328  0.996Age [  0.932 if female], where
SCysC is serum cystatin C (in mg/l), min indicates the minimum of SCysC/0.8 or 1, and max indicates the maximum of SCysC/0.8 or 1.

Equations expressed for serum cystatin C level

Female or male
Female or maleviii

Serum cystatin C

Equation for estimating GFR

p0.8 mg/l
40.8 mg/l

133  (SCysC/0.8) 0.499  0.996Age [  0.932 if female]
133  (SCysC/0.8) 1.328  0.996Age [  0.932 if female]

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http://www.kidney-international.org& 2013 KDIGO

2012 CKD-EPI creatinine–cystatin C equation: 135  min(SCr/k, 1)a  max(SCr/k, 1) 0.601  min(SCysC/0.8, 1) 0.375  max(SCysC/
0.8, 1) 0.711  0.995Age [  0.969 if female] [  1.08 if black], where SCr is serum creatinine (in mg/dl), SCysC is serum cystatin C (in mg/l),
k is 0.7 for females and 0.9 for males, a is 0.248 for females and 0.207 for males, min(SCr/k, 1) indicates the minimum of SCr/k or 1,
and max(SCr/k, 1) indicates the maximum of SCr/k or 1; min(SCysC/0.8, 1) indicates the minimum of SCysC/0.8 or 1 and max(SCysC/
0.8, 1) indicates the maximum of SCysC/0.8 or 1.

Equations expressed for specified sex, serum creatinine, and serum cystatin C level
GenderSerum creatinine

Serum cystatin C

Equation for estimating GFRFemalep0.7 mg/dl (p62 mmol/l)Female40.7 mg/dl (462 mmol/l)Malep0.9 mg/dl (p80 mmol/l)Male

40.9 mg/dl (480 mmol/l)

p0.8 mg/l
40.8 mg/l
p0.8 mg/l
40.8 mg/l
p0.8 mg/l
40.8 mg/l
p0.8 mg/l
40.8 mg/l

130  (SCr/0.7) 0.248  (SCysC/0.8) 0.375  0.995Age [  1.08 if black]130  (SCr/0.7) 0.248  (SCysC/0.8) 0.711  0.995Age [  1.08 if black]130  (SCr/0.7) 0.601  (SCysC/0.8) 0.375  0.995Age [  1.08 if black]130  (SCr/0.7) 0.601  (SCysC/0.8) 0.711  0.995Age [  1.08 if black]
135  (SCr/0.9) 0.207  (SCysC/0.8) 0.375  0.995Age [  1.08 if black]
135  (SCr/0.9) 0.207  (SCysC/0.8) 0.711  0.995Age [  1.08 if black]
135  (SCr/0.9) 0.601  (SCysC/0.8) 0.375  0.995Age [  1.08 if black]
135  (SCr/0.9) 0.601  (SCysC/0.8) 0.711  0.995Age [  1.08 if black]

PEDIATRIC GFR ESTIMATING EQUATIONSCreatinine-based equations
41.3  (height/SCr)
40.7  (height/SCr)0.64  (30/BUN)0.202
BUN, blood urea nitrogen in mg/dl; height in meters; SCr, serum creatinine in mg/dl

Cystatin C-based equations
70.69  (SCysC) 0.931
SCysC, serum cystatin C in mg/l.

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http://www.kidney-international.org& 2013 KDIGOCURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATUREUSED BY KDIGOCKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications forhealth and CKD is classified based on cause, GFR category, and albuminuria category (CGA).

Prognosis of CKD by GFR and albuminuria category
Persistent albuminuria categories
Description and range

GFR categories (ml/min/ 1.73 m2)
Description and range

Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012

G1

Normal or high

≥90

G2

Mildly decreased

60-89

G3a

Mildly to moderately
decreased

45-59

G3b

Moderately toseverely decreased

30-44

G4

Severely decreased

15-29

G5

Kidney failure

<15

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30-300 mg/g
3-30 mg/mmol>300 mg/g>30 mg/mmol

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk;
Orange: high risk; Red, very high risk.

x

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http://www.kidney-international.org& 2013 KDIGOCONVERSION FACTORS OF METRIC UNITS TO SI UNITS
Parameter
Albumin (serum)
Blood urea nitrogen (BUN)
Creatinine (serum)
Creatinine clearance
Hemoglobin
Phosphate (serum)
PTH (parathyroid hormone, serum)
Urea (plasma)
Uric acid
Vitamin D, 25-hydroxyvitamin D

Metric units

Conversion factor

SI units

g/dl
mg/dl
mg/dl
ml/min
g/dl
mg/dl
pg/ml
mg/dl
mg/dl
ng/ml

10
0.357
88.4
0.01667
10
0.323
0.106
0.167
59.4852.496g/l
mmol/lmmol/lml/s
g/l
mmol/lpmol/lmmol/lmmol/lnmol/lNote: Metric unit  conversion factor ¼ SI unit.

HbA1C CONVERSION CHART
DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9

31
32
33
34
36
37
38
39
40
41

6.0
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9

42
43
44
45
46
48
49
50
51
52

7.0
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9

53
54
55
56
57
58
60
61
62
63

8.0
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9

64
65
66
67
68
69
70
72
73
74

9.0
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
9.9

75
76
77
78
79
80
81
83
84
85

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

DCCT
(%)

IFCC
(mmol/mol)

10.0
10.1
10.2
10.3
10.4
10.5
10.6
10.7
10.8
10.9

86
87
88
89
90
91
92
93
95
96

11.0
11.1
11.2
11.3
11.4
11.5
11.6
11.7
11.8
11.9

97
98
99
100
101
102
103
104
105
107

12.0
12.1
12.2
12.3
12.4
12.5
12.6
12.7
12.8
12.9

108
109
110
111
112
113
114
115
116
117

13.0
13.1
13.2
13.3
13.4
13.5
13.6
13.7
13.8
13.9

119
120
121
122
123
124
125
126
127
128

14.0
14.1
14.2
14.3
14.4
14.5
14.6
14.7
14.8
14.9

130
131
132
133
134
135
136
137
138
139

IFCC-HbA1c (mmol/mol) ¼ [DCCT-HbA1c (%)2.15]  10.929
Abbreviations: DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry and Laboratory Medicine.
Source: Diabetes UK, www.diabetes.org.uk.

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xihttp://www.kidney-international.org& 2013 KDIGO

Abbreviations and Acronyms
4C
AASK
ABPM
ACCORD
ACE-I
ACR
ACS
ADVANCE

AER
AGREE
AKD
AKDN
AKI
ANP
APPROACH
AusDiab
ARB
BMD
BMI
BNP
BP
BSA
BUN
CAD
CAPRICORN
CGA
CHARM
CHF
CHS
CI
CIBIS IICKD
CKD-EPICKD-MBD
CKiD
COGS
COPERNICUS
COX-2
Cr-EDTA
CREATE
CREDO
CrCl
CRIC
CRP

Cardiovascular Comorbidity in Children with CKD
African American Study of Kidney Disease andHypertension
Ambulatory blood pressure monitoring
Action to Control Cardiovascular Risk in Diabetes
Angiotensin-converting enzyme inhibitor
Albumin-to-creatinine ratio
Acute coronary syndrome
Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release
Controlled Evaluation
Albumin excretion rate
Appraisal of Guidelines for Research and
Evaluation
Acute kidney disease
Alberta Kidney Disease Network
Acute kidney injury
Atrial natriuretic peptide
Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease
Australian Diabetes, Obesity and Lifestyle study
Angiotensin-receptor blocker
Bone mineral density
Body mass index
B-type natriuretic peptide
Blood pressure
Body surface area
Blood urea nitrogen
Coronary artery disease
Carvedilol Post-Infarct Survival Control in Left
Ventricular Dysfunction
Cause, GFR and Albuminuria categories
Candesartan in Heart Failure-Assessment ofReduction in Mortality and Morbidity
Congestive heart failure
Cardiovascular Health Study
Confidence interval
Cardiac Insufficiency Bisoprolol Study II
Chronic kidney disease
CKD Epidemiology Collaboration
Chronic Kidney Disease-Mineral and Bone
DisorderChronic Kidney Disease in Children
Conference on Guideline Standardization
Carvedilol Prospective Randomized Cumulative
Survival
Cyclooxygenase-2
Chromium-ethylenediamine tetraacetic acid
Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin Beta Trial
Clopidogrel for Reduction of Events During
Observation
Creatinine clearance
Chronic Renal Insufficiency Cohort
C-reactive protein

Kidney International Supplements (2013) 3, xii

cTnI
cTnT
CVD
DCCT/EDIC

DIG
DPI
DXA
ECG
eGFR
EMU
ERT
ESA
ESCAPE

ESRD
ESUR
FGF-23
GBCA
GFR
GN
GRADE
Hb
HbA1c
HBV
HDL-C
HOPE
HOT
HR
HR-pQCT
HUNT 2
ICD
ICU
IDF
IDMS
IQR
IRMM
ItalKid
JCTLM
KDIGO
KDOQI
LDL-C
LIFE
LPD
LVH
MAP
MDRD
MESA

Cardiac troponin I
Cardiac troponin T
Cardiovascular disease
Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions andComplications
Digitalis Intervention Group
Dietary protein intake
Dual-energy x-ray absorptiometry
Electrocardiography
Estimated GFREarly morning urine
Evidence review team
Erythropoiesis-stimulating agent
Effect of Strict Blood Pressure Control and
ACE-Inhibition on Progression of Chronic
Renal Failure in Pediatric Patients
End-Stage Renal Disease
European Society of Urogenital Radiology
Fibroblast growth factor-23
Gadolinium-based contrast agent
Glomerular filtration rate
Glomerulonephritis
Grading of Recommendations Assessment,
Development and Evaluation
Hemoglobin
Hemoglobin A1c
Hepatitis B virus
High-density lipoprotein cholesterol
Heart Outcomes Prevention Evaluation
Hypertension Optimal Treatment
Hazard ratio
High-resolution peripheral quantitative computed
tomography
Nord-Trøndelag Health Study (1995-1997)
International Classification of Diseases
Intensive-care unit
International Diabetes Federation
Isotope-dilution mass spectrometry
Interquartile range
Institute for Reference Materials and Measurements
Italian Pediatric Registry of Chronic Renal Failure
Joint Committee for Traceability in Laboratory
Medicine
Kidney Disease: Improving Global Outcomes
Kidney Disease Outcomes Quality Initiative
Low-density lipoprotein cholesterol
Losartan Intervention For Endpoint Reductionin Hypertension
Low-protein diet
Left ventricular hypertrophy
Mean arterial pressure
Modification of Diet in Renal Disease
Multi-Ethnic Study of Atherosclerosisxiihttp://www.kidney-international.org& 2013 KDIGOMIMRINAPRTCS
NCEP III
NECOSADNHANES
NICE
NIH
NKDEP
NKF
NSAID
NSF
NT-proBNPONTARGET
OR
PAD
PCR
PER
PICARDPICODDPREVEND

Myocardial infarction
Magnetic resonance imaging
North American Pediatric Renal Trials andCollaborative Studies
Third Report of the National Cholesterol
Education Program
Netherlands Cooperative Study on the Adequacyof Dialysis Study Group
National Health and Nutrition Examination Survey
National Institute for Health and ClinicalExcellence
National Institutes of HealthNational Kidney Disease Education Program
National Kidney Foundation
Nonsteroidal anti-inflammatory drug
Nephrogenic systemic fibrosis
N-terminal pro-BNP
Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint trial
Odds ratio
Peripheral arterial disease
Protein-to-creatinine ratio
Protein excretion rate
Program to Improve Care in Acute Renal Disease
Population, Intervention or Predictor, Comparator, Outcome, study Design, and Duration offollow-up
Prevention of Renal and Vascular Endstage
DiseaseKidney International Supplements (2013) 3, xiii

PTH
QOL
RAAS
RBC
RCT
RENAAL
RR
RRT
SCORE
SCr
SCysC
SD
SEEK
SHARP
SPECT
SUA
TREAT
UKPDS
USA-PRC

USRDS
VADT
Val-HeFT
VLPD
WBC
WHO

Parathyroid hormone
Quality of life
Renin-angiotensin-aldosterone system
Red blood cell
Randomized controlled trial
Reduction of Endpoints in NIDDM with theAngiotensin II Antagonist Losartan
Relative risk
Renal replacement therapy
Systematic COronary Risk Evaluation
Serum creatinine
Serum cystatin C
Standard deviation
Study for the Evaluation of Early Kidney disease
Study of Heart and Renal Protection
Single photon emission computed tomography
Serum uric acid
Trial to Reduce Cardiovascular Events with
Aranesp Therapy
United Kingdom Prospective Diabetes Study
USA–People’s Republic of China Collaborative
Study of Cardiovascular and Cardiopulmonary
Epidemiology
US Renal Data System
Veterans Affairs Diabetes Trial
Valsartan Heart Failure Trial
Very low-protein dietWhite blood cell
World Health Organization

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http://www.kidney-international.org& 2013 KDIGO

NoticeKidney International Supplements (2013) 3, 1; doi:10.1038/kisup.2012.73

SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINEThis Clinical Practice Guideline document is based upon systematic literature searches lastconducted in June 2011, supplemented with additional evidence through November 2012. It is
designed to provide information and assist decision making. It is not intended to define astandard of care, and should not be construed as one, nor should it be interpreted as prescribing
an exclusive course of management. Variations in practice will inevitably and appropriately occur
when clinicians take into account the needs of individual patients, available resources, andlimitations unique to an institution or type of practice. Every health-care professional making
use of these recommendations is responsible for evaluating the appropriateness of applying themin any particular clinical situation. The recommendations for research contained within thisdocument are general and do not imply a specific protocol.
SECTION II: DISCLOSURE

Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual orreasonably perceived conflicts of interest that may arise as a result of an outside relationship or apersonal, professional, or business interest of a member of the Work Group. All members of theWork Group are required to complete, sign, and submit a disclosure and attestation formshowing all such relationships that might be perceived as or are actual conflicts of interest. This
document is updated annually and information is adjusted accordingly. All reported information
is published in its entirety at the end of this document in the Work Group members’ Biographic
and Disclosure Information section, and is kept on file at the National Kidney Foundation(NKF), former Managing Agent for KDIGO.

Copyright & 2012 by KDIGO. All rights reserved.
Single photocopies may be made for personal use as allowed by national copyrightlaws. Special rates are available for educational institutions that wish to make photocopies
for non-profit educational use. No part of this publication may be reproduced, amended, ortransmitted in any form or by any means, electronic or mechanical, including photocopying,recording, or any information storage and retrieval system, without explicit permission inwriting from KDIGO. Details on how to seek permission for reproduction or translation,and further information about KDIGO’s permissions policies can be obtained by contacting
Danielle Green, Managing Director, at danielle.green@kdigo.org
To the fullest extent of the law, neither KDIGO, Kidney International Supplements, National
Kidney Foundation (KDIGO’s former Managing Agent) nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a matterof products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.

Kidney International Supplements (2013) 3, 1

1

http://www.kidney-international.org& 2013 KDIGO

Foreword
Kidney International Supplements (2013) 3, 2; doi:10.1038/kisup.2012.74

It is our hope that this document will serve several useful
purposes. Our primary goal is to improve patient care. We
hope to accomplish this, in the short term, by helping
clinicians know and better understand the evidence (or lackof evidence) that determines current practice. By providing
comprehensive evidence-based recommendations, this guideline will also help define areas where evidence is lacking andresearch is needed. Helping to define a research agenda is anoften neglected, but very important, function of clinicalpractice guideline development.
We used the Grading of Recommendations Assessment,
Development and Evaluation (GRADE) system to rate thequality of evidence and the strength of recommendations.
In all, there were 12 (17.1%) recommendations in thisguideline for which the overall quality of evidence wasgraded ‘A,’ whereas 36 (51.4%) were graded ‘B,’ 17 (24.3%)
were graded ‘C,’ and 5 (7.1%) were graded ‘D.’ Although
there are reasons other than quality of evidence to makea grade 1 or 2 recommendation, in general, there is acorrelation between the quality of overall evidence and thestrength of the recommendation. Thus, there were 43(62.3%) recommendations graded ‘1’ and 26 (37.7%) graded‘2.’ There were 9 (13.0%) recommendations graded ‘1A,’ 23(33.3%) were ‘1B,’ 10 (14.5%) were ‘1C,’ and 1 (1.4%) was‘1D.’ There were 2 (2.9%) recommendations graded ‘2A,’
13 (18.8%) were ‘2B,’ 7 (10.1%) were ‘2C,’ and 4 (5.8%)

2

were ‘2D.’ There were 41 (37.3%) statements that were notgraded.
Some argue that recommendations should not be madewhen evidence is weak. However, clinicians still need to makedecisions in their daily practice, and they often ask, ‘‘What dothe experts do in this setting?’’ We opted to give guidance,
rather than remain silent. These recommendations are often
rated with a low strength of recommendation and a low
quality of evidence, or were not graded. It is important for
the users of this guideline to be cognizant of this (see Notice).
In every case these recommendations are meant to be a place
for clinicians to start, not stop, their inquiries into specificmanagement questions pertinent to the patients they see indaily practice.
We wish to thank the Work Group Co-Chairs, Drs. Adeera
Levin and Paul Stevens, along with all of the Work Group
members who volunteered countless hours of their timedeveloping this guideline. We also thank the Evidence Review
Team members and staff of the National Kidney Foundation
who made this project possible. Finally, we owe a special debt
of gratitude to the many KDIGO Board members andindividuals who volunteered time reviewing the guideline,
and making very helpful suggestions.
Bertram L Kasiske, MD
KDIGO Co-ChairDavid C Wheeler, MD, FRCPKDIGO Co-Chair

Kidney International Supplements (2013) 3, 2

http://www.kidney-international.org& 2013 KDIGOWork Group Membership
Kidney International Supplements (2013) 3, 3; doi:10.1038/kisup.2012.75

WORK GROUP CO-CHAIRSPaul E Stevens, MB, FRCP
East Kent Hospitals University
NHS Foundation Trust
Canterbury, United Kingdom

Adeera Levin, MD, FRCPC
University of British Columbia
Vancouver, Canada

WORK GROUP
Rudy W Bilous, MD
Newcastle University and James Cook University Hospital
Middlesbrough, United Kingdom

Edmund J Lamb, PhD, FRCPath
East Kent Hospitals University
NHS Foundation Trust
Canterbury, United Kingdom

Josef Coresh, MD, PhD, MHS
Johns Hopkins University
Baltimore, USA

Andrew S Levey, MD
Tufts Medical Center
Boston, USA

Angel LM de Francisco, MD, PhD
Hospital Universitario Valdecilla
Santander, Spain

Miguel C Riella, MD, PhD, FACP
Evangelic University Hospital
Curitiba, Brazil

Paul E de Jong, MD, PhD
University Medical Center Groningen
Groningen, The Netherlands

Michael G Shlipak, MD, MPH
VA Medical Center, UCSF
San Francisco, USA

Kathryn E Griffith, BM, BS, MSc, MRCP, MRCGP
University Health Centre, York University
York, United Kingdom

Haiyan Wang, MD
Peking University First Hospital
Beijing, China

Brenda R Hemmelgarn, MD, PhD, FRCP(C)
University of Calgary
Alberta, Canada

Colin T White, MD, FRCPC
University of British Columbia
Vancouver, Canada

Kunitoshi Iseki, MD
University Hospital of the Ryukyus
Nishihara, Okinawa, Japan

Christopher G Winearls, MB, DPhil, FRCPOxford Radcliffe Hospitals NHS Trust
Oxford, United Kingdom

EVIDENCE REVIEW TEAM

Tufts Center for Kidney Disease Guideline Development and Implementation
Tufts Medical Center, Boston, MA, USA:
Katrin Uhlig, MD, MS, Project Director; Director, Guideline Development
Dana Miskulin, MD, MS, Staff Nephrologist
Amy Earley, BS, Project Coordinator
Shana Haynes, MS, DHSc, Research AssistantJenny Lamont, MS, Project Manager
In addition, support and supervision were provided by:
Ethan M Balk, MD, MPH; Program Director, Evidence Based Medicine

Kidney International Supplements (2013) 3, 33http://www.kidney-international.org& 2013 KDIGO

Abstract
Kidney International Supplements (2013) 3, 4; doi:10.1038/kisup.2012.76

The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for
the Evaluation and Management of Chronic Kidney Disease (CKD) serves to update the 2002
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, andStratification following a decade of focused research and clinical practice in CKD. The document
aims to provide state-of-the-art guidance on the evaluation, management and treatment for all
patients with CKD. Specifically, the guideline retains the definition of CKD but presents anenhanced classification framework for CKD; elaborates on the identification and prognosis of
CKD; discusses the management of progression and complications of CKD; and expands on thecontinuum of CKD care: timing of specialist referral, ongoing management of people with
progressive CKD, timing of the initiation of dialysis, and finally the implementation of atreatment program which includes comprehensive conservative management. The developmentof the guideline followed an explicit process of evidence review and appraisal. Treatment
approaches are addressed in each chapter and guideline recommendations are based on
systematic reviews of relevant trials. Practical comments or statements which serve as
educational purposes are ungraded, but included as important information for the readership.
Appraisal of the quality of the evidence and the strength of recommendations followed the
GRADE approach. Ongoing areas of controversies, limitations of the evidence, and international
relevance are discussed and additional suggestions are provided for future research.
Keywords: Albuminuria; Chronic kidney disease; Classification; Clinical practice guideline;
Evidence-based recommendation; GFR; Glomerular filtration rate; KDIGO; Proteinuria;
Systematic review

CITATION

In citing this document, the following format should be used: Kidney Disease: Improving Global
Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the
Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150.

4

Kidney International Supplements (2013) 3, 4

http://www.kidney-international.org& 2013 KDIGO

Summary of Recommendation Statements
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77

Chapter 1: Definition and classification of CKD
1.1: DEFINITION OF CKD
1.1.1: CKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications forhealth. (Not Graded)
Criteria for CKD (either of the following present for 43 months)
Markers of kidney damage (one or more)

Albuminuria (AER Z30 mg/24 hours; ACR Z30 mg/g [Z3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by imaging
History of kidney transplantation

Decreased GFRGFR o60 ml/min/1.73 m2 (GFR categories G3a–G5)

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.

1.2: STAGING OF CKD
1.2.1: We recommend that CKD is classified based on cause, GFR category, and albuminuria category (CGA). (1B)
1.2.2: Assign cause of CKD based on presence or absence of systemic disease and the location within the kidney ofobserved or presumed pathologic-anatomic findings. (Not Graded)
1.2.3: Assign GFR categories as follows (Not Graded):
GFR categories in CKD
GFR category

GFR (ml/min/1.73 m2)

Terms

G1
G2
G3a
G3b
G4
G5

Z90
60–89
45–59
30–44
15–29
o15

Normal or highMildly decreased*
Mildly to moderately decreased
Moderately to severely decreased
Severely decreased
Kidney failure

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.
*Relative to young adult level
In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill the criteria for CKD.

1.2.4: Assign albuminuria* categories as follows (Not Graded):*note that where albuminuria measurement is not available, urine reagent strip results can be substituted (Table 7)
Albuminuria categories in CKD
Category

ACR (approximate equivalent)

AER(mg/24 hours)(mg/mmol)(mg/g)

Terms

o30
30-300
4300

o3
3-30
430

o30
30-3004300

Normal to mildly increased
Moderately increased*
Severely increased**

A1
A2
A3

Abbreviations: AER, albumin excretion rate; ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease.
*Relative to young adult level.
**Including nephrotic syndrome (albumin excretion usually 42200 mg/24 hours [ACR 42220 mg/g; 4220 mg/mmol]).

1.3: PREDICTING PROGNOSIS OF CKD
1.3.1: In predicting risk for outcome of CKD, identify the following variables: 1) cause of CKD; 2) GFR category;3) albuminuria category; 4) other risk factors and comorbid conditions. (Not Graded)
Kidney International Supplements (2013) 3, 5–14

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summary of recommendation statements

1.3.2: In people with CKD, use estimated risk of concurrent complications and future outcomes to guide decisions
for testing and treatment for CKD complications. (Not Graded)
1.3.3: In populations with CKD, group GFR and albuminuria categories with similar relative risk for CKD outcomes
into risk categories. (Not Graded)
Persistent albuminuria categories
Description and range

GFR categories (ml/min/ 1.73 m2)
Description and range

Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012

G1

Normal or high

≥90

G2

Mildly decreased

60-89

G3a

Mildly to moderately
decreased

45-59

G3b

Moderately toseverely decreased

30-44

G4

Severely decreased

15-29

G5

Kidney failure

<15

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30-300 mg/g
3-30 mg/mmol>300 mg/g>30 mg/mmol

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk.

1.4: EVALUATION OF CKD
1.4.1: Evaluation of chronicity
1.4.1.1: In people with GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5) or markers of kidney damage, review
past history and previous measurements to determine duration of kidney disease. (Not Graded)
K If duration is 43 months, CKD is confirmed. Follow recommendations for CKD.
K If duration is not 43 months or unclear, CKD is not confirmed. Patients may have CKD or acute kidneydiseases (including AKI) or both and tests should be repeated accordingly.
1.4.2: Evaluation of cause
1.4.2.1: Evaluate the clinical context, including personal and family history, social and environmental factors,
medications, physical examination, laboratory measures, imaging, and pathologic diagnosis to determine
the causes of kidney disease. (Not Graded)
1.4.3: Evaluation of GFR
1.4.3.1: We recommend using serum creatinine and a GFR estimating equation for initial assessment. (1A)
1.4.3.2: We suggest using additional tests (such as cystatin C or a clearance measurement) for confirmatory testingin specific circumstances when eGFR based on serum creatinine is less accurate. (2B)
1.4.3.3: We recommend that clinicians (1B):
K use a GFR estimating equation to derive GFR from serum creatinine (eGFRcreat) rather than relying on
the serum creatinine concentration alone.
K understand clinical settings in which eGFRcreat is less accurate.
1.4.3.4: We recommend that clinical laboratories should (1B):
K measure serum creatinine using a specific assay with calibration traceable to the international standard referencematerials and minimal bias compared to isotope-dilution mass spectrometry (IDMS) reference methodology.
K report eGFRcreat in addition to the serum creatinine concentration in adults and specify the equation
used whenever reporting eGFRcreat.
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summary of recommendation statements

K

report eGFRcreat in adults using the 2009 CKD-EPI creatinine equation. An alternative creatinine-based
GFR estimating equation is acceptable if it has been shown to improve accuracy of GFR estimatescompared to the 2009 CKD-EPI creatinine equation.

When reporting serum creatinine:
K We recommend that serum creatinine concentration be reported and rounded to the nearest whole
number when expressed as standard international units (lmol/l) and rounded to the nearest 100th of awhole number when expressed as conventional units (mg/dl).
When reporting eGFRcreat:
K We recommend that eGFRcreat should be reported and rounded to the nearest whole number andrelative to a body surface area of 1.73 m2 in adults using the units ml/min/1.73 m2.
2
K We recommend eGFRcreat levels less than 60 ml/min/1.73 m should be reported as ‘‘decreased.’’1.4.3.5: We suggest measuring cystatin C in adults with eGFRcreat 45–59 ml/min/1.73 m2 who do not have markers
of kidney damage if confirmation of CKD is required. (2C)2
K If eGFRcys/eGFRcreat-cys is also o60 ml/min/1.73 m , the diagnosis of CKD is confirmed.
2
K If eGFRcys/eGFRcreat-cys is Z60 ml/min/1.73 m , the diagnosis of CKD is not confirmed.
1.4.3.6: If cystatin C is measured, we suggest that health professionals (2C):
K use a GFR estimating equation to derive GFR from serum cystatin C rather than relying on the serum
cystatin C concentration alone.
K understand clinical settings in which eGFRcys and eGFRcreat-cys are less accurate.
1.4.3.7: We recommend that clinical laboratories that measure cystatin C should (1B):
K measure serum cystatin C using an assay with calibration traceable to the international standard
reference material.
K report eGFR from serum cystatin C in addition to the serum cystatin C concentration in adults andspecify the equation used whenever reporting eGFRcys and eGFRcreat-cys.
K report eGFRcys and eGFRcreat-cys in adults using the 2012 CKD-EPI cystatin C and 2012 CKD-EPI
creatinine-cystatin C equations, respectively, or alternative cystatin C-based GFR estimating
equations if they have been shown to improve accuracy of GFR estimates compared to the 2012
CKD-EPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations.
When reporting serum cystatin C:th
K We recommend reporting serum cystatin C concentration rounded to the nearest 100
of a whole
number when expressed as conventional units (mg/l).
When reporting eGFRcys and eGFRcreat-cys:
K We recommend that eGFRcys and eGFRcreat-cys be reported and rounded to the nearest whole number
and relative to a body surface area of 1.73 m2 in adults using the units ml/min/1.73 m2.
2
K We recommend eGFRcys and eGFRcreat-cys levels less than 60 ml/min/1.73 m should be reported as‘‘decreased.’’1.4.3.8: We suggest measuring GFR using an exogenous filtration marker under circumstances where moreaccurate ascertainment of GFR will impact on treatment decisions. (2B)
1.4.4: Evaluation of albuminuria
1.4.4.1: We suggest using the following measurements for initial testing of proteinuria (in descending order ofpreference, in all cases an early morning urine sample is preferred) (2B):
1) urine albumin-to-creatinine ratio (ACR);
2) urine protein-to-creatinine ratio (PCR);
3) reagent strip urinalysis for total protein with automated reading;4) reagent strip urinalysis for total protein with manual reading.
1.4.4.2: We recommend that clinical laboratories report ACR and PCR in untimed urine samples in addition toalbumin concentration or proteinuria concentrations rather than the concentrations alone. (1B)
1.4.4.2.1: The term microalbuminuria should no longer be used by laboratories. (Not Graded)
Kidney International Supplements (2013) 3, 5–14

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summary of recommendation statements

1.4.4.3:

Clinicians need to understand settings that may affect interpretation of measurements of albuminuria
and order confirmatory tests as indicated (Not Graded):
K Confirm reagent strip positive albuminuria and proteinuria by quantitative laboratory measurement
and express as a ratio to creatinine wherever possible.
K Confirm ACRZ30 mg/g (Z3 mg/mmol) on a random untimed urine with a subsequent earlymorning urine sample.
K If a more accurate estimate of albuminuria or total proteinuria is required, measure albumin
excretion rate or total protein excretion rate in a timed urine sample.
1.4.4.4: If significant non-albumin proteinuria is suspected, use assays for specific urine proteins (e.g., a1-microglobulin, monoclonal heavy or light chains, [known in some countries as ‘‘Bence Jones’’ proteins]). (Not Graded)

Chapter 2: Definition, identification, and prediction of
CKD progression
2.1: DEFINITION AND IDENTIFICATION OF CKD PROGRESSION
2.1.1: Assess GFR and albuminuria at least annually in people with CKD. Assess GFR and albuminuria more often
for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions(see figure below). (Not Graded)
2.1.2: Recognize that small fluctuations in GFR are common and are not necessarily indicative of progression.
(Not Graded)
2.1.3: Define CKD progression based on one of more of the following (Not Graded):
K Decline in GFR category (Z90 [G1], 60–89 [G2], 45–59 [G3a], 30–44 [G3b], 15–29 [G4], o15 [G5] ml/min/
1.73 m2). A certain drop in eGFR is defined as a drop in GFR category accompanied by a 25% or greaterdrop in eGFR from baseline.
2
K Rapid progression is defined as a sustained decline in eGFR of more than 5 ml/min/1.73 m /yr.
K The confidence in assessing progression is increased with increasing number of serum creatinine
measurements and duration of follow-up.
2.1.4: In people with CKD progression, as defined in Recommendation 2.1.3, review current management, examine
for reversible causes of progression, and consider referral to a specialist. (Not Graded)
Persistent albuminuria categories
Description and range

GFR categories (ml/min/1.73 m2)
Description and range

Guide to Frequency of Monitoring(number of times per year) by
GFR and Albuminuria Category

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30–300 mg/g
3–30 mg/mmol>300 mg/g>30mg/mmol

G1

Normal or high≥90

1 if CKD

1

2

G2

Mildly decreased

60–89

1 if CKD

1

2

G3a

Mildly to moderately
decreased

45–59

1

2

3

G3b

Moderately toseverely decreased

30–44

2

3

3

G4

Severely decreased

15–29

3

3

4+

G5

Kidney failure

<15

4+

4+

4+

GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers inthe boxes are a guide to the frequency of monitoring (number of times per year).
8

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summary of recommendation statements

2.2: PREDICTORS OF PROGRESSION
2.2.1: Identify factors associated with CKD progression to inform prognosis. These include cause of CKD,
level of GFR, level of albuminuria, age, sex, race/ethnicity, elevated BP, hyperglycemia, dyslipidemia,
smoking, obesity, history of cardiovascular disease, ongoing exposure to nephrotoxic agents, and others.
(Not Graded)

Chapter 3: Management of progression andcomplications of CKD
3.1: PREVENTION OF CKD PROGRESSION
BP and RAAS interruption
3.1.1: Individualize BP targets and agents according to age, coexistent cardiovascular disease and other comorbidities,risk of progression of CKD, presence or absence of retinopathy (in CKD patients with diabetes), and toleranceof treatment as described in the KDIGO 2012 Blood Pressure Guideline. (Not Graded)
3.1.2: Inquire about postural dizziness and check for postural hypotension regularly when treating CKD patients with
BP-lowering drugs. (Not Graded)
3.1.3: Tailor BP treatment regimens in elderly patients with CKD by carefully considering age, comorbidities andother therapies, with gradual escalation of treatment and close attention to adverse events related to BP
treatment, including electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension anddrug side effects. (Not Graded)
3.1.4: We recommend that in both diabetic and non-diabetic adults with CKD and urine albumin excretion o30 mg/
24 hours (or equivalent*) whose office BP is consistently 4140 mm Hg systolic or 490 mm Hg diastolic betreated with BP-lowering drugs to maintain a BP that is consistently r140 mm Hg systolic and r90 mm Hg
diastolic. (1B)
3.1.5: We suggest that in both diabetic and non-diabetic adults with CKD and with urine albumin excretion of
Z30 mg/24 hours (or equivalent*) whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg
diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r130 mm Hg systolic andr80 mm Hg diastolic. (2D)
3.1.6: We suggest that an ARB or ACE-I be used in diabetic adults with CKD and urine albumin excretion 30–300 mg/
24 hours (or equivalent*). (2D)
3.1.7: We recommend that an ARB or ACE-I be used in both diabetic and non-diabetic adults with CKD and urine
albumin excretion 4300 mg/24 hours (or equivalent*). (1B)
3.1.8: There is insufficient evidence to recommend combining an ACE-I with ARBs to prevent progression of CKD.
(Not Graded)
3.1.9: We recommend that in children with CKD, BP-lowering treatment is started when BP is consistently above the90th percentile for age, sex, and height. (1C)
3.1.10: We suggest that in children with CKD (particularly those with proteinuria), BP is lowered to consistently
achieve systolic and diastolic readings less than or equal to the 50th percentile for age, sex, and height, unlessachieving these targets is limited by signs or symptoms of hypotension. (2D)
3.1.11: We suggest that an ARB or ACE-I be used in children with CKD in whom treatment with BP-lowering drugs isindicated, irrespective of the level of proteinuria. (2D)
*Approximate equivalents for albumin excretion rate per 24 hours—expressed as protein excretion rate per 24 hours, albumin-to-creatinine ratio, protein-tocreatinine ratio, and protein reagent strip results— are given in Table 7, Chapter 1.

CKD and risk of AKI
3.1.12: We recommend that all people with CKD are considered to be at increased risk of AKI. (1A)
3.1.12.1: In people with CKD, the recommendations detailed in the KDIGO AKI Guideline should be
followed for management of those at risk of AKI during intercurrent illness, or when undergoinginvestigation and procedures that are likely to increase the risk of AKI. (Not Graded)
Kidney International Supplements (2013) 3, 5–14

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summary of recommendation statements

Protein intake
3.1.13: We suggest lowering protein intake to 0.8 g/kg/day in adults with diabetes (2C) or without diabetes (2B) and
GFR o30 ml/min/ 1.73 m2 (GFR categories G4-G5), with appropriate education.
3.1.14: We suggest avoiding high protein intake (41.3 g/kg/day) in adults with CKD at risk of progression. (2C)
Glycemic control
3.1.15: We recommend a target hemoglobin A1c (HbA1c) of B7.0% (53 mmol/mol) to prevent or delay progression of
the microvascular complications of diabetes, including diabetic kidney disease. (1A)
3.1.16: We recommend not treating to an HbA1c target of o7.0% (o53 mmol/mol) in patients at risk ofhypoglycemia. (1B)
3.1.17: We suggest that target HbA1c be extended above 7.0% (53 mmol/mol) in individuals with comorbidities orlimited life expectancy and risk of hypoglycemia. (2C)
3.1.18: In people with CKD and diabetes, glycemic control should be part of a multifactorial intervention strategy
addressing blood pressure control and cardiovascular risk, promoting the use of angiotensin-converting
enzyme inhibition or angiotensin receptor blockade, statins, and antiplatelet therapy where clinicallyindicated. (Not Graded)
Salt intake
3.1.19: We recommend lowering salt intake to o90 mmol (o2 g) per day of sodium (corresponding to 5 g of sodium
chloride) in adults, unless contraindicated (see rationale). (1C)
3.1.19.1: We recommend restriction of sodium intake for children with CKD who have hypertension (systolic and/or diastolic blood pressure 495th percentile) or prehypertension (systolic and/or diastolic blood pressure
490th percentile and o95th percentile), following the age-based Recommended Daily Intake. (1C)
3.1.19.2: We recommend supplemental free water and sodium supplements for children with CKD and polyuria to
avoid chronic intravascular depletion and to promote optimal growth. (1C)
Hyperuricemia
3.1.20: There is insufficient evidence to support or refute the use of agents to lower serum uric acid concentrations inpeople with CKD and either symptomatic or asymptomatic hyperuricemia in order to delay progression of CKD.
(Not Graded)
Lifestyle3.1.21: We recommend that people with CKD be encouraged to undertake physical activity compatible withcardiovascular health and tolerance (aiming for at least 30 minutes 5 times per week), achieve a healthy weight(BMI 20 to 25, according to country specific demographics), and stop smoking. (1D)
Additional dietary advice
3.1.22: We recommend that individuals with CKD receive expert dietary advice and information in the context of an
education program, tailored to severity of CKD and the need to intervene on salt, phosphate, potassium, andprotein intake where indicated. (1B)
3.2: COMPLICATIONS ASSOCIATED WITH LOSS OF KIDNEY FUNCTION
Definition and identification of anemia in CKD
3.2.1: Diagnose anemia in adults and children 415 years with CKD when the Hb concentration is o13.0 g/dl
(o130 g/l) in males and o12.0 g/dl (o120 g/l) in females. (Not Graded)
3.2.2: Diagnose anemia in children with CKD if Hb concentration is o11.0 g/dl (o110 g/l) in children 0.5–5 years,
o11.5 g/dl (115 g/l) in children 5–12 years, and o12.0 g/dl (120 g/l) in children 12-15 years. (Not Graded)
Evaluation of anemia in people with CKD
3.2.3: To identify anemia in people with CKD measure Hb concentration (Not Graded):2
K when clinically indicated in people with GFR Z60 ml/min/1.73 m (GFR categories G1-G2);
2
K at least annually in people with GFR 30–59 ml/min/1.73 m (GFR categories G3a-G3b);2
K at least twice per year in people with GFRo30 ml/min/1.73 m (GFR categories G4-G5).
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summary of recommendation statements

3.3: CKD METABOLIC BONE DISEASE INCLUDING LABORATORY ABNORMALITIES
3.3.1: We recommend measuring serum levels of calcium, phosphate, PTH, and alkaline phosphatase activity at least
once in adults with GFR o45 ml/min/1.73 m2 (GFR categories G3b-G5) in order to determine baseline values
and inform prediction equations if used. (1C)
3.3.2: We suggest not to perform bone mineral density testing routinely in those with eGFR o45 ml/min/1.73 m2(GFR categories G3b-G5), as information may be misleading or unhelpful. (2B)
3.3.3: In people with GFR o45 ml/min/1.73 m2 (GFR categories G3b-G5), we suggest maintaining serum phosphateconcentrations in the normal range according to local laboratory reference values. (2C)
3.3.4: In people with GFR o45 ml/min/1.73 m2 (GFR categories G3b-G5) the optimal PTH level is not known.
We suggest that people with levels of intact PTH above the upper normal limit of the assay are first evaluatedfor hyperphosphatemia, hypocalcemia, and vitamin D deficiency. (2C)
Vitamin D supplementation and bisphosphonates in people with CKD
3.3.5: We suggest not to routinely prescribe vitamin D supplements or vitamin D analogs, in the absence of suspected or
documented deficiency, to suppress elevated PTH concentrations in people with CKD not on dialysis. (2B)
3.3.6: We suggest not to prescribe bisphosphonate treatment in people with GFR o30 ml/min/1.73 m2 (GFR categories
G4-G5) without a strong clinical rationale. (2B)
3.4: ACIDOSIS
3.4.1: We suggest that in people with CKD and serum bicarbonate concentrations o22 mmol/l treatment with oral
bicarbonate supplementation be given to maintain serum bicarbonate within the normal range, unlesscontraindicated. (2B)

Chapter 4: Other complications of CKD: CVD,
medication dosage, patient safety, infections,
hospitalizations, and caveats for investigatingcomplications of CKD
4.1:CKD AND CVD
4.1.1: We recommend that all people with CKD be considered at increased risk for cardiovascular disease. (1A)
4.1.2: We recommend that the level of care for ischemic heart disease offered to people with CKD should not be
prejudiced by their CKD. (1A)
4.1.3: We suggest that adults with CKD at risk for atherosclerotic events be offered treatment with antiplatelet agentsunless there is an increased bleeding risk that needs to be balanced against the possible cardiovascular benefits. (2B)
4.1.4: We suggest that the level of care for heart failure offered to people with CKD should be the same as is offered tothose without CKD. (2A)
4.1.5: In people with CKD and heart failure, any escalation in therapy and/or clinical deterioration should prompt
monitoring of eGFR and serum potassium concentration. (Not Graded)
4.2: CAVEATS WHEN INTERPRETING TESTS FOR CVD IN PEOPLE WITH CKD
BNP/N-terminal-proBNP (NT-proBNP)
4.2.1: In people with GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5), we recommend that serum concentrationsof BNP/NT-proBNP be interpreted with caution and in relation to GFR with respect to diagnosis of heart
failure and assessment of volume status. (1B)
Troponins4.2.2: In people with GFRo60 ml/min/1.73 m2 (GFR categories G3a-G5), we recommend that serum concentrationsof troponin be interpreted with caution with respect to diagnosis of acute coronary syndrome. (1B)
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summary of recommendation statements

Non-invasive testing
4.2.3: We recommend that people with CKD presenting with chest pain should be investigated for underlying
cardiac disease and other disorders according to the same local practice for people without CKD (andsubsequent treatment should be initiated similarly). (1B)
4.2.4: We suggest that clinicians are familiar with the limitations of non-invasive cardiac tests (e.g., exercise
electrocardiography [ECG], nuclear imaging, echocardiography, etc.) in adults with CKD and interpret theresults accordingly. (2B)
4.3: CKD AND PERIPHERAL ARTERIAL DISEASE
4.3.1: We recommend that adults with CKD be regularly examined for signs of peripheral arterial disease and beconsidered for usual approaches to therapy. (1B)
4.3.2: We suggest that adults with CKD and diabetes are offered regular podiatric assessment. (2A)
4.4: MEDICATION MANAGEMENT AND PATIENT SAFETY IN CKD
4.4.1: We recommend that prescribers should take GFR into account when drug dosing. (1A)
4.4.2: Where precision is required for dosing (due to narrow therapeutic or toxic range) and/or estimates may be unreliable(e.g., due to low muscle mass), we recommend methods based upon cystatin C or direct measurement of GFR. (1C)
4.4.3: We recommend temporary discontinuation of potentially nephrotoxic and renally excreted drugs in people with a
GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5) who have serious intercurrent illness that increases the risk of
AKI. These agents include, but are not limited to: RAAS blockers (including ACE-Is, ARBs, aldosterone inhibitors,
direct renin inhibitors), diuretics, NSAIDs, metformin, lithium, and digoxin. (1C)
4.4.4: We recommend that adults with CKD seek medical or pharmacist advice before using over-the-counter medicines or
nutritional protein supplements. (1B)
4.4.5: We recommend not using herbal remedies in people with CKD. (1B)
4.4.6: We recommend that metformin be continued in people with GFR Z45 ml/min/1.73 m2 (GFR categories G1-G3a);
its use should be reviewed in those with GFR 30–44 ml/min/1.73 m2 (GFR category G3b); and it should be
discontinued in people with GFR o30 ml/min/1.73 m2 (GFR categories G4-G5). (1C)
4.4.7: We recommend that all people taking potentially nephrotoxic agents such as lithium and calcineurin
inhibitors should have their GFR, electrolytes and drug levels regularly monitored. (1A)
4.4.8: People with CKD should not be denied therapies for other conditions such as cancer but there should beappropriate dose adjustment of cytotoxic drugs according to knowledge of GFR. (Not Graded)
4.5: IMAGING STUDIES
4.5.1: Balance the risk of acute impairment in kidney function due to contrast agent use against the diagnostic value
and therapeutic implications of the investigation. (Not Graded)Radiocontrast
4.5.2: We recommend that all people with GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5) undergoing elective
investigation involving the intravascular administration of iodinated radiocontrast media should be managed
according to the KDIGO Clinical Practice Guideline for AKI including:
K Avoidance of high osmolar agents (1B);
K Use of lowest possible radiocontrast dose (Not Graded);
K Withdrawal of potentially nephrotoxic agents before and after the procedure (1C);K Adequate hydration with saline before, during, and after the procedure (1A);
K Measurement of GFR 48–96 hours after the procedure (1C).
Gadolinium-based contrast media
4.5.3: We recommend not using gadolinium-containing contrast media in people with GFR o15 ml/min/1.73 m2(GFR category G5) unless there is no alternative appropriate test. (1B)
4.5.4: We suggest that people with a GFR o30 ml/min/1.73 m2 (GFR categories G4-G5) who require gadoliniumcontaining contrast media are preferentially offered a macrocyclic chelate preparation. (2B)
Bowel preparation
4.5.5: We recommend not to use oral phosphate-containing bowel preparations in people with a GFR o60 ml/min/
1.73 m2 (GFR categories G3a-G5) or in those known to be at risk of phosphate nephropathy. (1A)
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4.6: CKD AND RISKS FOR INFECTIONS, AKI, HOSPITALIZATIONS, AND MORTALITYCKD and risk of infections
4.6.1: We recommend that all adults with CKD are offered annual vaccination with influenza vaccine, unlesscontraindicated. (1B)
4.6.2: We recommend that all adults with eGFR o30 ml/min/1.73 m2 (GFR categories G4-G5) and those at high riskof pneumococcal infection (e.g., nephrotic syndrome, diabetes, or those receiving immunosuppression) receive
vaccination with polyvalent pneumococcal vaccine unless contraindicated. (1B)
4.6.3: We recommend that all adults with CKD who have received pneumococcal vaccination are offeredrevaccination within 5 years. (1B)
4.6.4: We recommend that all adults who are at high risk of progression of CKD and have GFR o30 ml/min/1.73 m2(GFR categories G4-G5) be immunized against hepatitis B and the response confirmed by appropriate
serological testing. (1B)
4.6.5: Consideration of live vaccine should include an appreciation of the patient’s immune status and should be inline with recommendations from official or governmental bodies. (Not Graded)
4.6.6: Pediatric immunization schedules should be followed according to official international and regional
recommedations for children with CKD. (Not Graded)
CKD and risk of AKI
4.6.7: We recommend that all people with CKD are considered to be at increased risk of AKI. (1A)
4.6.7.1: In people with CKD, the recommendations detailed in the KDIGO AKI Guideline should be followed
for management of those at risk of AKI during intercurrent illness, or when undergoing investigationand procedures that are likely to increase the risk of AKI. (Not Graded)
CKD and risk of hospitalization and mortality
4.6.8: CKD disease management programs should be developed in order to optimize the community management ofpeople with CKD and reduce the risk of hospital admission. (Not Graded)
4.6.9: Interventions to reduce hospitalization and mortality for people with CKD should pay close attention to the
management of associated comorbid conditions and cardiovascular disease in particular. (Not Graded)

Chapter 5: Referral to specialists and models of care
5.1: REFERRAL TO SPECIALIST SERVICES
5.1.1: We recommend referral to specialist kidney care services for people with CKD in the following circumstances (1B):
K AKI or abrupt sustained fall in GFR;
2
K GFR o30 ml/min/1.73 m (GFR categories G4-G5)*;
K a consistent finding of significant albuminuria (ACR Z300 mg/g [Z30 mg/mmol] or AER Z300 mg/
24 hours, approximately equivalent to PCR Z500 mg/g [Z50 mg/mmol] or PER Z500 mg/24 hours);
K progression of CKD (see Recommendation 2.1.3 for definition);
K urinary red cell casts, RBC 420 per high power field sustained and not readily explained;K CKD and hypertension refractory to treatment with 4 or more antihypertensive agents;
K persistent abnormalities of serum potassium;
K recurrent or extensive nephrolithiasis;
K hereditary kidney disease.
5.1.2: We recommend timely referral for planning renal replacement therapy (RRT) in people with progressive CKD
in whom the risk of kidney failure within 1 year is 10–20% or higherw, as determined by validated risk
prediction tools. (1B)
*If this is a stable isolated finding, formal referral (i.e., formal consultation and ongoing care management) may not be necessary and advice
from specialist services may be all that is required to facilitate best care for the patients. This will be health-care system dependent.
w
The aim is to avoid late referral, defined here as referral to specialist services less than 1 year before start of RRT.
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summary of recommendation statements

GFR categories (ml/min/ 1.73 m2)
Description and range

Persistent albuminuria categories
Description and range
A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30–300 mg/g
3–30 mg/mmol>300 mg/g>30 mg/mmol

G1

Normal or high≥90

Monitor

Refer*

G2

Mildly decreased

60–89

Monitor

Refer*

G3a

Mildly to moderately
decreased

45–59

MonitorMonitor

Refer

G3b

Moderately toseverely decreased

30–44

MonitorMonitor

Refer

G4

Severely decreased

15–29

Refer*

Refer*

Refer

G5

Kidney failure

<15

Refer

Refer

Refer

Referral decision making by GFR and albuminuria. *Referring clinicians may wish to discuss with their nephrology service depending on
local arrangements regarding monitoring or referring.

5.2: CARE OF THE PATIENT WITH PROGRESSIVE CKD
5.2.1: We suggest that people with progressive CKD should be managed in a multidisciplinary care setting. (2B)
5.2.2: The multidisciplinary team should include or have access to dietary counseling, education and counselingabout different RRT modalities, transplant options, vascular access surgery, and ethical, psychological, andsocial care. (Not Graded)
5.3: TIMING THE INITIATION OF RRT
5.3.1: We suggest that dialysis be initiated when one or more of the following are present: symptoms or signs
attributable to kidney failure (serositis, acid-base or electrolyte abnormalities, pruritus); inability to control
volume status or blood pressure; a progressive deterioration in nutritional status refractory to dietaryintervention; or cognitive impairment. This often but not invariably occurs in the GFR range between 5 and
10 ml/min/1.73 m2. (2B)
5.3.2: Living donor preemptive renal transplantation in adults should be considered when the GFR is o20 ml/min/
1.73 m2, and there is evidence of progressive and irreversible CKD over the preceding 6–12 months.
(Not Graded)
5.4: STRUCTURE AND PROCESS OF COMPREHENSIVE CONSERVATIVE MANAGEMENT
5.4.1: Conservative management should be an option in people who choose not to pursue RRT and this should be
supported by a comprehensive management program. (Not Graded)
5.4.2: All CKD programs and care providers should be able to deliver advance care planning for people witha recognized need for end-of-life care, including those people undergoing conservative kidney care. (Not
Graded)5.4.3: Coordinated end-of-life care should be available to people and families through either primary care or
specialist care as local circumstances dictate. (Not Graded)
5.4.4: The comprehensive conservative management program should include protocols for symptom and pain
management, psychological care, spiritual care, and culturally sensitive care for the dying patient and theirfamily (whether at home, in a hospice or a hospital setting), followed by the provision of culturally
appropriate bereavement support. (Not Graded)

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http://www.kidney-international.org

introduction& 2013 KDIGO

Introduction: The case for updating and context
Kidney International Supplements (2013) 3, 15–18; doi:10.1038/kisup.2012.63

Justification for updating the guideline for CKD Definition,
Evaluation, Classification, and Stratification from aninternational perspective
In 2002, the US-based Kidney Disease Outcomes Quality
Initiative (KDOQI) group published a guideline on definition, classification and evaluation of chronic kidney disease(CKD). The guideline proposed uniform definitions of CKD
together with a staging system1 and described issues related
to measurement of kidney function that had not previously
been identified by the clinical community. This publication
revolutionized the concept and management of CKD,
generating substantial research and controversy, stimulating
discussion, and influencing public policy and laboratory
practice. The research generated has led to new insights
which require contextualizing in the current era, providing
the evidence drivers for updating guidance for defining,
diagnosing, staging and managing CKD, and promoting
improved care of those with early CKD. Successive international controversies conferences, under the direction of
Kidney Disease: Improving Global Outcomes (KDIGO), haveshaped the scope of this international update through:1. Facilitating global implementation of the definition andclassification of CKD, identifying areas of uncertainty, anddeveloping a collaborative research agenda to improve theevidence base and facilitate implementation (November 2004).
2. Evaluating the definition and classification of CKD from a
global public health perspective (October 2006).
3. Reviewing the definition and classification of CKD
based on data on patient prognosis derived from aunique research collaboration on prognosis (October2009).
Given the international interest in understanding andimproving the outcomes of people living with kidney disease
and the tremendous amount of data generated since 2002, aneed was identified to review, revise, and update the original
2002 KDOQI guideline.
There has been a wealth of published data highlighting
the risk of adverse consequences and outcomes in people
with albumin excretion rate (AER) 430 mg/24 hours and/or
glomerular filtration rate (GFR) o60 ml/min/1.73 m2 (GFR
categories G3a-G5), irrespective of the etiology or duration of
reduced kidney function. Description of the relationshipbetween GFR, albuminuria and prognosis has significantly
improved the understanding of CKD in multiple populations.2–5 Internationally, the widespread use of albumin-tocreatinine ratio (ACR) and reagent strip urine testing todetect elevated albuminuria together with reporting of
estimated GFR (eGFR) has led to easier identification of
Kidney International Supplements (2013) 3, 15–18

people with CKD. However elevated albuminuria or reduced
GFR alone are not necessarily indicators of need for specialist
referral. Clinicians and medical systems are still adjusting to
the improved ‘‘identification’’ of CKD and guidance about
appropriate stratification of risk and modified action plansfor different subgroups of individuals regarding further
evaluation, referral, or treatment is needed.
The goal of this guideline is to clarify the definition andclassification system of CKD, and to develop appropriate
guidance as to the management and care of people with CKD.
In addition, we present a framework which should foster an
extended collaborative research agenda over the next decadeand inform guidelines in the future.

Kidney disease is an important problem worldwide

Kidney disease is defined as an abnormality of kidney
structure or function with implications for the health of anindividual, which can occur abruptly, and either resolve or
become chronic. CKD is a general term for heterogeneous
disorders affecting kidney structure and function withvariable clinical presentation, in part related to cause, severity
and the rate of progression. The concept of CKD evolved
after the recognition of the contribution of disordered kidney
structure and function on the health of individuals across awide range of severity.1 The utility of the concept is thatrecognition of CKD will have implications for the individual
and their care. Kidney failure is traditionally considered as
the most serious outcome of CKD. Symptoms are usually due
to complications of decreased kidney function and whensevere, they can be treated only by dialysis or transplantation.
Earlier stages of kidney disease are often asymptomatic, aredetected during the evaluation of comorbid conditions, andmay be reversible. Rapidly progressive diseases may lead tokidney failure within months but most diseases evolve overdecades, and some patients do not progress during many
years of follow-up.
Figure 1 shows a conceptual model for the development,
progression, and complications of CKD.1,6 The model
includes antecedents associated with increased risk fordevelopment of CKD, stages of disease, and complications
including death. Risks for development of CKD may be
categorized either as susceptibility to kidney disease due tosociodemographic and genetic factors or exposure to factorsthat can initiate kidney disease. Abnormalities in kidney
structure (damage) usually precede abnormalities in function. Outcomes of CKD may be progression, as shown by thehorizontal arrows, and complications, as shown by the
diagonal arrows, or both.
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introduction

Figure 1 | Conceptual model of CKD. Continuum ofdevelopment, progression, and complications of CKD andstrategies to improve outcomes. Horizontal arrows between
circles represent development, progression, and remission of CKD.
Left-pointing horizontal arrowheads signify that remission is lessfrequent than progression. Diagonal arrows represent occurrenceof complications of CKD, including drug toxicity, endocrine andmetabolic complications, cardiovascular disease, and others suchas infection, cognitive impairment, and frailty. Complications
might also arise from adverse effects of interventions to preventor treat the disease. CKD, chronic kidney disease; EOL, end-of-lifecare and/or conservative management; GFR, glomerular filtration
rate. Adapted from Levey AS, Stevens LA, Coresh J.6 Conceptualmodel of CKD: applications and implications.
Am J Kidney Dis. 2009; 53:S4-16 with permission from the
National Kidney Foundation; accessed http://download.journals.
elsevierhealth.com/pdfs/journals/0272-6386/PIIS02726386080
17186.pdf

Although the need for treatment of chronic kidney failure
with dialysis and/or kidney transplantation arises in only
1% of people with CKD, it remains the most expensive ofchronic diseases and reduces lifespan significantly. The costsof dialysis and transplantation consume disproportionate
amounts within the health-care budgets in all jurisdictions(5% of annual budgets consumed by less than 1% of the
population). Failure to recognize CKD results in neglect of its
consequences and complications, and late referral of people
with advanced CKD resulting in worse renal replacement
therapy (RRT) outcomes. In addition, there is a growing
body of evidence that indicates people with CKD are atincreased risk of acute kidney injury (AKI), which is also
associated with poor outcomes and may accelerate progression of CKD. Therefore, identification of people at earlier
time points in the trajectory of CKD, with appropriate
management and earlier referral of those who would benefit
from specialist kidney services, should lead to both economic
and clinical benefits.
In those countries where access to dialysis and transplantation services may be limited or unavailable, the final
consequence of progressive CKD is death. In all locations,irrespective of availability of dialysis and transplantation,
early identification of CKD therefore assumes great importance, as delay or prevention of progression has thepotential to prolong health and save lives for much lower costthan RRT. Although etiologies vary in frequency or absolute
numbers in different countries, the proportion of people with
16

important antecedents to CKD, such as diabetes, is growing
alarmingly worldwide in both developed and developing
countries.
Complications of CKD affect all organ systems. Kidney
failure leads to the commonly recognized symptoms of
uremia. Less severe CKD has been recognized as anindependent risk factor for cardiovascular disease (CVD)
and other common conditions affecting the elderly, such as
infection and impairments in physical function and cognition. In addition, CKD is associated with increased risk fromadverse effects of drugs, intravascular radiocontrast administration, surgery and other invasive procedures. Altogether,
these complications are associated with higher morbidity,
mortality and cost. If CKD is detected early, the associatedcomplications and the progression to kidney failure can bedelayed or even prevented through appropriate interventions.
Regular testing of high-risk groups (i.e., people with diabetes,
hypertension, CVD, structural renal tract disease, multisystem diseases with potential kidney involvement such assystemic lupus erythematosus, family history of kidney
failure, hereditary kidney disease, the elderly, those receiving
potential nephrotoxic drugs or those opportunistically foundto have hematuria or proteinuria) can give an early
indication of kidney damage, thus permitting the introduction of available interventions at an early stage, and thetesting of novel interventions with potential added value.
Factors associated with progression of CKD and withincreased cardiovascular risk are overlapping to a large
extent. Thus targeting of those risk factors that are modifiable
may both reduce CVD in people with CKD and reduce
progression of CKD to end-stage renal disease (ESRD). Thereis strong evidence that blockade of the renin-angiotensinaldosterone system (RAAS) is a blood pressure (BP) lowering
strategy which is more effective in reducing risk of kidneyand cardiovascular disease in the presence of albuminuria.
The development of guidance for health-care providers will
provide opportunities to improve the care of people with kidneydisease. We hope that this publication serves to stimulate
strategic research initiatives from basic, translational, clinicaland health outcome perspectives.
General summary for the reader: what you will andwill not find in this guideline

1. The guideline will offer best practice and evidence-based
advice on the evaluation and approach to managementof CKD.
a. The target population for the guideline is all people
identified with CKD who are not on RRT (i.e., not on
dialysis or have not received a kidney transplant).
b. The target population includes adults and children.
The guideline will cover the spectrum of individuals
with CKD, from children to the elderly who form
important subgroups, underscoring current issues atthe extremes of age with respect to the evidence base,especially in relation to implementation and management issues. Where the guideline does not apply to
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children, statements to that effect will be made. It isbeyond the scope of this guideline to address all issues
related to children with CKD, given the heterogeneous nature of this group of individuals who range
from newborn to post-adolescents, with specificphysiological differences within each of those groups.
Specific evidence and rationale will be articulated as
appropriate in each section.
c. The target condition is CKD of any or unknown
etiology. Identifying the cause of the CKD is strongly
encouraged, both because treatment may need to be
adjusted according to etiology and because it
influences the prognosis and relative importance ofrisk factors associated with CKD. A comprehensive
list of possible etiologies is not practical and guidanceon detailed work-up for specific causes of CKD is
beyond the scope of this document (readers will bereferred to other pertinent sources). We will describe
how knowledge of the etiology of CKD in an
individual may be important in prognostication andmanagement.
d. The target audience of the guideline includes
nephrologists, primary care physicians, non-nephrology specialists (e.g., cardiologists, diabetologists, etc),
clinical chemists and other practitioners caring for
adults and children with CKD. The guideline is also
expected to be suitable for use in public policy andother health-care arenas.
e. As a global guideline it is written for use in different
health-care settings, but unavoidably its full implementation relies on health-care resources thatare not universally available. We recognize this overtly
in some of the discussion sections within theguideline.
f. The target health-care settings include primary,secondary, and tertiary care.
2. The guideline will provide information, advice, andeducation to support self-management for people withCKD and aid caregivers with the diagnosis and management of CKD. To avoid redundancy and potential forbecoming outdated, the reader is asked to refer to existing
KDIGO guidance on anemia, metabolic bone disease, BP,
AKI, hepatitis C, lipid management, glomerulonephritis(GN) and other pertinent guidelines.
3. The guideline will provide a blueprint for an approach to
CKD care in an international context. While the guideline
will be sensitive to issues related to ethnicity and also
geographical considerations, it is expected that subsequent
regional adaptation will be required for specific healthcare settings or contexts.
4. Research recommendations in general are described to
inform a framework for ongoing research agendas in theinternational community. We have attempted to identify
important study questions in need of answers. Throughidentification of gaps in knowledge, the reader will bebetter able to define methodologies, definitions ofKidney International Supplements (2013) 3, 15–18

populations, and outcome measures of relevance to study
designs in the future.

Topics that will not be covered

This document is not intended to provide enough detail toreplace training and education in nephrology, nor is it
intended to serve as a textbook of medicine or nephrology.
Thus, there are some specific topics that will not becovered. Specifically we will not discuss:
1. Evaluation and management of people receiving RRT(management of kidney failure by dialysis or kidneytransplantation).
2. Specific approaches to the diagnosis of people with AKI
and other acute kidney diseases. This topic has been
extensively reviewed in KDIGO Clinical Practice Guideline
for Acute Kidney Injury.7
3. Diagnostic work-up or treatment of specific causes of
CKD, including GN.8
4. Management of pregnancy in women with CKD or of
pregnant women who develop kidney disease.
5. Detailed management of endocrine and metabolic complications of CKD. These are reviewed extensively byrecent KDIGO guidelines on CKD-MBD,9 management of
BP10 and anemia11 in CKD.
6. Detailed management of CVD and CVD risk factors in
CKD. This is reviewed in a recent KDIGO publication.12
7. Drug dosing in CKD. This topic has been addressed in a
recent KDIGO publication.13
8. Details of resource implications and barriers to implementation are beyond the scope of this guideline.
By virtue of its being international, the variability inthese aspects by country, region, and even jurisdiction isvast. We look to the individual commentaries fromaround the world to inform those aspects more fully.

Brief overview on methodology

The Work Group included an international group of kidneyspecialists, primary care physicians, diabetologists, epidemiologists, clinical chemists, administrators, and a professional Evidence Review Team (ERT) who provided support
and guidance to the group. Details of the methods used by
the ERT are described in Methods for Guideline Development,along with the systematic searches for areas identified byWork Group members and performed by the ERT.
The recommendations and statements created herein
will serve to direct both care and research in the next
decade. Importantly, we expect the renewed classification
system and risk stratification concepts to direct research andenrollment into trials which address test therapies to improve
patient outcomes.
Statement grading and wording. The methods for formulating recommendations were based on modified Gradingof Recommendations Assessment, Development, andEvaluation (GRADE) system, and have used the words
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introduction

Table 1 | KDIGO nomenclature and description for grading recommendations
Implications
Grade*

Patients

Clinicians

PolicyLevel 1‘‘We
recommend’’

Most people in your situation would
want the recommended course ofaction and only a small proportion
would not.

Most patients should receive therecommended course of action.

The recommendation can be evaluatedas a candidate for developing a policy
or a performance measure.

Level 2‘‘We suggest’’

The majority of people in your situation
would want the recommended courseof action, but many would not.

Different choices will be appropriate
for different patients. Each patientneeds help to arrive at a management
decision consistent with her or hisvalues and preferences.

The recommendation is likely torequire substantial debate andinvolvement of stakeholders before
policy can be determined.

*The additional category ‘‘Not Graded’’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence.
The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations
are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

‘recommend’ when the balance of evidence would support
the notion that the majority of patients would benefit fromthe implementation of this recommendation. The words‘suggest’ are used when the balance of evidence would
support the notion that some patients would benefit from theimplementation of the recommendation, but that individual
patient, physician and health-care system considerations
would be necessary to adopt the practice. There arealso ungraded statements many of which are often key
practice points or educational issues (Table 1). The WorkGroup had struggled whether to organize them differently or
move them to the rationale section. Ultimately they remain
here in the guideline statement format so that they are notoverlooked by those wishing to understand the condition
better.
A significant proportion of statements in this guideline areungraded because the grading system is most appropriate
for statements of intervention. The international system,
GRADE, allows for such statements which guide thoughts
and attitude, and not specific actions. In the descriptive
statements identifying, classifying, and defining the conditionof CKD, grading is not possible. Since few studies havecompared different methods of evaluation or care models,
those statements too are difficult to grade. Thus, grading ofspecific statements is reserved for interventions or alternative
diagnostic test strategies for which there is a substantial bodyof evidence.

18

Consideration of health benefits, side effects, and risks.

These have been considered when formulating the recommendations but given the paucity of data in many of the areas
reviewed, this has been less consistent than the Work Groupwould have liked. We see this as an area of research andfuture study that will inform future updates.
Review process. As with all KDIGO guidelines a two step
process was used. This included a review by the Board of
Directors, with feedback to the Work Group Chairs followedby revisions to the document. The public review, consistingof interested stakeholders from international communities,
organizations and individuals, was then undertaken. The
draft document was sent to a total of 2320 external reviewers,
with 293 responses received and tabulated. The feedback was
carefully reviewed and where appropriate, suggested changes
were incorporated into the final document. In the interest oftransparency, the Work Group prepared individual responses
to each reviewer comment and these will be posted on the
KDIGO website.
Planned update. At the current time there is no official
plan to update the guideline in its entirety. Given the breadthand depth of the current undertaking and with knowledge of
new studies and applications of some of these recommendations, the Work Group recommends that individual sectionsof this guideline be updated every 3-5 years as new evidence
becomes available. We believe that this will be more practical
for the readership.

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http://www.kidney-international.org& 2013 KDIGO

Chapter 1: Definition and classification of CKD
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1.1: DEFINITION OF CKD
1.1.1: CKD is defined as abnormalities of kidney structure or function, present for 43 months, with
implications for health (Table 2). (Not Graded)
RATIONALE

The definition of CKD remains intact, but we have clarified
the classification and risk stratification as indicated below.
The addition of ‘with implications for health’ is intended toreflect the notion that a variety of abnormalities of kidney
structure or function may exist, but not all have implications
for health of individuals, and therefore need to becontextualized.
Kidney damage refers to a broad range of abnormalities
observed during clinical assessment, which may be insensitive
and non-specific for the cause of disease but may precede
reduction in kidney function (Table 2). Excretory, endocrine
and metabolic functions decline together in most chronic
kidney diseases. GFR is generally accepted as the best overall
index of kidney function. We refer to a GFR o60 ml/min/
1.73 m2 as decreased GFR (Table 2) and a GFR o15 ml/min/
1.73 m2 as kidney failure. AKI may occur in patients withCKD and hasten the progression to kidney failure.14
Complications include drug toxicity, metabolic andendocrine complications, increased risk for CVD, and avariety of other recently recognized complications, including
infections, frailty, and cognitive impairment.15–18 Complications may occur at any stage, often leading to death without
progression to kidney failure. Complications may also arise
from adverse effects of interventions to prevent or treat thedisease and associated comorbidity.

diseases (such as acute GN), including AKI, which may
require different interventions, and have different etiologies
and outcomes.7 We did not define acute kidney disease(AKD) because there does not appear be an evidence base fora precise definition.
The duration of kidney disease may be documented orinferred based on the clinical context. For example, a patientwith decreased kidney function or kidney damage in the
midst of an acute illness, without prior documentation of
kidney disease, may be inferred to have AKI. Resolution overdays to weeks would confirm the diagnosis of AKI. A patientwith similar findings in the absence of an acute illness may beinferred to have CKD, and if followed over time would be
confirmed to have CKD. In both cases, repeat ascertainmentof kidney function and kidney damage is recommended for
accurate diagnosis. The timing of the evaluation depends on
clinical judgment, with earlier evaluation for the patientssuspected of having AKI and later evaluation for the patientsuspected of having CKD. For further details on the
Evaluation of CKD, see Chapter 1.4.
Reversibility. Most kidney diseases do not have symptoms
or findings until later in their course and are detected only
when they are chronic. Most causes of CKD are irreversible
with a life-long course, and treatment aimed at slowing
progression to kidney failure. However, chronicity is notsynonymous with irreversibility. In some cases, CKD isentirely reversible, either spontaneously or with treatment,
and in other cases, treatment can cause partial regression of
kidney damage and improvement in function (e.g., immunosuppressive therapies for GN). Even kidney failure may bereversed with transplantation. Because of the long course of
most cases of CKD, patients often have one or more episodesof AKI, superimposed upon CKD.

Criteria for CKD
Defining terms: The following section aims to define specificterms and concepts so as to ensure clarity among all users.
In addition, the rationale for including these terms is included.

Table 3 provides a justification for the criteria for CKD. The
criteria for definition of CKD are objective and can beascertained by means of simple laboratory tests without
identification of the cause of disease, thereby enabling
detection of CKD by non-nephrologist physicians and other
health professionals.
Duration 43 Months

Kidney diseases may be acute or chronic. We explicitly but
arbitrarily define duration of 43 months (490 days) as
delineating ‘‘chronic’’ kidney disease. The rationale fordefining chronicity is to differentiate CKD from acute kidney
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Decreased GFR

The kidney has many functions, including excretory,
endocrine and metabolic functions. The GFR is one component of excretory function, but is widely accepted as the best
overall index of kidney function because it is generally
reduced after widespread structural damage and most otherkidney functions decline in parallel with GFR in CKD.
We chose a threshold of GFR o60 ml/min/1.73 m2 (GFR
categories G3a-G5) for 43 months to indicate CKD. A GFRo60 ml/min/1.73 m2 is less than half of the normal value inyoung adult men and women of approximately 125 ml/min/
1.73 m2. Figure 2 shows a compilation of GFR measurements
in apparently healthy men and women in the US and Europe
by age from more than 40 years ago.20 The age-associated
GFR decline is observed in longitudinal as well as cross19chapter 1

Table 2 | Criteria for CKD (either of the following present for 43 months)
Markers of kidney damage (one or more)

Albuminuria (AERZ30 mg/24 hours; ACRZ30 mg/g [Z3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by imaging
History of kidney transplantation

Decreased GFRGFRo60 ml/min/1.73 m2 (GFR categories G3a-G5)

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.

Table 3 | Criteria for definition of CKD19
Criteria

Comment

Duration 43 months, based on documentation orinference

Duration is necessary to distinguish chronic from acute kidney diseases
K Clinical evaluation will often enable documentation or inference of duration
K Documentation of duration is usually not declared in epidemiologic studies

GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5)

GFR is the best overall index of kidney function in health and disease
2
K The normal GFR in young adults is approximately 125 ml/min/1.73 m . GFRo15 ml/min/1.73 m2 (GFR category G5) is defined as kidney failure
K Decreased GFR can be detected by current estimating equations for GFR basedon SCr or cystatin C but not by SCr or cystatin C alone
K Decreased eGFR can be confirmed by measured GFR, if required

Kidney damage as defined by structural abnormalities orfunctional abnormalities other than decreased GFRAlbuminuria as a marker of kidney damage [increased glomerular permeability],urine AER Z30 mg/24 hours, approximately equivalent to urine ACRZ30 mg/g
(Z3 mg/mmol)*
K The normal urine ACR in young adults is o10 mg/g (o1 mg/mmol)
K Urine ACR 30-300 mg/g (3–30 mg/mmol; category A2) generally corresponds to‘‘microalbuminuria,’’ now referred to as ‘‘moderately increased’’K Urine ACR 4300 mg/g (430 mg/mmol; category A3) generally corresponds to‘‘macroalbuminuria,’’ now termed ‘‘severely increased’’K Urine ACR42200 mg/g (220 mg/mmol) may be accompanied by signs andsymptoms of nephrotic syndrome (e.g., low serum albumin, edema, and highserum cholesterol)
K Threshold value corresponds approximately to urine reagent strip values of trace
or +, depending on urine concentration.
K High urine ACR can be confirmed by urine albumin excretion in a timed urine
collection expressed as AER
Urinary sediment abnormalities as markers of kidney damage
K Isolated non-visible (microscopic) hematuria with abnormal RBC morphology(anisocytosis) in GBM disorders
K RBC casts in proliferative glomerulonephritis
K WBC casts in pyelonephritis or interstitial nephritis
K Oval fat bodies or fatty casts in diseases with proteinuria
K Granular casts and renal tubular epithelial cells in many parenchymal diseases(non-specific)
Renal tubular disorders
K Renal tubular acidosis
K Nephrogenic diabetes insipidus
K Renal potassium wasting
K Renal magnesium wasting
K Fanconi syndrome
K Non-albumin proteinuria
K Cystinuria
Pathologic abnormalities detected by histology or inferred (examples of causes)
K Glomerular diseases (diabetes, autoimmune diseases, systemic infections, drugs,
neoplasia)
K Vascular diseases (atherosclerosis, hypertension, ischemia, vasculitis, thrombotic
microangiopathy)
K Tubulointerstitial diseases (urinary tract infections, stones, obstruction, drug
toxicity)
K Cystic and congenital diseases

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Table 3 | Continued
Criteria

Comment
Structural abnormalities as markers of kidney damage detected by imaging(ultrasound, computed tomography and magnetic resonance with or without contrast,
isotope scans, angiography)
K Polycystic kidneys
K Dysplastic kidneys
K Hydronephrosis due to obstruction
K Cortical scarring due to infarcts, pyelonephritis or associated with vesicoureteral
refluxK Renal masses or enlarged kidneys due to infiltrative diseases
K Renal artery stenosis
K Small and hyperechoic kidneys (common in more severe CKD due to many
parenchymal diseases)
History of kidney transplantation
K Kidney biopsies in most kidney transplant recipients have histopathologic
abnormalities even if GFR is 460 ml/min/1.73 m2 (GFR categories G1-G2) and
ACR is o30 mg/g (o3 mg/mmol)
K Kidney transplant recipients have an increased risk for mortality and kidney
failure compared to populations without kidney disease
K Kidney transplant recipients routinely receive subspecialty care

Abbreviations: ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GBM, glomerularbasement membrane; GFR, glomerular filtration rate; RBC, red blood cell; SCr, serum creatinine; WBC, white blood cell.
*For conversion, see Table 7, Chapter 1

sectional studies, but varies substantially among individuals
within the population.21 More recent data in kidney donors
confirm these general trends.22,23 Limited data are available
for non-whites in the US and Europe or in other countries,
although data suggest that the normal range for measured
GFR and the age-associated decline is similar.24–26
A GFR o60 ml/min/1.73 m2 can be detected by routine
laboratory testing. Current estimating equations for GFR(eGFR) based on serum creatinine (SCr), but not SCr alone,
are sensitive for detecting measured GFRo60 ml/min/
1.73 m2.27 A decreased eGFR using SCr can be confirmed
by GFR estimation using an alternative filtration marker(cystatin C) or GFR measurement, as necessary.
A GFRo60 ml/min/1.73 m2 is associated with a higher
risk of complications of CKD than in subjects with CKD andconserved GFR. The causal mechanisms underlying theseassociations are not fully understood. We consider three maintypes of complications, which are of relevance to all patientswith CKD and reduced GFR, irrespective of country, age or
etiology:
Drug toxicity. Altered pharmacokinetics of drugs excretedby the kidney and an increased risk of drug-interactions arecommon and require adjustment in the dosage of many
drugs (see Chapter 4.4).13 At lower GFR, altered pharmacokinetics and pharmacodynamics of drugs not excreted by thekidney may also be observed. Errors in drug dosing arecommon in patients with CKD and may be associated with
toxicity to the kidney (resulting in AKI) or systemic toxicity,
resulting in threats to patient safety.
Metabolic and endocrine complications. As GFR declines avariety of complications reflecting loss of endocrine or
exocrine function of the kidneys develop including anemia,
acidosis, malnutrition, bone and mineral disorders (described in Chapters 3 and 4).
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Risk of CVD and death. A meta-analysis by the CKD Prognosis Consortium demonstrated associations of eGFR o60 ml/
min/1.73 m2 with subsequent risk of all-cause and cardiovascular mortality, kidney failure, AKI, and CKD progression in
the general population and in populations with increased risk
for CVD.3-5 Figure 3 shows the relationship for total andcardiovascular mortality in general population cohorts. The
risk for all outcomes was relatively constant between eGFR
of 75-105 ml/min/1.73 m2, with a suggestion of a U-shaped
curve for total mortality. The increased relative risk (RR) for
all outcomes was significant for eGFR of o60 ml/min/1.73 m2.
Kidney Damage

Damage to the kidney can be within the parenchyma,
large blood vessels or collecting systems, and is most often
inferred from markers rather than direct examination of
kidney tissue. The markers of kidney damage often provide
a clue to the likely site of damage within the kidney and inassociation with other clinical findings, the cause of kidneydisease.
Proteinuria. Proteinuria is a general term for the presenceof increased amounts of protein in the urine. Proteinuria may
reflect abnormal loss of plasma proteins due to a) increased
glomerular permeability to large molecular weight proteins(albuminuria or glomerular proteinuria), b) incomplete
tubular reabsorption of normally filtered low-molecularweight proteins (tubular proteinuria), or c) increased plasma
concentration of low-molecular-weight proteins (overproduction proteinuria, such as immunoglobulin light chains).
Proteinuria may also reflect abnormal loss of proteins derived
from the kidney (renal tubular cell constituents due totubular damage) and lower urinary tract. Albuminuria,
tubular proteinuria and renal tubular cell constituentsare pathognomonic of kidney damage. In addition, findings
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Figure 2 | Normal values for GFR by age. GFR is shown for men (Panel a) and women (Panel b) of various ages, with the GFR measured as
the urinary clearance of inulin. The horizontal line indicates a GFR value of 60 ml/min/1.73 m2, which is the threshold for the definition of
CKD. Solid lines represent the mean value of GFR per decade of age, and dashed lines represent the value 1 SD from the mean value of GFR
per decade of age. CKD, chronic kidney disease; GFR, glomerular filtration rate; SD, standard deviation. Adapted with permission from
Wesson L.20 Physiology of the Human Kidney. Grune & Stratton: New York, 1969.

from experimental and clinical studies have suggested an
important role for proteinuria in the pathogenesis of diseaseprogression of CKD.28
Albuminuria. Albuminuria refers to abnormal loss ofalbumin in the urine. Albumin is one type of plasma protein
found in the urine in normal subjects and in larger quantityin patients with kidney disease.
For a number of reasons, clinical terminology is changing
to focus on albuminuria rather than proteinuria: a) albuminis the principal component of urinary protein in most kidneydiseases; recent recommendations for measurement of urine
proteins emphasize quantification of albuminuria rather than
total protein; b) recent epidemiologic data from studies
around the world demonstrate a strong graded relationshipof the quantity of urine albumin with both kidney and CVD
risk; and c) later recommendations in these guidelines classify
kidney disease by level of albuminuria. In this guideline, wewill refer to proteinuria when discussing general concepts
and will refer either to total protein, albumin or other specificproteins when discussing measurements, patterns, andinterpretation of proteinuria.
Albuminuria is a common but not uniform finding in
CKD. It is the earliest marker of glomerular diseases,
including diabetic glomerulosclerosis, where it generally
appears before the reduction in GFR. It is a marker ofhypertensive nephrosclerosis but may not appear until after
the reduction in GFR. It is often associated with underlying
hypertension, obesity, and vascular disease, where theunderlying renal pathology is not known.
Normative values for albuminuria and proteinuria are
generally expressed as the urinary loss rate. The urinary loss
rate of albumin and protein has commonly been referred to22

as AER and protein excretion rate (PER), respectively,
although in the strict physiological sense they are notexcreted. The terms AER and PER will be retained herein.
We chose a threshold for urinary AER of Z30 mg/
24 hours sustained for 43 months to indicate CKD.
This value is considered to be approximately equivalent
to an ACR in a random untimed urine sample of Z30 mg/g
or Z3 mg/mmol. The rationale for this threshold is asfollows:
An AER of Z30 mg/24 hours (ACRZ30 mg/g [Z3 mg/mmol]) is greater than 3 times the normal value in young
adult men and women of approximately 10 mg/24 hours(ACR 10 mg/g or 1 mg/mmol).
K An AER of Z30 mg/24 hours (ACRZ30 mg/g [Z3 mg/mmol]) may sometimes be detectable as ‘trace’ using a urine
reagent strip, depending on urine concentration, but this is
not a consistent finding until AER exceeds approximately
300 mg/24 hours (ACRZ300 mg/g [Z30 mg/mmol]). As
described later, trace or positive reagent strip values/readings
can be confirmed by ACR, and an elevated ACR can be
confirmed by urine AER in a timed urine collection, as
necessary.
K An
AERZ30 mg/24 hours (ACRZ30 mg/g [Z3 mg/mmol]) is associated with an increased risk forcomplications of CKD. A meta-analysis by the CKD
Prognosis Consortium demonstrated associations of an
ACRZ30 mg/g (Z3 mg/mmol) or reagent strip 1 þprotein with subsequent risk of all-cause and cardiovascular mortality, kidney failure, AKI, and CKD
progression in the general population and in populations
with increased risk for CVD3-5 (Figure 4).
K

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Figure 3 | Relationship of eGFR with mortality. HRs and 95% CIs
for all-cause (a) and cardiovascular mortality (c) according tospline eGFR. HRs and 95% CIs (shaded areas) are adjusted for ACR,
age, sex, ethnic origin, history of CVD, systolic BP, diabetes,smoking, and total cholesterol. The reference (diamond) was eGFR
95 ml/min/1.73 m2 and ACR 5 mg/g (0.6 mg/mmol), respectively.
Circles represent statistically significant and triangles represent
not significant. ACR, albumin-to-creatinine ratio; BP, bloodpressure; CI, confidence interval; CVD, cardiovascular disease;
eGFR, estimated glomerular filtration rate; HR, hazard ratio.
Reprinted from The Lancet, vol 375, Matshushita K, van de Velde
M, Astor BC, et al.4 Association of estimated glomerular filtration
rate and albuminuria with all-cause and cardiovascular mortality
in general population cohorts: a collaborative meta-analysis, p.
2073-2081, 2010, with permission from Elsevier; accessed http://
download.thelancet.com/pdfs/journals/lancet/
PIIS0140673610606745.pdf

Figure 4 | Relationship of albuminuria with mortality. HRs and
95% CIs for all-cause (b) and cardiovascular mortality (d)according to ACR. HRs and 95% CIs (shaded areas) are adjusted forage, sex, ethnic origin, history of CVD, systolic BP, diabetes,smoking, and total cholesterol and spline eGFR. The reference(diamond) was ACR 5 mg/g (0.6 mg/mmol) and eGFR 95 ml/min/
1.73 m2, respectively. Circles represent statistically significant andtriangles represent not significant. ACR plotted in mg/g. To
convert ACR in mg/g to mg/mmol multiply by 0.113. Approximate
conversions to mg/mmol are shown in parentheses. ACR,
albumin-to-creatinine ratio; BP, blood pressure; CI, confidence
interval; CVD, cardiovascular disease; eGFR, estimated glomerular
filtration rate; HR, hazard ratio. Reprinted from The Lancet, vol375, Matshushita K, van de Velde M, Astor BC, et al.4 Association of
estimated glomerular filtration rate and albuminuria with all-cause
and cardiovascular mortality in general population cohorts: acollaborative meta-analysis, p. 2073-2081, 2010, with permission
from Elsevier; accessed http://download.thelancet.com/pdfs/
journals/lancet/PIIS0140673610606745.pdf

Urine sediment abnormalities. Formed elements, such as
cells, casts, crystals, and microorganisms may appear in theurine sediment in a variety of disorders of the kidney andurinary tract, but renal tubular cells, red blood cell (RBC)
casts, white blood cell (WBC) casts, coarse granular casts,
wide casts, and large numbers of dysmorphic RBCs arepathognomonic of kidney damage.

parenchyma in kidney biopsies irrespective of eGFR or othermarkers of kidney damage must be acknowledged as animportant parameter in defining kidney damage. The
pathologic classification of diseases of the renal parenchyma
reflects the localization of the disease to glomeruli, vessels,
tubules and interstitium, or cysts. Renal biopsies are
performed in the minority of CKD patients.
Imaging abnormalities. Imaging techniques allow thediagnosis of diseases of the renal structure, vessels and/orcollecting systems. Thus, patients with significant structuralabnormalities are considered to have CKD if the abnormality persists for greater than 3 months (note that this does
not include simple cysts and clinical context is required
for action).
History of kidney transplantation. Kidney transplant recipients are defined as having CKD, irrespective of the level of
GFR or presence of markers of kidney damage. The rationale

Electrolyte and other abnormalities due to tubular disorders.

Abnormalities of electrolytes and other solutes may result fromdisorders of renal tubular reabsorption and secretion. These
syndromes are uncommon but pathognomonic of kidneydisease. Often the diseases are genetic without underlying
pathologic abnormalities. Other diseases are acquired, due todrugs or toxins, and are usually with prominent tubularpathologic lesions.
Pathologic abnormalities directly observed in kidney tissue
obtained by biopsy. Evidence of abnormalities of renal
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for this designation is that biopsies in kidney transplant recipients reveal pathologic abnormalities even inpatients without decreased GFR or albuminuria. Kidneytransplant recipients have an increased risk of mortality andkidney outcomes compared to the general population andthey require specialized medical management.29
Implications for Health

CKD is associated with a wide range of complications leading
to adverse health outcomes. For some complications, thecausal pathway between kidney disease and adverse outcomesis well-known. For these complications, there are clinicalpractice guidelines for testing and treatment for modifiablefactors to prevent adverse outcomes. Since 2002 a large
number of epidemiologic studies have linked decreased GFR
and albuminuria to the risk of adverse health outcomes notpreviously identified as CKD complications. The explorationof the mechanisms for the relationships of CKD withthese complications is a rapidly growing topic for basic
and clinical research. Because of the high prevalence,
adverse outcomes, and high cost of CKD, especially kidney
failure, some countries have developed public healthprograms for early identification and treatment of CKD
and its complications. The effectiveness of these programs isbeing evaluated.
Implications for Clinical Practice and Public Policy

CKD was first defined in the 2002 KDOQI Guidelines andendorsed at subsequent KDIGO Controversies Conferenceswith minor modifications.30,31 The definition of CKD proposed
here is intended for use in clinical practice, research and publichealth, and has not changed. Thus, the updated version does
not change any of the initiatives that have been commenced
with respect to public policy. We recognize the variation aroundthe world regarding measurement of urine albumin versus total
protein in clinical practice, and we anticipate variation in
implementation of the guideline until more widespreaddissemination of the guideline has occurred. For additional
discussion about methods for ascertainment of urine albumin
versus total protein, see Recommendation 1.4.4 (Evaluation ofalbuminuria). The implications of highlighting the importanceof albuminuria for general practitioners in evaluation andprognostication may help with identification and care planning.
Nonetheless, a number of concerns about the definition remain,which are clarified below.30,32–36
Areas of Controversy, Confusion, or Non-consensus andClarification of Issues and Key Points

General concerns:a) The use of single thresholds without consideration ofpatient specific factors
The use of single thresholds to define decreased GFR andincreased AER, without consideration for cause of disease,age, sex, race-ethnicity and clinical context is consistent withthe use of single thresholds for disease markers to define
other chronic non-communicable diseases, such as hyperten24

sion, diabetes, and hypercholesterolemia, that primarily affectthe elderly and are associated with an increased risk for
cardiovascular mortality. Biologic variability and error inascertainment of GFR and AER can lead to misclassificationand false negative and false positive diagnosis. Furthermore,these single thresholds appear to differentiate groups ofindividuals and outcomes, irrespective of specific patientcharacteristics in a multitude of studies. However, theycorrespond to thresholds for RRs for complications, rather
than predictions of absolute risk. Furthermore, as with any
diagnostic tests, findings must be interpreted with considerations of likelihood of disease based on the clinical context but
this should not negate the application of a standard
definition for CKD.
Specific concerns:b) Relationship of CKD criteria to aging
Epidemiologic studies show an increased prevalence of
decreased eGFR and increased ACR in older subjects. There
has been vigorous debate as to whether decreased GFR or
increased ACR in older people represent a disease or ‘‘normal
aging.’’ Numerous studies show pathologic abnormalities
associated with aging, including glomerular sclerosis, tubular
atrophy and vascular sclerosis. The cause for this association
is not clear but has been hypothesized to reflect disparate
processes, such as vascular disease or senescence.37–39
Irrespective of cause, there appears to be increased risk
associated with decreased eGFR or increased ACR in older
people, and for this reason, we consider all individuals withpersistently decreased GFR or increased albuminuria to have
CKD. Comparison of the magnitude of risk to younger
individuals is complicated. As with other CVD risk factors,
absolute risk appears to be higher in older than in younger
individuals, but RR appears to be lower.3-5 Note is also madethat healthy older individuals do not necessarily havedecreased GFR, so that while one may expect some decline,
levels below 60 ml/min/1.73 m2 in individuals without
comorbidity is the exception.20c) Isolated decreased GFR without markers of kidneydamageA variety of clinical circumstances are associated with GFR
o60 ml/min/1.73 m2 for 43 months in the absence ofknown structural alterations. Below are examples of these
conditions and the rationale for considering them as CKD:K Heart failure, cirrhosis of the liver, and hypothyroidism.
Decreased GFR complicates the management of the
primary disease and patients with these disorders withdecreased GFR have a worse prognosis than those
without decreased GFR. In addition, renal biopsy inthese patients may reveal renal parenchymal lesions.
K Kidney donors. The usual level of GFR in kidney donors
after transplantation is approximately 70% of the predonation level, in the range of 60-90 ml/min/1.73 m2 in
most donors. However, a minority of donors have GFR
o60 ml/min/1.73 m2. The prognosis of these donors
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compared to those with higher GFR has not been
carefully studied. However, as with decreased GFR due
to recognized kidney diseases, donors with decreased
GFR require closer follow-up for adjustment of drug
doses.
K Malnutrition. The level of GFR is affected by habitual
protein intake.40 Healthy adults with lower protein
intake may have lower mean GFR, but usually do nothave GFR o60 ml/min/1.73 m2. Older studies ofpatients with protein-calorie malnutrition and more
recent studies of subjects with anorexia nervosa havedocumented reduced measured GFR that can improve
following restoration of nutritional status. However,renal biopsies may reveal structural abnormalities inthese conditions and decreased GFR can complicate their
management.
d) Isolated albuminuria without decreased GFR
As described later, transient ACR Z30 mg/g (Z3 mg/mmol) can occur in disorders other than CKD. Remission ofalbuminuria within 3 months in association with recovery
from these disorders is not defined as CKD. Patients withpersistent albuminuria would be considered to have CKD.
Below are examples of these conditions and the rationale forconsidering them as CKD:K Obesity and metabolic syndrome. Albuminuria can beassociated with obesity and metabolic syndrome, and canremit during weight loss. The mechanism of albuminuria
in these conditions is not known but renal biopsies may
reveal prominent vascular lesions. Patients with obesity
and metabolic syndrome are at increased risk fordevelopment of diabetes and hypertension. The risk ofpersistent albuminuria in this condition has not been
carefully studied.
41
K Orthostatic (postural) proteinuria.
Albuminuria may
rarely be observed in the upright but not recumbent
posture in patients with the syndrome of posturalproteinuria. This condition is not associated with anincreased risk of long-term adverse outcomes but athorough evaluation is required to exclude other causesof CKD. Exclusion is generally possible by studying a firstpass early morning urine (EMU) after overnight
recumbency: total protein loss of 41000 mg/24 hours is
unlikely to be explained by orthostatic proteinuria.
e) Remission of decreased GFR or markers of kidneydamageIf decreased GFR and markers of kidney damage resolve
while on treatment, the patient would be considered to havetreated CKD, consistent with nomenclature for treatedhypertension, treated diabetes, or treated hypercholesterolemia if blood pressure, blood glucose and blood cholesterol
are within normal range while on medications. If resolutionof decreased GFR and markers of kidney damage is sustained
after withdrawal of treatment, the patient would beconsidered to have a history of CKD.
Kidney International Supplements (2013) 3, 19–62f) Kidney disease in the absence of decreased GFR andmarkers of kidney damage
A GFR Z60 ml/min/1.73 m2 may reflect a decline from ahigher value, and an AER of o30 mg/24 hours (ACR
o30 mg/g or o3 mg/mmol) may reflect a rise from a lower
value. Both findings may be associated with a pathologic
process, even in the absence of other markers of kidneydamage. Although such patients do not fulfill the criteria for
CKD, a clinician’s high index of suspicion may warrant
additional diagnostic testing or close follow-up to detect theonset of CKD.
Pediatric Considerations

In general the definition of CKD in adults applies to children(birth-18 years) with the following exceptions or allowances:
K the criteria for duration 43 months does not apply to
newborns or infants r3 months of age.
2
K the criteria of a GFR o60 ml/min/1.73 m does not apply
to children o2 years of age in whom an age appropriate
value should be applied.
K a urinary total protein or albumin excretion rate above
the normal value for age may be substituted foralbuminuria Z30 mg/24 hours.
K all electrolyte abnormalities are to be defined in light ofage normative values.
Developmental renal abnormalities account for as many as
30-50% of the children with CKD or ESRD.42 As such many
infants while born with normal SCr for age will in fact meetthe definition of CKD based on structural abnormalities
despite the appearance of a normal GFR and may be classified
as such within the first few days of life.
Normal GFR in newborns is less than 60 ml/min/1.73 m2,
and it is not until approximately 2 years of age that one
expects to see body surface area (BSA) adjusted GFR values
comparable to those seen in the adult.43,44 The expected
increases in GFR that occur in the first months of life are due
to increases in mean arterial pressure (MAP), decrease inrenal vascular resistance, and redistribution of intrarenal
blood flows to the superficial cortical nephrons in the
newborn and increases in glomerular size and capillarypermeability in the infant.45–48 As such direct applicationof the GFR threshold values in the current CKD definition
would not be appropriate in children less than 2 yearsof age as their normative maximal values would be below
those of the adult or older child; hence most neonates
and infants would be classified a priori at a decreased GFRbased not on a reduction in GFR from a higher value, butrather failure of maturity of the kidney.
Numerous references exist for fetal,49 neonatal term,44,48
pre-term,46,50,51 infant, child and adolescent GFR values43,44
and the reader is strongly encouraged to use such references
when comparison to a normative range is required forapproximating the reduction in renal clearance of theindividual child. It should be noted that across these ages
the method of GFR measurement has often varied with the25chapter 1

majority of such measurements in the neonate (term or
preterm) or infant being derived from urinary collections andcreatinine clearance (CrCl) measurements, whereas the older
children and adolescents are often investigated with exogenous markers including inulin, radionuclides, and othermarkers such as iohexol or iothalamate.
The most comprehensive list of GFR based on the gold
standard of inulin clearance and stratified by age forboth term and preterm babies and children up to theage of young adults can be found in Schwartz and Furth’s
review on GFR measurements and estimation in pediatric
CKD.52
Similarly, age relevant normative values should be
utilized when interpreting urinary protein (albumin)
excretions as well as other important urinary andserum laboratory values. Such values may be found in a
number of pediatric nephrology texts. For neonates
and infants this includes Waters53 and for post-neonate toyoung adults, more comprehensive values can be found in
Langlois.54
1.2 STAGING OF CKD
1.2.1: We recommend that CKD is classified based on
cause, GFR category, and albuminuria category(CGA). (1B)
RATIONALE

This statement is worded in this way because a classificationencompassing cause and severity, as expressed by the level of
GFR and the level of albuminuria, links to risks of adverse
outcomes including mortality and kidney outcomes. These
factors will therefore guide management of CKD and thisrecommended classification is consistent with other classification systems of disease which are based on the generaldomains of cause, duration and severity which provide a
guide to prognosis. We included only kidney measures asfactors in the classification of kidney disease, although we
acknowledge that factors other than kidney measures, such aslevel of BP, also affect prognosis in CKD.
This recommended staging with inclusion of two additional
domains represents a revision of the previous CKD guidelines,
which included staging only by level of GFR. Cause of disease isincluded because of its fundamental importance in predicting
the outcome of CKD and choice of cause-specific treatments.
With inclusion of cause of kidney disease in the classification,
we considered that it was no longer necessary to retain the useof the letter ‘‘T’’ to refer to kidney transplant recipients.
Albuminuria is included as an additional expression of severityof disease not only because it is a marker of the severity of
injury but also because albuminuria itself strongly associateswith progression of kidney disease. Numerous studies haveidentified the adverse prognostic implication of albuminuria
irrespective of level of kidney function.
We propose that this classification of CKD by Cause, GFR
and Albuminuria, respectively be referred to as CGA
26

staging. It can be used to inform the need for specialist
referral, general medical management, and indications forinvestigation and therapeutic interventions. It will also be atool for the study of the epidemiology, natural history, andprognosis of CKD.
Pediatric Considerations

The principles inherent in this guideline are fully applicable
to children.
While large scale trials in children relating cause, GFR andalbuminuria or proteinuria are rare, the principles of amultimodal classification in these three spheres should apply
to children.
To date the only large scale trial utilizing a validated
exogenously measured GFR (iohexol) and urinary protein
excretion in a well-described cohort of children with renal
disease is the Chronic Kidney Disease in Children (CKiD)
trial.55 They have enrolled over 600 children aged 1-16 years
and have described GFR and urinary proteinuria related
outcomes in the areas of neurodevelopment, cognition,
behavior, cardiovascular health and risk, and somatic growth.
They have also collected samples for ongoing and future
genetic study. While these data are sparse in relation to
overall adult numbers, this represents one of the largest
pediatric nephrology trials. The use of true measured GFR,
the quality and completeness of the data, and the long term
longitudinal follow-up will form the basis for the best
evidence-based outcomes in children with CKD for theforeseeable future. A recent review article by Copelovitch
et al.56 summarizes the major findings of the trial up to thepresent time.
1.2.2: Assign cause of CKD based on presence or absence ofsystemic disease and the location within the kidneyof observed or presumed pathologic-anatomic
findings. (Not Graded)
RATIONALE

This statement has been included so as to ensure thatclinicians are alerted to the fact that CKD is not a diagnosis inand of itself, and that the assignment of cause is importantfor prognostication and treatment.
The cause of CKD has been traditionally assigned
based on presence or absence of underlying systemic
diseases and location of known or presumed pathologicanatomic abnormalities. The distinction between systemic
diseases affecting the kidney and primary kidney diseases
is based on the origin and locus of the disease process.
In primary kidney disease the process arises and is confinedto the kidney whereas in systemic diseases the kidney
is only one victim of a specific process, for example
diabetes mellitus. Certain genetic diseases cross this boundary by affecting different tissues, e.g., adult polycystic
kidney disease. The location of pathologic-anatomic findings
is based on the magnitude of proteinuria, findings from theurine sediment examination, imaging, and renal pathology.
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Table 4 | Classification* of CKD based on presence or absence of systemic disease and location within the kidney of pathologicanatomic findings
Examples of systemic diseases
affecting the kidney

Examples of primary kidney diseases (absence ofsystemic diseases affecting the kidney)

Glomerular diseases

Diabetes, systemic autoimmune diseases, systemic
infections, drugs, neoplasia (including amyloidosis)

Tubulointerstitialdiseases

Systemic infections, autoimmune, sarcoidosis,
drugs, urate, environmental toxins(lead, aristolochic acid), neoplasia (myeloma)
Atherosclerosis, hypertension, ischemia, cholesterol
emboli, systemic vasculitis, thrombotic
microangiopathy, systemic sclerosis
Polycystic kidney disease, Alport syndrome,
Fabry disease

Diffuse, focal or crescentic proliferative GN; focal andsegmental glomerulosclerosis, membranous nephropathy,
minimal change disease
Urinary-tract infections, stones, obstruction

Vascular diseases

Cystic and congenital
diseases

ANCA-associated renal limited vasculitis, fibromusculardysplasia
Renal dysplasia, medullary cystic disease, podocytopathies

Abbreviations: ANCA, antineutrophil cytoplasmic antibody; CKD, chronic kidney disease, GN, glomerulonephritis
Genetic diseases are not considered separately because some diseases in each category are now recognized as having genetic determinants.
*Note that there are many different ways in which to classify CKD. This method of separating systemic diseases and primary kidney diseases is only one, proposed by theWork Group, to aid in the conceptual approach.

Table 4 represents an example of a classification of causesof kidney diseases based on these two domains.
There is wide geographic variation in the cause of kidneydisease. In developed countries, hypertension and diabetes
are the most frequent causes of CKD, especially in the elderly.
In populations with a high prevalence of diabetes andhypertension, it can be difficult to distinguish CKD due tohypertension and diabetes from CKD due to other disorders.
In other countries, other causes of CKD may be as frequent as
hypertension and diabetes (e.g., glomerular disease in East
Asia) or coexist with them. Specialized diagnostic testing,such as kidney biopsy or invasive imaging studies are
performed only when it is essential to confirm somediagnoses and the benefits justify the risks and cost. It is
anticipated that cause of disease will not be known withcertainty for many patients with CKD but can be either
inferred or not known.

RATIONALE

1.2.3: Assign GFR categories as follows [Table 5] (Not
Graded):The purpose of this statement is to ensure clarity incommunication. The terms associated with each of the
GFR categories are descriptors which need to be taken in
the context of the individual and are all references tonormal young adults. Note that mildly decreased kidney
function (G2) in the absence of other markers, does notconstitute CKD.
The associations of lower categories of GFR and risks ofmetabolic and endocrine complications formed the basis of theprevious stratification into 5 stages. This current classification
further acknowledges the importance of dividing Stage 3 basedon data supporting different outcomes and risk profiles into
categories G3a and G3b (Figure 5). A number of otherconcurrent complications are associated with decreased categories of GFR including infection, impaired cognitive andphysical function, and threats to patient safety.57
Figures 6 and 7 detail the RRs of decreased eGFR
and increasing ACR with future complications, including
mortality and kidney outcomes.30 Even for the group withthe lowest value of albuminuria, the increased RR for all
outcomes is significant for eGFRs below 60 ml/min/1.73 m2
in the continuous analysis and in the range of 45–59 ml/min/
1.73 m2 for the categorical analysis.

Table 5 | GFR categories in CKD

Pediatric Considerations

Pediatric Considerations

The principles inherent in this guideline are fully applicable
to children.

GFR category GFR (ml/min/1.73 m2) Terms
G1
G2
G3a
G3b
G4
G5

Z90
60–89
45–59
30–44
15–29
o15

Normal or highMildly decreased*
Mildly to moderately decreased
Moderately to severely decreased
Severely decreased
Kidney failure

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.
*Relative to young adult level
In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill
the criteria for CKD.

Kidney International Supplements (2013) 3, 19–62

In children o2 years of age with CKD, the GFR categories as
per the adult in Table 5 do not apply; these children should
be categorized as having normal, moderately reduced, orseverely reduced age-adjusted GFR.
No currently agreed upon set of international normativevalues or categories exist for GFR in children under the age of
1-2 years. However, the international pediatric nephrology
community has embraced the adult CKD staging system as
per the 2002 KDOQI guidelines in children over the age of
2 years, as suggested by Hogg et al.43
27

chapter 1

importantly these values are expected to increase in a nonlinear fashion over the first 2 years of life with significant
changes seen in the first few months post-birth and nocurrent evidence of presence of comorbid conditions at any
given level of measured or estimated GFR in this population.
As such, specific categorization of G1-5 as suggested in thisRecommendation would seem not be of value, and might bemisleading if applied to a child less than 2 years of age.
With this in mind, it is suggested that based on the chosen
method of GFR measurement or comparison for theindividual (i.e., CrCl, radioactive or cold exogenous serum
markers, or estimating formula), that one should attempt toclassify the child under the age of 2 years as having normal,
moderate or severe reductions in GFR based on thenormative range and standard deviations (SDs) for the
method. No evidence exists for this recommendation but
recognition that values of GFR more than 1 SD below themean would seem likely to raise concern of the clinician andfoster the need for closer monitoring. For drug dosing
adjustments it is suggested that those children with GFRs
below the mean by 41 but o2 SD be classified as having amoderate reduction in GFR whereas those more than 2 SD
below the mean for the method be classified as having asevere reduction in GFR.
1.2.4: Assign albuminuria* categories as follows [Table 6](Not Graded):*note that where albuminuria measurement is
not available, urine reagent strip results can besubstituted (Table 7)
Table 6 | Albuminuria categories in CKD
ACR (approximate
equivalent)

AER(mg/24 hours)(mg/mmol)(mg/g)

A1

o30

o3

o30

A2
A3

30-300
4300

3-30
430

30-3004300

Category

Terms
Normal to mildlyincreased
Moderately increased*
Severely increased**Abbreviations: AER, albumin excretion rate; ACR, albumin-to-creatinine ratio;
CKD, chronic kidney disease.
*Relative to young adult level.
**Including nephrotic syndrome (albumin excretion usually 42200 mg/24 hours[ACR 42220 mg/g; 4220 mg/mmol]).

Figure 5 | Age-standardized rates of death from any cause(panel a), cardiovascular events (panel b), and hospitalization(panel c), according to the eGFR among 1,120,295 ambulatory
adults. eGFR, estimated glomerular filtration rate. From N Engl J
Med, Go AS, Chertow GM, Fan D, et al.58 Chronic kidney disease andthe risks of death, cardiovascular events, and hospitalization, 351:
1296-1305. Copyright & (2004) Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society;accessed http://www.nejm.org/doi/pdf/10.1056/NEJMoa041031

As indicated in Pediatric Considerations for Guideline 1.1,
the normative GFR values for children less than 2 years varyquite widely by both age and method of measurement. More28

RATIONALE

The purpose of this statement is to ensure communicationand to reflect that albuminuria category is an important
predictor of outcomes. The association of high levels ofproteinuria with signs and symptoms of nephrotic syndrome
is well known. The detection and evaluation of lesser
quantities of proteinuria have gained additional significanceas multiple studies have demonstrated its diagnostic,
pathogenic, and prognostic importance. There is a continuous risk associated with albuminuria but the use of a simple
categorical approach was selected to simplify the concept for
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chapter 1

Cardiovascular mortality
16

8

8

Adjusted HR

Summary of
relative risks
fromcontinuous
meta-analysis

Adjusted HR

All-cause mortality
16

4
2
1
0.5

End stage renal disease

2
1
0.5

15 30 45 60 75 90 105 120
eGFR, ml/min per 1.73 m2

15 30 45 60 75 90 105 120
eGFR, ml/min per 1.73 m2

Acute kidney injury

Progressive CKD

64

8192

256

1024
256
64
16
4
1
0.5

16

Adjusted OR

Adjusted HR

Adjusted HR

4

4
1
0.5

15 30 45 60 75 90 105 120
eGFR, ml/min per 1.73 m2

64
16
4
1
0.5

15 30 45 60 75 90 105 120
eGFR, ml/min per 1.73 m2

15 30 45 60 75 90 105 120
eGFR, ml/min per 1.73 m2

Figure 6 | Summary of continuous meta-analysis (adjusted RRs) for general population cohorts with ACR. Mortality is reported forgeneral population cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported for general population cohorts assessing
albuminuria as either urine ACR or reagent strip. eGFR is expressed as a continuous variable. The three lines represent urine ACR of o30,
30-299 and Z300 mg/g (o3, 3-29, and Z30 mg/mmol, respectively) or reagent strip negative and trace, 1 þ positive, Z2 þ positive. All
results are adjusted for covariates and compared to reference point of eGFR of 95 ml/min/1.73 m2 and ACR of o30 mg/g (o3 mg/mmol) or
reagent strip negative (diamond). Each point represents the pooled RR from a meta-analysis. Solid circles indicate statistical significancecompared to the reference point (P o0.05); triangles indicate non-significance. Red arrows indicate eGFR of 60 ml/min/1.73 m2, thresholdvalue of eGFR for the current definition of CKD. ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular
filtration rate; HR, hazard ratio; OR, odds ratio, RR, relative risk. Reprinted with permission from Macmillan Publishers Ltd: Kidney
International. Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO
controversies conference report. Kidney Int 2011; 80: 17-2830; accessed http://www.nature.com/ki/journal/v80/n1/full/ki2010483a.html

clinical practice. Several groups had suggested subdividing one or more GFR categories based on albuminuria
category.
For the detection of diabetic nephropathy some guidelines
recommend the use of different ACR thresholds for males
and females (425 mg/g [42.5 mg/mmol] and 435 mg/g
[43.5 mg/mmol], respectively) to take into account variations in creatinine excretion. A single threshold is used in
North America (30 mg/g or 3.4 mg/mmol). Earlier KDIGO
guidance was reluctant to adopt gender-specific thresholds
due to greater complexity, uncertainty about assay precision,and effects of race, ethnicity, diet and measures of body sizeon creatinine and this stance is maintained here. For
simplicity, and to reflect the fact that it is an approximation,
3.4 mg/mmol as the current guideline threshold has beenrounded to 3.0 mg/mmol.
There is a graded increase in risk for higher albuminuria
categories, at all GFR categories, without any clear thresholdvalue. Even for subjects with GFR 460 ml/min/1.73 m2,
the increased RR is statistically significant for urine
ACR Z30 mg/g (Z3 mg/mmol) for mortality and kidney
outcomes (Figures 6 and 7). The predictive ability ofalbuminuria at all categories of GFR supports the suggestion
to add albuminuria categories to all GFR categories. Since therelationship with albuminuria is continuous, the selection of
the number of categories and the cutoff values appears
Kidney International Supplements (2013) 3, 19–62

arbitrary. The Work Group has recommended the classification of albuminuria into only 3 categories, based on practicalconsiderations, but recognized that further subdivisions
within the category of o30 mg/24 hours (ACRo30 mg/g
or o3 mg/mmol) may be useful for risk stratification,and that subdivisions within the category of 4300 mg/
24 hours (ACR4300 mg/g or 430 mg/mmol) may be
useful for diagnosis and management. Specifically there
is a recognition that nephrotic range proteinuria(AER42200 mg/24 hours [ACR42200 mg/g;4220 mg/mmol]; PER43000 mg/24 hours [43000 mg/g;4300 mg/mmol]) confers unique additional risks and is usuallyassociated with specific conditions (such as GN). As these
are relatively rare in general practices, the simplicity of the
AER categorization was preferred. Table 7 shows theapproximate relationships of categories of AER to othermeasures of albuminuria and proteinuria.
Implications for Clinical Practice and Public Policy

Data from around the world suggest that CKD prevalence isbetween 10-16% but information concerning population
prevalence by category of GFR and ACR is scant. Figure 8
shows the proportion of adults in the US by categories
of GFR and albuminuria.19 While CKD is common, few
individuals have severely reduced GFR or kidney failure or
severely increased albuminuria.
29chapter 1

Cardiovascular mortality

All-cause mortality
eGFR
> 105

Summary of
relative risks
fromcategoricalmeta-analysis(dipstick included)(–, ±, +, ++)

ACR
10–29

ACR
30–299

ACR
300

1.1

1.5

2.2

5.0

ACR
<10

ACR
10–29

ACR
30–299

ACR
300

eGFR
> 105

0.9

1.3

2.3

2.1

eGFR
90–105

Ref

1.4

1.5

3.1

eGFR
90–105

Ref

1.5

1.7

3.7

eGFR
75–90

1.0

1.3

1.7

2.3

eGFR
75–90

1.0

1.3

1.6

3.7

eGFR
60–75

1.0

1.4

1.8

2.7

eGFR
60–75

1.1

1.4

2.0

4.1

eGFR
45–60

1.3

1.7

2.2

3.6

eGFR
45–60

1.5

2.2

2.8

4.3

eGFR
30–45

1.9

2.3

3.3

4.9

eGFR
30–45

2.2

2.7

3.4

5.2

6.6

eGFR
15–30

14

7.9

4.8

8.1

eGFR
15–30

Kidney failure (ESRD)

ACR
<10

5.3

3.6

4.7

Acute kidney injury (AKI)

ACR
<10

ACR
10–29

ACR
30–299

ACR
300

eGFR
> 105

Ref

Ref

7.8

18

eGFR
> 105

eGFR
90–105

Ref

Ref

11

20

eGFR
90–105

Ref

Ref

eGFR
75–90

Ref

Ref

3.8

48

eGFR
75–90

Ref

Ref

eGFR
60–75

Ref

Ref

7.4

67

eGFR
60–75

Ref

Ref

3.3

eGFR
45–60

5.2

22

40

147

eGFR
45–60

2.2

4.9

eGFR
30–45

56

74

294

763

eGFR
30–45

7.3

10

eGFR
15–30

433

1044

1056

2286

eGFR
15–30

17

17

21

Progressive CKD
ACR
<10

ACR
10–29

ACR
30–299

ACR
300

eGFR
> 105

Ref

Ref

0.4

3.0

5.8

eGFR
90–105

Ref

Ref

0.9

3.3

4.1

eGFR
75–90

Ref

Ref

1.9

5.0

6.4

eGFR
60–75

Ref

Ref

3.2

8.1

6.4

5.9

eGFR
45–60

3.1

4.0

9.4

57

12

20

eGFR
30–45

3.0

19

15

22

29

eGFR
15–30

4.0

12

21

7.7

ACR
<10

ACR
10–29

ACR
30–299

ACR
300

Ref

Ref

2.7

8.4

2.4
2.5

Figure 7 | Summary of categorical meta-analysis (adjusted RRs) for general population cohorts with ACR. Mortality is reported forgeneral population cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported for general population cohorts assessing
albuminuria as either urine ACR or reagent strip. eGFR and albuminuria are expressed as categorical variables. All results are adjusted forcovariates and compared to the reference cell (Ref). Each cell represents a pooled RR from a meta-analysis; bold numbers indicate statisticalsignificance at P o0.05. Incidence rates per 1000 person-years for the reference cells are 7.0 for all-cause mortality, 4.5 for CVD mortality,
0.04 for kidney failure, 0.98 for AKI, and 2.02 for CKD progression. Colors reflect the ranking of adjusted RR. The point estimates for each cellwere ranked from 1 to 28 (the lowest RR having rank number 1, and the highest number 28). The categories with a rank number 1-8 aregreen, rank numbers 9-14 are yellow, the rank numbers 15-21 are orange and the rank numbers 22-28 are colored red. (For the outcome of
CKD progression, two cells with RR o1.0 are also green, leaving fewer cells as yellow, orange and red). ACR, albumin-to-creatinine ratio; AKI,
acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage
renal disease; RR, relative risk. Reprinted with permission from Macmillan Publishers Ltd: Kidney International. Levey AS, de Jong PE, Coresh J,
et al.30 The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int 2011; 80:
17-28; accessed http://www.nature.com/ki/journal/v80/n1/full/ki2010483a.html

The classification of kidney disease by cause, category of
GFR and category of albuminuria does not conform to theInternational Classification of Diseases (ICD) maintained by
the World Health Organization (WHO). Currently the WHO
is developing an update (ICD 11). It will be important tocommunicate and coordinate efforts with the kidney disease
subgroup for ICD 11. However, the proposed current
classification does address the need in clinical practice toacknowledge the multiple dimensions and variables by which
individual patients are assessed. Table 8 gives examples of theuse of CGA nomenclature.
Definition of GFR categories have been deliberately based
upon the concept of ‘‘true’’ GFR, whereas clinical practiceand research has predominantly used creatinine-based
estimates of GFR. The belief of the Work Group is that the
non-GFR determinants of creatinine and the imprecision ofcreatinine-based GFR estimates have resulted in the absenceof strong dose-dependent association of eGFR with clinicaloutcomes in the GFR range of 460 ml/min/1.73 m2. The
Work Group felt confident that GFR levels of Z90 ml/min/
1.73 m2 portend better prognosis than GFR levels 60-89 ml/
min/1.73 m2, if they could be estimated accurately. Therefore,
30

the GFR categories include separate G1 (Z90 ml/min/
1.73 m2) and G2 (60-89 ml/min/1.73 m2) designations despite
limited data from creatinine-based estimates that prognosis
differs between these two categories. It is also an acknowledgement that the degree of precision of some of ourmeasurements may not be able to differentiate between these2 categories reliably. As described later, studies that have usedcystatin C have found gradients in prognosis at eGFR levels
above 60 ml/min/1.73 m2, which supports the belief of thecommittee that separating these 2 GFR categories isappropriate for CKD classification.
Albuminuria categories are ‘‘wide’’ with respect to risk,
with significant gradients within each category. The decision
to propose only 3 categories is based on the perceived needfor simplification in clinical practice. In specialized clinicalnephrology centers, A3 (4300 mg/g or 430 mg/mmol) isoften more precisely assessed and divided into additional
categories. For example, nephrotic range proteinuria isdefined as PER43500 mg/24 hours or PCR (proteinto-creatinine ratio) 43500 mg/g [4350 mg/mmol] which
is approximately equivalent to AER42200 mg/24 hours
or ACR42200 mg/g [220 mg/mmol]. It is clearly recognized
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Table 7 | Relationship among categories for albuminuria and proteinuria
Categories
MeasureNormal to mildly increased (A1)Moderately increased (A2)

Severely increased (A3)

o30
o150

30–300150–500

4300
4500

o3
o30

3–30
30–300

430
4300

o15
o150
Negative to trace

15–50
150–500
Trace to +

450
4500
+ or greater

AER (mg/24 hours)
PER (mg/24 hours)
ACR(mg/mmol)(mg/g)
PCR(mg/mmol)(mg/g)
Protein reagent strip

Abbreviations: ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; PCR, protein-to-creatinine ratio; PER, protein excretion rate.
Albuminuria and proteinuria can be measured using excretion rates in timed urine collections, ratio of concentrations to creatinine concentration in spot urine samples, andusing reagent strips in spot urine samples. Relationships among measurement methods within a category are not exact. For example, the relationships between AER and ACR
and between PER and PCR are based on the assumption that average creatinine excretion rate is approximately 1.0 g/d or 10 mmol/d. The conversions are rounded for
pragmatic reasons. (For an exact conversion from mg/g of creatinine to mg/mmol of creatinine, multiply by 0.113.) Creatinine excretion varies with age, sex, race and diet;
therefore the relationship among these categories is approximate only. ACR o10 mg/g (o1 mg/mmol) is considered normal; ACR 10–30 mg/g (1-3 mg/mmol) is considered‘‘high normal.’’ ACR 42200 mg/g (4220 mg/mmol) is considered ‘‘nephrotic range.’’ The relationship between urine reagent strip results and other measures depends onurine concentration.

Persistent albuminuria categories
Description and range

GFR categories (ml/min/ 1.73m2)
Description and range

Percentage of US Population by
eGFR and Albuminuria
Category: KDIGO 2012 andNHANES 1999-2006

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30-300 mg/g
3-30 mg/mmol>300 mg/g>30mg/mmol

G1

Normal or high

≥90

55.6

1.9

0.4

57.9

G2

Mildly decreased

60-89

32.9

2.2

0.3

35.4

G3a

Mildly to moderately
decreased

45-59

3.6

0.8

0.2

4.6

G3b

Moderately toseverely decreased

30-44

1.0

0.4

0.2

1.6

G4

Severely decreased

15-29

0.2

0.1

0.1

0.4

G5

Kidney failure

<15

0.0

0.0

0.1

0.1

93.2

5.4

1.3

100.0

Figure 8 | Prevalence of CKD in the USA by GFR and albuminuria. Cells show the proportion of adult population in the USA. Data fromthe NHANES 1999-2006, N ¼ 18,026. GFR is estimated with the CKD-EPI equation and standardized serum creatinine.19 Albuminuria isdetermined by one measurement of ACR and persistence is estimated as described elsewhere.59 Values in cells do not total to values inmargins because of rounding. Category of very high albuminuria includes nephrotic range. Green, low risk (if no other markers of kidneydisease, no CKD); Yellow, moderately increased risk; Orange, high risk; Red, very high risk. ACR, albumin-to-creatinine ratio; CKD, chronic
kidney disease; CKD-EPI, CKD Epidemiology Collaboration; GFR, glomerular filtration rate; NHANES, National Health and Nutrition
Examination Survey. Modified with permission from Macmillan Publishers Ltd: Kidney International. Levey AS, de Jong PE, Coresh J, et al.30
The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int 2011; 80: 17-28;
accessed http://www.nature.com/ki/journal/v80/n1/full/ki2010483a.html

that these very high levels of proteinuria carry a different
risk than lower values within the same category. Further
differentiation after quantification and evaluation would
inform treatment decisions for an individual patient. These
categories serve as an initial assessment and prognostication
tool; further classification is appropriate for specific circumKidney International Supplements (2013) 3, 19–62

stances and is not limited by the initial classification into only
3 categories.
Note that the term ‘microalbuminuria’ is not used and is
discouraged in this classification system. This will require aformal education program and review of existing guidelines
in other disciplines so that consistency of terminology and31chapter 1

Table 8 | CGA staging of CKD: examples of nomenclature and comments
GFR
category

Albuminuria
category

Criterion for CKD

Comment

Diabetic kidney disease
Idiopathic focal sclerosis
Kidney transplant
recipient
Polycystic kidney disease

G5
G2
G2

A3
A3
A1

Decreased GFR, Albuminuria
Albuminuria
History of kidney transplantation

Most common patient in the low clearance clinic
Common cause of nephrotic syndrome in childhood
Best outcome after kidney transplantation

G2

A1

Imaging abnormality

Vesicoureteral reflex
Distal renal tubularacidosis

G1
G1

A1
A1

Imaging abnormality
Electrolyte abnormalities

Most common disease caused by a mutation in a single
gene
Common condition in children
Rare genetic disorder

Hypertensive kidneydiseaseG4

A2

Decreased GFR and albuminuria

CKD presumed due todiabetes and hypertension
CKD presumed due todiabetes and hypertension
CKD presumed due todiabetes and hypertension
CKD cause unknown

G4

A1

Decreased GFR

G2A3Albuminuria

G3a

A1

Decreased GFRUsually due to long-standing poorly controlled
hypertension, likely to include patients with genetic
predisposition- more common in blacks- who should
be referred to nephrologist because of severely
decreased GFRShould be referred to nephrologist because of severely
decreased GFRShould be referred to nephrologist because ofalbuminuria
Very common, may not require referral to nephrologist

G3a

A1

Decreased GFR

May be the same patient as above

Cause

Abbreviations: CGA, Cause, GFR category and albuminuria category; CKD, chronic kidney disease; GFR, glomerular filtration rate.
Note: Patients above the thick horizontal line are likely to be encountered in nephrology practice. Patients below the thick horizontal line are likely to be encountered inprimary care practice and in nephrology practice.

understanding of the changes are universal (see Recommendation 1.4.4.2.1).
Pediatric Considerations

This statement would need to be altered for application inpediatric practice in the following way. In children with CKD
any expression of abnormal urinary protein excretion,
irrespective of the marker:
K must account for variation in that measurement as seen
across age, sex, puberty and or body size (height, weight,
body mass index [BMI]).
K should account for the possibility of tubular versus
glomerular proteinuria dominance dependent on theunderlying disease.
K may utilize proteinuria in place of albuminuria.
There is no set standard encompassing all children withrespect to the normal range of urinary protein (or albumin)
excretion. Values vary across age, sex, race, pubertal status,
the presence of obesity (high BMI) and may be modified byexercise, fever, and posture.60–63
In general, neonates and young infants/ children are both
expected and allowed to have higher urinary losses of bothglomerular and tubular proteinuria due to lack of maturationin the proximal tubular reabsorption of proteins. The roughequivalences for ACR and PCR quoted in the pediatric
literature are similar, but not identical to those quoted in theadult literature. Normal ranges vary but at least one reference
suggests as much as 6-8 mg/m2/hr or 4240 mg/m2/day ofproteinuria as being acceptable at o6 months of age;64
normal ranges for urinary albumin losses are not known at
this age.
32

The normal range of protein excretion for children 6-24
months of age in a 24-hour urine collection is quoted as
being o4 mg/m2/hr (o150 mg/m2/day), whereas the firstmorning spot urine protein sample is said to be normal atlevels of o500 mg/g creatinine (o50 mg/mmol). In children
older than 24 months these values are o4 mg/m2/hr(o150 mg/m2/day) for the 24-hour collection and PCRo200 mg/g creatinine (o20 mg/mmol) in the first morning
urine sample, or a first morning urine ACR o30 mg/g
(o3 mg/mmol).43,65
At all ages, total urinary protein excretion 440 mg/m2/hr(43 grams/1.73 m2/day) is considered to represent ‘nephrotic
range’ loss of protein, with intermediate values, i.e.,
4-40 mg/m2/hr or its equivalent representing abnormal but‘non-nephrotic’ losses.43,65
Children older than 24 months of age are expected toachieve normal (‘adult’) urinary protein values with the
caveat of an exaggerated postural loss of glomerular proteins(albumin) as can commonly be seen in the 2-5% of theadolescent population (i.e., orthostatic proteinuria).62
Based on National Health and Nutrition Examination
Survey III (NHANES III) data from just under 6000 healthy
6-19 year old children using either immunonephelometry orradioimmunoassay, the definition of urinary albumin excretion was determined to be 30-300 mg/24 h collection;
20-200 mg/min in an overnight collection and 30-300 mg/g
creatinine (3-30 mg/mmol) in a first morning urine sample.66
Of note, to date the majority of studies that haveexamined the effects of urinary protein losses or therapeuticinterventions have concentrated on so-called total protein
excretion or random or first morning PCRs. The utilityof measuring the albumin only fraction, and in particular
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quantitating this at the lower level of detection, i.e.,
o30 mg/g (o3 mg/mmol) creatinine, is only now being
investigated in more detail in large pediatric studies. As suchit should be recognized that in children the quantification of
total protein, as compared to the albumin only fraction, may
be the preferred method for assigning risk as it relates tothe presence of urinary protein loss.
In summary, for children older than 2 years of age theassignment of ‘proteinuria’ categories can be used as per the
adult guidelines with the understanding that modification to
the upper limit of expected values may be necessary inconsideration of the factors outlined above. Although there isa preference for reporting albumin values, currently many
clinicians still categorize these children based on total protein
and in the child o2 years of age or the adolescent withdemonstrable orthostatic proteinuria, the current albuminuria categories are unlikely to apply.
1.3: PREDICTING PROGNOSIS OF CKD
1.3.1: In predicting risk for outcome of CKD, identify
the following variables: 1) cause of CKD; 2) GFR
category; 3) albuminuria category; 4) other risk
factors and comorbid conditions. (Not Graded)
1.3.2: In people with CKD, use estimated risk ofconcurrent complications and future outcomesto guide decisions for testing and treatment for
CKD complications (Figure 9). (Not Graded)
1.3.3: In populations with CKD, group GFR andalbuminuria categories with similar relative risk
for CKD outcomes into risk categories (Figure 9).
(Not Graded)
RATIONALE

These statements are worded in this way because for all CKD
complications, prognosis will vary depending on: 1) cause; 2)

GFR; 3) degree of albuminuria; and 4) other comorbid
conditions. The relative strength of each of these factors willvary for each complication or outcome of interest. Risk forkidney disease end points, such as kidney failure and AKI, ispredominately driven by an individual patient’s clinicaldiagnosis, GFR, and the degree of albuminuria or othermarkers of kidney damage and injury. For CVD, risk will be
determined by history of CVD and traditional and nontraditional CVD risk factors. For other conditions, the risk
will be determined by risk factors specific for thoseconditions. For all conditions, the cause of CKD, GFR
category, and albuminuria category will still have important
influence as ‘‘risk multipliers,’’ but will have smaller overall
influence on disease prediction than risk factors specific forthe condition. All these conditions have an impact on life
expectancy and quality of life (QOL) and contribute
substantially to predicting the prognosis of CKD. CKD is
associated with numerous complications directly or indirectly
related to the cause of CKD, decreased GFR, or albuminuria(Table 9).
The risk associations of GFR and albuminuria categories
appear to be largely independent of one another. Therefore,
neither the category of GFR nor the category of albuminuria
alone can fully capture prognosis for a patient with CKD. The
magnitude and gradients of risk across categories of GFR andalbuminuria will likely differ for each specific adverse event.
This heterogeneity across the GFR and ACR grids in RRs fordifferent outcomes makes it impractical to have a simple
hierarchical staging of prognosis across all cells. Thus, thestaging using CGA should be descriptive, but encompassing
the ordered categories of GFR and ACR (Figure 9).
The CGA staging system proposed in this guideline
provides a framework for future recommendations on CKD
clinical management. At present, much of the evidence on
clinical decision making in CKD is based solely on GFR. This
recommendation serves to highlight the multidimensional

Table 9 | Prognosis of CKD: Relationship of outcomes and strength of relationship to Cause (C), GFR (G), Albuminuria (A) andother measures*67,68
Kidney measures
Outcomes

Cause

GFR

Albuminuria

Other measures

Kidney outcomes
GFR decline
Albuminuria rise
AKI
Chronic kidney failure (GFR o15 ml/min/1.73 m2; category G5)

+++
+++
+
+++

+
+
+++
+++

+++
+++
+
+

High BP, male sex, black race, younger age
High BP, diabetes
Older age
Younger age

+
+
++
++

+++
+++
+++
++

+
+
+++
++

Drug exposure, liver disease
VariousOlder age, history of CVD, CVD risk factors
Older age, comorbid conditions

Complications (current and future)
Drug toxicity
Endocrine and metabolic
CVD and mortality
Others (infection, cognitive impairment, frailty, etc)

Abbreviations: AKI, acute kidney injury; BP, blood pressure; CVD, cardiovascular disease; GFR, glomerular filtration rate.
Plus signs indicate the strength of the risk relationship between the CKD characteristic and the outcome: +, somewhat associated; ++, moderately associated; +++, strongly
associated.
*Note that the + designations refer to strength of relationship not strength of evidence to support, and are based on consensus overview by the Work Group members.
Adapted with permission from Uhlig K, Levey AS.68 Developing guidelines for chronic kidney disease: we should include all of the outcomes. Ann Intern Med 2012; 156(8):599-601.

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Persistent albuminuria categories
Description and range

GFR categories (ml/min/ 1.73m2)
Description and range

Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012

G1

Normal or high

≥90

G2

Mildly decreased

60-89

G3a

Mildly to moderately
decreased

45-59

G3b

Moderately toseverely decreased

30-44

G4

Severely decreased

15-29

G5

Kidney failure

<15

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30-300 mg/g
3-30 mg/mmol>300 mg/g>30 mg/mmol

Figure 9 | Prognosis of CKD by GFR and albuminuria category. Green, low risk (if no other markers of kidney disease, no CKD); Yellow,
moderately increased risk; Orange, high risk; Red, very high risk. CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney
Disease: Improving Global Outcomes. Modified with permission from Macmillan Publishers Ltd: Kidney International. Levey AS, de Jong PE,
Coresh J, et al.30 The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int
2011; 80: 17-28; accessed http://www.nature.com/ki/journal/v80/n1/full/ki2010483a.html

aspect of CKD so as to ensure appropriate consideration of
the complexity of the condition.

category of albuminuria) influences prognosis irrespective of
ethnicity or country of origin.

Evidence Base

Implications for Clinical Practice and Public Policy

The evidence base from which these statements arederived includes large observational cohort studies fromdiverse populations. For some outcomes, including
mortality, CVD, and kidney disease progression, metaanalyses have summarized the risk associations. For outcomes that occur predominately in older adults (e.g.,dementia, fracture), the evidence is largely limited to cohortsof older people.
Extensive work by the CKD Prognosis Consortium has
defined the RRs across GFR and albuminuria categories forseveral important outcomes, including all-cause mortality,
CVD, and kidney failure (Figures 6 and 7). Risk increases
incrementally in both directions - down the GFR categories
and across the albuminuria categories. Levels of risk can be
identified and grouped into categories, but they may differ
somewhat for each outcome. Additional research is needed
to map these GFR and albuminuria categories and causeof kidney disease to other important outcomes of CKD(Table 9).

Providers must incorporate cause of kidney disease, GFR
category and albuminuria category in order to better develop
an accurate assessment of an individual’s prognosis related to
CKD. Many providers who are not nephrologists will needguidance in the local methods for requesting and interpretinga urine albumin assessment and an eGFR. Use of risk scores
which are being developed and refined is advised.
Public policy and estimates of total burden of illness in acommunity need to take into account the incidence andprevalence of specific conditions (such as diabetes andcongestive heart failure). In addition, knowledge of distribution of levels of eGFR and ACR may be valuable for resource
planning. Community or health-system based interventions
to reduce the incidence of kidney failure in populations
should be targeted and prioritized based on these 3 criteria.
The primary impact on clinical practice will relate tokidney-specific complications of CKD and referral patterns to
help prevent and manage them. Decisions related to screening and monitoring CKD disorders will be informed andguided by the CGA system. At present, this evidence forissues such as management of anemia, CKD bone andmineral disorders, and acid-base disorders has not beenorganized and presented in this way.
Decisions on screening and referral strategies have major
impact on the costs and quality of health-care. The value ofInternational Relevance

The above statements appear to be robust when applied in
North America, Europe and Asia.30 Thus, it appears for all
methods used to determine GFR and to detect albuminuria,
the use of the 3 parameters (cause, category of GFR and
34

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chapter 1

this revised system of classification is that it will allow theevaluation of different referral patterns and the impact oftreatment strategies in those with diverse CGA assignment. In
this way, we will develop additional evidence which will
inform practice patterns. These will necessarily be developed
locally and reflect the values and economic realities of eachhealth-care system.
Areas of Controversy, Confusion, or Non-consensus andClarification of Issues and Key points

Current clinical practice has not overtly incorporated these 3
variables into all decision making activities. The utility of thesystem will need to be vetted by those referring and those towhom patients are referred. The overt description of the 3
dimensions of diagnosis and staging of kidney disease which
include the cause, the category of GFR and the category ofalbuminuria, should help to inform referral and treatment
patterns of large groups of individuals. Risk calculators for
specific events are under development.
K The
CGA classification system will be useful for
quantifying risk for specific outcomes of CKD but its
utility has not been fully assessed in clinical practice andresearch studies.
K Additional evidence is required before decisions on screening, monitoring, and referral patterns can be fully informed.

Pediatric Considerations

For Recommendation 1.3.1 the rationale and principles
behind this statement would apply to pediatrics though thedata are not available.
Unlike in adults, the knowledge of risk of progression oroutcomes of CKD is less robust in children, with the majorityof such information gleaned from either registry datasets orlongitudinal trials. In a 2008 report of a select group of patientsenrolled by various North American pediatric nephrology
centers in the North American Pediatric Renal Trials andCollaborative Studies (NAPRTCS) registry, 46% of nearly 7100
cases had reached a final ‘end point’ with 86% progressing to
ESRD over their time in the registry.69 Data from theprospective registry and population-based Italian Pediatric
Registry of Chronic Renal Failure (ItalKid) study demonstrated
a risk of progression to ESRD of B68% by age 20 years.70
Cause of CKD. Specific information related to rate ofprogression for all pediatric causes of CKD is not easily
available. However data from the prospective longitudinal
CKiD trial has demonstrated a more rapid decline in renal
function in children whose underlying cause of CKD isclassified as glomerular with an annualized rate of change
in iohexol GFR of 10.5% as compared to those witha non-glomerular cause in whom the annualized rate ofchange is only 3.9%.71 In terms of absolute rates ofchange in measured iohexol GFR this translated, in a
separate analysis from the same dataset, into a medianchange of GFR of 4.3 ml/min/1.73 m2 versus 1.5 ml/min/
1.73 m2 in the glomerular versus non-glomerular groups,
Kidney International Supplements (2013) 3, 19–62

respectively.72 This paper also provides the only current
individual disease-specific estimate of annual decline in apediatric population. Table 10 illustrates that the medianvalues for annualized change in GFR for various diagnosis
categories.
Similarly, a randomized controlled trial (RCT) from
Europe73 examining the effects of diet on rate of progression
demonstrated a statistically significant difference in CrCl
between their glomerular and non-glomerular cohorts at 2
years of follow-up; with the mean decline [SD] in theglomerular group being 10.7 [11.3] versus 8.4 [13.5] ml/
min/1.73 m2 in the non-glomerular patients (P ¼ 0.048).
GFR category. It is also well recognized that there is aninverse relationship between the rates of progression of
kidney disease to the level of kidney function present at that
presentation with more rapid decline seen in patients withlower initial levels of GFR. Staples et al.74 in their retrospective review of the NAPRTCS CKD database involving
nearly 4200 children registered with GFR categories G2-G4(GFR 15-89 ml/min/1.73m2) demonstrated significantly
higher rates of progression, defined by progression to GFR
category G5 (GFR o15 ml/min/1.73m2) or initiation of
dialysis or transplant, for children in GFR categories G3a-G4(GFR 15–59 ml/min/1.73m2) as compared to those withCKD and GFR category G2 (GFR 60–89 ml/min/1.73m2) attime of enrollment: hazard ratio (HR) of GFR categories 3aand 3b (GFR 30–59 ml/min/1.73m2) (GFR category 2 (GFR
60–89 ml/min/1.73m2) ¼ 1.00 as referent): 2.00; 95%
confidence interval (CI) 1.64-2.42; Po0.0001 and HR of
GFR category 4 (GFR 15–29 ml/min/1.73m2): 6.68; 95% CI
5.46-8.18; Po0.0001.
Albuminuria (proteinuria). Several studies have also demonstrated the effect of proteinuria on rate of progression of
CKD in children. Using registry data, and in non-glomerularconditions the ItalKids trial75 demonstrated a significantly
slower decline in CrCl in patients with baseline PCRs ofo200 mg/g (20 mg/mmol) and 200–900 mg/g (20–90 mg/mmol) when compared to those patients with a PCR of
4900 mg/g (490 mg/mmol); slope þ 0.16±3.64 andTable 10 | Annual percentage change in GFR across diagnosis
categories
DiseaseAnnualized percentage change[number of patients]

Focal and segmental
glomerulosclerosis
Hemolytic uremic syndrome
Other glomerular
Obstructive uropathy
Aplastic/hypoplastic/dysplastic
kidneys
Reflux nephropathy
Autosomal recessive polycystic
kidney disease
Other non-glomerular-13.3% [N=34]-1.3% [N=27]-15.5% [N=51]-4.6% [N=109]-3.3% [N=96]-3.8% [N=82]-4.4% [N=18]-2.5% [N=119]

Abbreviation: GFR, glomerular filtration rate.
Data from Furth et al.72

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0.54±3.67 versus 3.61 ±5.47 (P o0.0001). Thistranslated to higher rates of kidney survival over 5 years in
the lower proteinuria groups, 96.7% and 94.1% versus
44.9%, (P o0.01). Multivariate analysis confirmed that thebaseline PCR correlated with a more rapid decline in CrCl forany given level of baseline function.
In a prospective multicenter randomized trial of protein
intake on rates of progression in children aged 2-18 years ofage, Wingen et al. employed the Schwartz equation toestimate CrCl and demonstrated that baseline proteinuria in
multivariate analysis was the most important independent
predictor of change in CrCl. The authors reported a partial
R2 of 0.259 at 2 years follow-up and similar results were
found after the study was extended for a third year.73 Lifetable analysis in this study also suggested a cutoff value of
50 mg/kg/day of proteinuria as a strong predictor of time to a
decline in CrCl410 ml/min/1.73 m2 and found a risk ratio of
4.01 (95% CI 2.23–7.25; Po0.001).
Finally Wong et al.76 used cross sectional data from theprospective longitudinal CKiD trial to demonstrate that evenafter controlling for age, race, BMI, cause of CKD and use of
RAAS antagonists they could expect an average decline inmeasured GFR of 10% for every increase in urinary PCR of
14% (95% CI 10-18%).
Other risk factors and comorbid conditions. Many otherrisk factors and comorbid conditions have also been
associated with greater risk of progression of CKD in adults
but only a few of these have been convincingly proven inchildren due to lack of pediatric prospective trials.
Hypertension is by far the best studied of these risk factors
in children, with clear evidence from multiple sources todocument the value of aggressive BP control on slowing therate of progression of CKD. Wingen et al.73 demonstrated theimportance of systolic BP in rate of progression in both
univariate and multivariate models. In this study Cox
proportional hazards analysis demonstrated a systolic BP
4120 mm Hg was an independent risk for decline in CrCl by
410 ml/min/1.73 m2; risk ratio was 3.1 (95% CI 1.74-5.53;
Po0.001).
The most important prospective pediatric BP trial to date,the Effect of Strict Blood Pressure Control and ACEInhibition on Progression of Chronic Renal Failure in
Pediatric Patients (ESCAPE) study, used ambulatory BP
monitoring (ABPM) and a fixed dose of ramipril plus
additional antihypertensive agents that do not target the
RAAS to assess (as primary outcomes) the time to decline of
50% in GFR or development of ESRD. Their results
demonstrated a 35% reduction in the risk of achieving the
primary end point in the more intensely treated BP: HR 0.65;
95% CI 0.44-0.94; P ¼ 0.02. Further sub-analysis as reported
in the KDIGO BP Guideline10 demonstrated that kidneysurvival was 66.1% at 5 year follow-up in patients withsystolic BPo90th percentile for age whereas it was 41% in thepatients who did not achieve this level of reduction(P ¼ 0.0002); similar numbers were seen if diastolic BP wasthe metric considered.
36

The issue of puberty and its effect on rate of progression
has recently been addressed by the ItalKids investigators.77
While the methodology of their analysis is less than ideal as
they did not determine actual Tanner stages in the majority of
their cohort and used estimated rather than measured GFR,
they do appear to demonstrate a decrease in kidney survival
probability beginning around 10.9 years in girls and 11.6
years in boys with CKD. Of note, the rate of decline in kidneysurvival, using these age points as ‘inflection’ or break points,
is dramatically increased in both sexes based on theirevidence provided in graphical form, although more precise
analyses are not possible from the data provided.
As in adults, other factors for consideration and value inmonitoring in children with respect to risk of progression
include obesity, metabolic acidosis, anemia, calcium-phosphate metabolism, chronic inflammation, diabetes, hyperuricemia, dyslipidemia, and smoking.
The most comprehensive review of many of these factors
in children comes from a retrospective study of the
NAPRTCS CKD database. Staples et al.74 demonstrated thatin a multivariate analysis of nearly 4200 children registeredwith CKD and GFR categories G2-G4 (GFR 15–89 ml/min/
1.73m2), the following factors were significantly associatedwith the risk of CKD progression (defined by progression to
GFR category G5 (GFRo15 ml/min/1.73m2) or initiation of
dialysis or transplant): age; primary disease; GFR category;registration year; hypertension; corrected calcium, phosphorus, albumin, and hematocrit; and as proxies, the use of
medications for anemia and short stature. The ability of thispaper to prove causation or value in treating any of these
conditions in hopes of delaying CKD progression is limited
by its retrospective nature, and the fact that data were
accrued from a voluntary registry.
There is optimism that prospective data from current large
pediatric trials such as CKiD55 and the European Cardiovascular Comorbidity in Children with CKD (4C) trial78 willlead to a better understanding of how risk factors may be
influencing the rate of progression of CKD in children.
For Recommendation 1.3.2 the rationale and principles
behind this statement would apply to pediatrics, though thedata are not available. Insufficient evidence currently exists
with respect to the predictive value of prevalent risk factors to
guide future decisions for testing or treatment for CKD
complications in an individual child.
It is hoped that well powered, prospective trials withadequate follow-up, such as the CKiD55 and European 4C78
trials, will gather sufficient numbers of patients, comorbidities, and outcomes to allow for predictive models to be built
in pediatric CKD that incorporate traditional and nontraditional cardiac risk factors including dyslipidemia andhypertension, proteinuria (albuminuria), specific diseaserelated issues (e.g., diabetes, tubulopathy), prematurity, andbirth weight.
For Recommendation 1.3.3 the rationale and principles
behind this statement would apply to pediatrics, though thedata are not available. Current evidence and a paucity ofKidney International Supplements (2013) 3, 19–62

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numbers do not allow for the statistically relevant categorization of RR for CKD outcomes based solely on GFR andalbuminuria or proteinuria. Again both the CKiD55 andEuropean 4C78 trials may be able to address these shortcomings.

modify risk projections. The diagnosis will be reached bystandard clinical method (i.e., history examination) andspecial investigation, based on knowledge of the common
causes of CKD and their manifestations. Not all evaluations
are required in all patients, and will be directed by clinicalcontext, and resource availability. For most patients thefollowing evaluations are indicated:

1.4: EVALUATION OF CKDReagent strip urinalysis to detect hematuria or pyuria. If
positive, use urine microscopy to detect RBC casts or
WBC casts.
K Ultrasound to assess kidney structure (i.e., kidney shape,size, symmetry and evidence of obstruction) as clinicallyindicated.
K Serum and urine electrolytes to assess renal tubular
disorders, as clinically indicated.
K

1.4.1: Evaluation of chronicity
1.4.1.1: In people with GFR o60 ml/min/1.73 m2 (GFR
categories G3a-G5) or markers of kidneydamage, review past history and previous
measurements to determine duration of kidneydisease. (Not Graded)K
If duration is 43 months, CKD is confirmed. Follow recommendations for CKD.
K
If duration is not 43 months or unclear,
CKD is not confirmed. Patients may have
CKD or acute kidney diseases (includingAKI) or both and tests should be
repeated accordingly.
RATIONALE

When evidence of CKD is first ascertained, proof ofchronicity can be obtained or confirmed by:(i) review of past measurements of GFR;(ii) review of past measurements of albuminuria orproteinuria and urine examinations;(iii) imaging findings such as reduced kidney size andreduction in cortical thickness;(iv) pathological findings such as fibrosis and atrophy;(v) medical history especially duration of disorders known
to cause CKD;(vi) repeat measurements within and beyond the 3 month
point.
Chronicity should not be assumed as AKI can present withsimilar abnormalities.
Pediatric Considerations

See Pediatric Considerations for next section.
1.4.2: Evaluation of cause
1.4.2.1: Evaluate the clinical context, including personaland family history, social and environmental
factors, medications, physical examination,
laboratory measures, imaging, and pathologic
diagnosis to determine the causes of kidneydisease. (Not Graded)
RATIONALE

Once the presence of CKD is proven it is essential to establish
a cause for this which will inform specific management andKidney International Supplements (2013) 3, 19–62

Many individuals found to have CKD will not have a
primary kidney disease but kidney damage caused by diabetes
mellitus, vascular disease, and hypertension. The issue for theclinician will be to decide whether the presence of these is asufficient explanation and if not, to investigate further. The
prevalence of other conditions will vary depending on region,age, and other factors.
It is beyond the scope of this guideline to describe how
specific diagnoses are reached but non-nephrologists in thefirst instance should review the family history, medications,
symptoms and signs for manifestations of systemic diseases.
Urinalysis should be performed, along with imaging of thekidneys if obstruction of the urinary tract or polycystic
kidney disease is considered.
Pediatric Considerations

For Recommendations 1.4.1.1 and 1.4.2.1, the statements
would need to be altered for application in pediatric practicein the following way.
In any child with GFRo60 ml/min/1.73 m2 (or morethan 1 SD below expected for their age and sex) or withmarkers of kidney damage, a complete review of their pasthistory and previous measurement or estimate of renal
function and full consideration of the clinical context,
including prenatal history, drug exposures of fetus or mother,genetic conditions, coincident organ abnormalities, physicalexamination, fetal and post-natal laboratory measures
including amniotic fluid, pre- and post-natal imaging
and pathologic diagnosis including those of the fetus andplacenta should be used to determine the cause(s) of kidneydisease.
As noted in Pediatric Considerations for Recommendation
1.1.1, developmental renal abnormalities account for as manyas 30-50% of the children with CKD.42 A careful review of all
fetal or maternal exposures, genetic risks factors, and any
relevant information on the intrauterine environment during
gestation are all relevant to the determination of the presenceof CKD either prior to or present immediately at the time ofdelivery. An infant may be born with CKD, leading to37

chapter 1

immediate classification within the CGA framework – up to
and including that of dialysis dependency.
1.4.3 Evaluation of GFRThis section describes the various methods by which GFR
can be estimated. We describe laboratory techniques that satisfy
the requirements for robust result reporting and we compare
the accuracy of available equations for the purpose of reportingeGFR using a single equation where applicable. We emphasize
equations based on standardized measurements of SCr, but also
consider newly developed equations based on standardized
measurements of serum cystatin C (SCysC) because they arebeing introduced into clinical practice. We encourage practitioners to have a clear understanding of the value andlimitations of both filtration markers, the importance ofstandardization of assays for both, and to understand thatwhen an accurate assessment of kidney function is required,direct measurement should be undertaken.
1.4.3.1: We recommend using serum creatinine anda GFR estimating equation for initial assessment.
(1A)
1.4.3.2: We suggest using additional tests (such as cystatin
C or a clearance measurement) for confirmatory
testing in specific circumstances when eGFR basedon serum creatinine is less accurate. (2B)

is warranted in specific circumstances when GFR estimates
based on SCr are thought to be inaccurate and when
decisions depend on more accurate knowledge of GFR, suchas confirming a diagnosis of CKD, determining eligibility forkidney donation, or adjusting dosage of toxic drugs that are
excreted by the kidneys.79 The choice of confirmatory test
depends on the clinical circumstance and the availability ofmethods where the patient is treated.
Pediatric Considerations

For Recommendation 1.4.3.1, the statements would need
to be altered for application in pediatric practice in thefollowing way. The use of SCr and a recently derived pediatricspecific GFR estimating equation, which incorporates aheight term,80 is preferred over the use of SCr alone in theinitial assessment of pediatric renal function.
For Recommendation 1.4.3.2, this guideline is fully
applicable in pediatrics.

1.4.3.3: We recommend that clinicians (1B):K
use a GFR estimating equation to derive
GFR from serum creatinine (eGFRcreat)rather than relying on the serum creatinine
concentration alone.
K
understand clinical settings in which
eGFRcreat is less accurate.

RATIONALERATIONALE

These statements specifically address the need to ensure that
estimating equations are put into routine clinical practice,and that clinicians understand the utility of further evaluation with additional methods if required.
GFR is measured by the clearance of an exogenous or
endogenous filtration marker.27 All clearance methods arecomplex so in clinical practice, GFR is estimated from theserum concentration of the endogenous filtration marker
creatinine. Cystatin C is an alternative endogenous filtration
marker; other filtration markers are also under evaluation.
The principles of GFR estimation are discussed in therationale for recommendations regarding the use of creatinine as a filtration marker but the concepts apply to GFRestimation from all endogenous filtration markers. Specificcomments about GFR estimation using cystatin C arepresented separately.
For most clinical circumstances, estimating GFR from SCr
is appropriate for diagnosis, staging, and tracking the
progression of CKD. However, like all diagnostic tests,
interpretation is influenced by varying test characteristics inselected clinical circumstances and the prior probability of
disease. In particular, an isolated decreased eGFR inotherwise healthy individuals is more likely to be false
positive than in individuals with risk factors for kidneydisease or markers of kidney damage. Confirmation of
decreased eGFR by measurement of an alternative endogenous filtration marker (cystatin C) or a clearance measurement

Estimating GFR from the SCr concentration alone requires
implicit judgments that are difficult in routine clinical care,including reciprocal transformation, consideration of the
non-GFR determinants, and conversion to the GFR scale.
Using GFR estimating equations provides a more direct
assessment of GFR than SCr alone. The SCr concentration is
influenced by GFR and other physiological processes,
collectively termed ‘‘non-GFR determinants,’’ including
creatinine generation by muscle and dietary intake, tubular
creatinine secretion by organic anion transporters, andextrarenal creatinine elimination by the gastrointestinal tract(Figure 10).
GFR estimating equations are developed using regression torelate the measured GFR to steady state SCr concentration anda combination of demographic and clinical variables assurrogates of the non-GFR determinants of SCr. By definition,
GFR estimates using SCr concentration are more accurate inestimating measured GFR than the SCr concentration alone in
the study population in which they were developed. Sources oferror in GFR estimation from SCr concentration include nonsteady state conditions, non-GFR determinants of SCr,measurement error at higher GFR, and interferences withthe creatinine assays (Table 11). GFR estimates are less precise
at higher GFR levels than at lower levels.
The clinician should remain aware of caveats for any
estimating equation which may influence the accuracy in agiven individual patient.

38

Kidney International Supplements (2013) 3, 19–62

chapter 1

Because of the physiologic and statistical considerations indeveloping GFR estimating equations, GFR estimates are lessprecise at higher GFR levels than at lower levels. In principle,
equations based on multiple endogenous filtration markers

can overcome some of the imprecision of GFR estimates athigher levels, due to cancellation of errors from noncorrelated non-GFR determinants.
Pediatric Considerations

This guideline is fully applicable in pediatrics.

Figure 10 | Determinants of the serum level of endogenous
filtration markers. The plasma level (P) of an endogenous
filtration marker is determined by its generation (G) from cells anddiet, extrarenal elimination (E) by gut and liver, and urinary
excretion (UV) by the kidney. Urinary excretion is the sum offiltered load (GFR X P), tubular secretion (TS), and reabsorption(TR). In the steady state, urinary excretion equals generation andextrarenal elimination. By substitution and rearrangement, GFR
can be expressed as the ratio of the non-GFR determinants (G, TS,
TR, and E) to the plasma level. GFR, glomerular filtration rate.
Reprinted with permission of American Society of Nephrology,
Measured GFR as a confirmatory test for estimated GFR, Stevens
LA, Levey AS.79 J Am Soc Nephrol 20: 2305-2313, 2009; permission
conveyed through Copyright Clearance Center, Inc.; accessed
http://jasn.asnjournals.org/content/20/11/2305.full.pdf

1.4.3.4: We recommend that clinical laboratories should (1B):K
measure serum creatinine using a specificassay with calibration traceable to the international standard reference materials andminimal bias compared to isotope-dilution
mass spectrometry (IDMS) reference methodology.
K
report eGFRcreat in addition to the serum
creatinine concentration in adults andspecify the equation used whenever reportingeGFRcreat.
K
report eGFRcreat in adults using the 2009
CKD-EPI creatinine equation. An alternative
creatinine-based GFR estimating equation is
acceptable if it has been shown to improveaccuracy of GFR estimates compared to the2009 CKD-EPI creatinine equation.
When reporting serum creatinine:K
We recommend that serum creatinine concentration be reported and rounded to thenearest whole number when expressed as
standard international units (lmol/l) androunded to the nearest 100th of a whole
number when expressed as conventional units(mg/dl).

Table 11 | Sources of error in GFR estimating using creatinine
Source of error

ExampleNon-steady state
Non-GFR determinants of SCr that differ from study populations
in which equations were developed
Factors affecting creatinine generation

K

AKI

Race/ethnicity other than US and European black and white
Extremes of muscle mass
K Extremes of body size
K Diet and nutritional status
K high protein diet
K creatine supplements
K Muscle wasting diseases
K Ingestion of cooked meat
K Decrease by drug-induced inhibition
K trimethoprim
K cimetidine
K fenofibrate
K Dialysis
K Decrease by inhibition of gut creatininase by antibiotics
K Increased by large volume losses of extracellular fluid
Higher biological variability in non-GFR determinants relative to GFR
K Higher measurement error in SCr and GFRK Spectral interferences (e.g., bilirubin, some drugs)
K Chemical interferences (e.g., glucose, ketones, bilirubin, some drugs)
K

K

Factors affecting tubular secretion of creatinine

Factors affecting extra-renal elimination of creatinine

Higher GFR
Interference with creatinine assay

Abbreviations: AKI, acute kidney injury; GFR, glomerular filtration rate; SCr, serum creatinine.

Kidney International Supplements (2013) 3, 19–62

39

chapter 1

When reporting eGFRcreat:K
We recommend that eGFRcreat should bereported and rounded to the nearest whole
number and relative to a body surface area of
1.73 m2 in adults using the units ml/min/
1.73 m2.
K
We recommend eGFRcreat levels less than
60 ml/min/1.73 m2 should be reported as‘‘decreased.’’RATIONALE

The statement is worded this way to acknowledge thatcalibration of assays is essential to interpretation of kidney
function measures. This recommendation is directed tolaboratories with the intent to clarify the details of suchcalibration and the use of specific equations so as to facilitate
international standardization.81
There are numerous assay methods for creatinine for use
in clinical laboratories. Variation in assigned values for SCr
concentration among methods is greater at low concentrations, corresponding to high levels of GFR. Variation in
assays at low SCr concentrations contributes to imprecision
of GFR estimates at high GFR levels.
Currently available assays fall into two broad categories, thealkaline picrate (Jaffe) assay and enzymatic assays. In general,
enzymatic assays are less biased compared to a standardized
reference material and less susceptible to interferences. All assays
are available on a number of platforms.
We recommend that laboratories use assays that are
traceable to pure creatinine standards via a valid calibration
hierarchy and that are specific and minimally-biased
compared with isotope-dilution mass spectrometry (IDMS)
reference method results. Results should be traceable toreference materials and methods listed on the Joint
Committee for Traceability in Laboratory Medicine (JCTLM)
database. Ideally laboratories should move to enzymatic
assays for creatinine measurement: as a minimum, the use of
traditional kinetic or end point Jaffe assays should cease andbe replaced with IDMS aligned Jaffe methods.
Clinical laboratory information systems generally haveaccess to patient age and sex and thus can report eGFR basedon SCr age and sex, thus providing the clinician with the test
result in units which are recommended for interpretation.
Estimated GFR is now reported together with SCr whencreatinine is ordered in more than 75% of clinicallaboratories in the US.82 In the UK, 93% of NHS laboratories
report eGFR with SCr,83 as is the case in Australia, Canada,
and many European countries.
Selection of a single equation for use, where applicable,
would facilitate communication among providers, patients,
researchers and public health officials. Criteria for selection
should be based on accuracy compared to measured GFR and
usefulness in clinical care and public health.
The interpretation of measured and eGFR is based oncomparison to normative values, which are adjusted for BSA
because of the physiologic matching of GFR to kidney size,
40

which is in turn related to BSA. The value of 1.73 m2 reflects
the average value of BSA of 25-year old men and women in
the USA in 1927.84 While it is known that modern
populations may have different normal values for BSA, the1.73 m2 value will be maintained for normalization purposes.
Drug dosing should be based on GFR which is not
adjusted for BSA. The effect of drug dosing based on GFRadjusted for BSA compared to GFR unadjusted for BSA has
not been studied rigorously and more precise recommendations are not available.
Flagging decreased values for eGFR can alert clinicians to
the possibility of AKD or CKD, and may indicate the need for
additional investigations or treatments, including adjustmentof doses of drugs that are excreted by the kidney. However,values for GFR between 60 and 89 ml/min/1.73 m2 are mildly
decreased compared to the usual values in young healthypeople. Thus it is important that clinicians appreciate thateGFR values that are not flagged because they are 460 ml/
min/1.73 m2 are not necessarily normal.
Evidence Base

Numerous equations have been developed to estimate GFRor CrCl in adults. In general, GFR estimating equations using
creatinine include age, sex, race, and body size as surrogatesfor creatinine generation by muscle. For our review of GFRestimating equations, we only considered equations that weredeveloping using assays that were traceable to reference
methods and study populations in which SCr concentration
was measured using traceable assays (Supplemental
Table 1).85
Based on published data, only the Modification of Diet in
Renal Disease (MDRD) Study equation, Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equationand modifications of these equations were developed using
creatinine assays traceable to the international referencematerial for creatinine (Table 12).86,87 The Cockcroft andGault formula and others were developed before standardization of creatinine assays but cannot be re-expressed
for use with standardized creatinine assays (Supplemental
Table 2).
The MDRD Study equation was developed in 1999 and iscurrently recommended for eGFR reporting in adults by the
National Kidney Disease Education Program (NKDEP) andby the Department of Health in the UK. It uses standardized
SCr, age, sex, and race (black versus white and other) toestimate GFR adjusted for BSA (ml/min/1.73 m2).86,94
Because of imprecision at higher GFR, NKDEP recommends
that eGFR Z60 ml/min/1.73 m2 computed using the MDRD
Study equation not be reported as a numeric value. For asimilar reason, the UK Department of Health recommends
not reporting eGFR 490 ml/min/1.73 m2 using the MDRD
Study equation as a numeric value.
The CKD-EPI equation was developed in 2009 and uses
the same four variables as the MDRD Study equation.87 TheCKD-EPI equation had less bias than the MDRD Studyequation, especially at GFRZ60 ml/min/1.73 m2, a small
Kidney International Supplements (2013) 3, 19–62

Equation name

Kidney International Supplements (2013) 3, 19–62

CKD-EPI equation

Imai et al.89

Japanese-modified MDRD
equation

Outside of North America, Europe, and Australia
Horio et al.88
MDRD equation with Japanesecoefficient

Levey et al.87

MDRD equation without ethnicity
factor*North America, Europe, and Australia
Levey et al.86
MDRD equation

Study

413 Japanese patients in 80
medical centers (mean age, 51.4 y)

248 inpatients with CKD for
estimating and determining thecoefficient of the MDRD Studyequation for Japanese patients(mean age, 50.1 y)

0.741  175  SCr1.154  age0.203
 0.742 (if female)8254 participants from 6 researchstudies and 4 clinical populations(mean age, 47 y)

1628 patients enrolled in the
MDRD Study (mean age, 50.6 y)

Development and internal
validation population, N

0.808  175  SCr1.154  age0.203
 0.742 (if female)

141  min(SCr/k, 1)a  max(SCr/k,1)1.209  0.993age  1.018(if female)  1.159 (if black),
where k is 0.7 for females and 0.9 formales, a is 0.329 for females and 0.411
for males, min indicates the minimum of
SCr/k or 1, and max indicates the
maximum of SCr/k or 1.

175  SCr1.154  age0.203  0.742 (if female)

175  SCr1.154  age0.203  0.742 (if female) 1.212 (if black)

Equation

Inulin (urine) GFR measured in ml/
min per 1.73 m2 (ND fordevelopment or internal validation
set)
Inulin (urine) GFR measured in ml/
min per 1.73 m2 (ND fordevelopment or internal validation
set)

125
I-Iothalamate (urine); GFR
measured in ml/min per 1.73 m2;
mean GFR, 68 ml/min per 1.73 m2(SD, 40)125
I-Iothalamate (urine); GFR
measured in ml/min per 1.73 m2;
mean GFR, 39.8 ml/min per 1.73 m2(SD, 21.2)

GFR measurement method

Table 12 | Equations based on serum creatinine assays in adults that are traceable to the standard reference material

SCr levels were measured by using a Hitachi
enzymatic creatinine assay and the values
obtained were compared with those of theCleveland Clinic.
SCr levels were assayed by both enzymaticand noncompensated kinetic Jaffe methods
for the 116 patients in the inulin clinicalstudy and by an enzymatic method for the
132 inpatients at Tokyo Women’s Medical
University between 2003 and 2004 and the
168 patients with CKD at the University ofTsukuba Hospital from 1988 to 1994. The
SCr levels of the samples from the 101
patients from Tokyo Women’s Medical
University between 2001 and 2002 were
measured by a noncompensated kinetic
Jaffe method. SCr levels used in the inulin
clinical trial were simultaneously measured
by both the noncompensated kinetic Jaffe
method and enzymatic method at theInternational Organization forStandardization–approved central
laboratory. SCr values from thenoncompensated Jaffe method were 0.207
higher than those from the enzymatic
method throughout the measured range,
based on calibrated standards which wereindirectly calibrated with IDMS.

SCr values were recalibrated tostandardized SCr measurements at the
Cleveland Clinic by using a Roche enzymatic
assay (Roche–Hitachi P-Module instrumentwith Roche Creatininase Plus assay,
Hoffman-La Roche, Basel, Switzerland).

Samples from MDRD Study were assayedfrom 1988 to 1994 with the Beckman
Synchron CX3 kinetic Jaffe assay (Global
Medical Instrumentation, Inc., Ramsey,
Minnesota). Samples were reassayed in
2004 with the same instrument. The
Beckman assay (Global Medical
Instrumentation, Inc., Ramsey, Minnesota)
was calibrated to the Roche enzymatic
assay (Roche Diagnostics, Basel,
Switzerland), which is traceable to an IDMS
assay at NIST.

SCr assay method

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41

42

90

Levey et al.92

250 Thai patients with CKD whowere in stable condition (meanage, 59.5 y)

454 patients from 9 renal institutesof university hospitals located in 9
geographic regions of China (meanage, 49.9 y)1628 patients whose GFR was
measured as part of the MDRD
Study (mean age, 50.6 y)

413 Japanese patients in 80
medical centers; data collectedfrom 1 December 2006 to 20 April
2007 (mean age, 51.4 y)

Tc-DTPA (plasma) GFR
measured in ml/min per 1.73 m2(ND for development or internal
validation set)

99m

125
I-Iothalamate (urine)
GFR measured in ml/min per
1.73 m2; mean GFR, 39.8 ml/min
per 1.73 m2 (SD, 21.2)
99m
Tc-DTPA (plasma) GFR
measured in ml/min per 1.73 m2(ND for development or internal
validation set)

Inulin (urine)
Mean GFR, 59.1 ml/min per
1.73 m2 (SD, 35.4)

Inulin (urine) GFR measured in
ml/min per 1.73 m2 (ND fordevelopment or internal validation
set)

Tc-DTPA (plasma); GFR
measured in ml/min per 1.73 m2(ND for development or internal
validation set)

99m

GFR measurement method

Fasting SCr levels measured by using a
Roche enzymatic assay (Roche Diagnostics,
Indianapolis, IN) and values adjusted byusing IDMS reference SCr (SRM 967) from
NIST. SCr also measured by a Roche kinetic
Jaffe assay (Roche Diagnostics, Indianapolis,
IN) without adjustments to IDMS reference.
SCr levels obtained from enzymatic andJaffe assays used in each estimated GFRequation accordingly.

SCr levels measured by using Hitachi kinetic
Jaffe assay and values calibrated to theCleveland Clinic Laboratory.

Serum and urine creatinine levels measured
by using kinetic Jaffe assay.

SCr levels measured by Hitachi enzymatic
assay (Hitachi, Tokyo, Japan) and values
obtained compared with those of theCleveland Clinic.

Fasting SCr levels measured by using a
Roche enzymatic assay (Roche Diagnostics,
Indianapolis, IN) and values adjusted byusing IDMS reference SCr (SRM 967) from
NIST. SCr levels also measured by a Roche
kinetic Jaffe assay Roche (Roche
Diagnostics, Indianapolis, IN) without
adjustments to IDMS reference. SCr levels
obtained from enzymatic and Jaffe assays
were used in each estimated GFR equationaccordingly.
SCr levels measured by Hitachi enzymatic
assay and values obtained compared withthose of the Cleveland Clinic.

SCr assay method

Abbreviations: CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate; IDMS, isotope-dilution mass spectrometry; JSN-CKDI, Japanese Society of NephrologyChronic Kidney Disease Initiatives; MDRD, Modification of Diet in Renal Disease; ND, not documented; NIST, National Institute of Standards and Technology; SCr, serum creatinine; SRM, standard reference material; Tc-DTPA,
technetium-diethylenetriamine pentaacetic acid.
*African American coefficient of the MDRD Study equation.
wDerived by using the original MDRD equation (with the 186 coefficient). For use with an SCr traceable to the SRM, the 186 coefficient should be replaced with the 175 coefficient from the reexpressed MDRD equation.
zDerived by using the original MDRD equation (with the 186 coefficient). For use with an SCr traceable to the SRM, the SCr should be replaced by SCr  0.95, which represents the calibration factor relating the SCr assay in the
Cleveland Clinic laboratory to the standardized SCr assay.
Reprinted with permission from Earley A, Miskulin D, Lamb EJ, et al.85 Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med 2012; 156(11): 785-795.

Praditpornsilpa et al.90

206  SCr1.234  age0.227  0.803 (if female),with SCr calibrated to the Cleveland Clinic
375.5  SCr0.848  age0.364  0.712 (if female);r2 = 0.869

186  SCr1.154  age0.203  0.742 (iffemale)  1.227 (if Chinese), with SCr calibrated
to the Cleveland Clinic

3-variable Japanese equation(equation 4)
Original MDRD equation, calibrated
to the Cleveland Clinic creatinine
measurements (study equation 2)w

Original MDRD equation, calibrated
to Cleveland Clinic creatinine
measurements, with Chinese
coefficient (study equation 4)w
Chinese equation (study
equation 6)zThai estimated GFR equation

194  SCr1.094  age0.287
 0.739 (if female)
186  SCr1.154  age0.203
 0.742 (if female)

JSN-CKDI equation (equation 2)

Matsuo et al.91

Ma et al.93

0.813  141  min(SCr/k, 1)a max(SCr/k, 1)1.209  0.993age
 1.018 (if female)  1.159 (if black),
where k is 0.7 for females and 0.9 formales, a is 0.329 for females and 0.411
for males, min indicates the minimumof SCr/k or 1, and max indicates the
maximum of SCr/k or 1.
171  SCr1.004  age0.287
 0.782 (if female)
413 Japanese patients in 80
medical centers (mean age, 51.4 y)0.203250 cases of Thai patients with CKD
patients who were in stablecondition (mean age, 59.5 y)1.154Development and internal
validation population, N

175  SCr
 age
 0.742(if female)  1.129 (if Thai)

Equation

CKD-EPI equation with Japanesecoefficient

MDRD equation with Thai
coefficient

Equation nameHorio et al.88

Praditpornsilpa et al.

Study

Table 12 | Continued

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chapter 1

Figure 11 | Performance of the CKD-EPI and MDRD Study equations in estimating measured GFR in the external validation data set.
Both panels show the difference between measured and estimated versus estimated GFR. A smoothed regression line is shown with
the 95% CI (computed by using the lowest smoothing function in R), using quantile regression, excluding the lowest and highest
2.5% of estimated GFR. To convert GFR from ml/min per 1.73 m2 to ml/s per m2, multiply by 0.0167. CKI-EPD, Chronic Kidney Disease
Epidemiology Collaboration; CI, confidence interval; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. Reprinted
with permission from Levey AS, Stevens LA, Schmid CH, et al.87 A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;
150(9): 604-612.

improvement in precision, and greater accuracy (Figure 11).
Most but not all studies from North America, Europe andAustralia show that the CKD-EPI equation is more accurate
than the MDRD Study equation, especially at higher GFR(Table 13),85 which enables reporting of numeric values
across the range of GFR. At this time, large commercial
clinical laboratories in the US have changed from using the
MDRD Study equation to the CKD-EPI equation for eGFR
reporting.
Lesser bias of the CKD-EPI equation compared to the
MDRD Study equation reflects higher eGFR throughout
most of the range for age and creatinine, especially inyounger individuals, women and whites. Higher eGFR resultsin lower prevalence estimates for CKD in these groups(Figure 12), with more accurate risk relationships of lower
eGFR and adverse outcomes (Figure 13).107
To account for possible differences in muscle massand diet according to race, ethnicity and geographic region,
the MDRD Study and CKD-EPI equations have been
modified for use in other racial and ethnic groups andin other countries. In some, but not all studies, thesemodifications are associated with increased accuracy(Table 14), and should be used in preference to unmodified
equations. Where tested, the CKD-EPI equation and its
modifications were generally more accurate than the MDRD
Study and its modifications. In the absence of specificmodifications for race, ethnicity, or regional difference, it isreasonable to use the CKD-EPI equation for GFR estimation.
Reliance upon SCr alone is not an appropriate alternative
since the uncertainty about the effect of non-GFR determinants affects interpretation of SCr as much as it affects
interpretation of eGFR. More widespread testing of GFRestimating equations is necessary to resolve uncertainties
about the need for racial, ethnic, and geographic modifications.108
Kidney International Supplements (2013) 3, 19–62

Pediatric Considerations

This recommendation would need to be altered for application in pediatric practice in the following way.
K Creatinine measurements in all infants and children
should be derived from methods that minimize confounders and are calibrated against an international
standard.
K eGFRcreat may only be reported when the height of thechild is known by the laboratory.
K If reporting eGFRcreat laboratories should utilize themost current and accurate pediatric derived equations
based on the demographic and laboratory markers
available.
In infants or small children the level of creatinine whenmeasured is often below that of the normal ‘bottom range’ of
the adult assay. As such laboratories measuring creatinine ininfants or small children must ensure their lower calibration
samples include the lowest end of the expected range ofvalues for the group of interest.
As the majority and the most accurate of the publishedpediatric eGFRcreat formulas require height, standard laboratory reporting of eGFRcreat is neither practical nor recommended in children. In a pediatric CKD population, andusing the plasma disappearance of iohexol as the gold
standard measure of GFR, Schwartz et al. derived a numberof novel GFR prediction equations.80 Their analysis demonstrated the importance of the height/SCr variable in the
population as it provided the best correlation with theiohexol GFR (R2 ¼ 65%). The simplest of such formula, using
only height and SCr and a constant of either 41.3 or 0.413
depending on whether height was expressed as meters or
centimeters respectively, provided 79% of estimated GFRs
within 30% of the iohexol values and 37% of estimated GFRs
within 10% of the iohexol values.
43

44

The Netherlands

The Netherlands

United States

Michels
et al.97

Tent et al.98

Kukla et al.99

Australian patients referred for routine GFR
169
measurements (women, 43%; mean age, 61 y)Australia

Jones andImam102 andJones103

170

Patients with stable renal function after
transplantation (women, 40%; white, 99%;
mean age, 49 y)GermanyPöge et al.101

207

Stable KTRs (women, 36%; white, 92%;
receiving trimethoprim, 19%)

81 on steroid-free
immunosuppression at
1y

107 onsteroid-free
immunosuppression
early
posttransplantation

253 after
donation

253 before
donation

271

White et al.100 Canada

KTRs receiving immunosuppression (women,
40%; white, 86%; mean age, 49 y; receiving
trimethoprim, 100%)

Living kidney donors who donated from1996–2007 (women, 57%; white, 100%; meanage, 50 y)

Potential kidney donors and adults who
underwent GFR measurement for clinicalreasons at the Academic Medical Center in
Amsterdam (women, 56%; black, 12%; meanage, 44 y)

425

United States

Lane et al.96

Patients before and after nephrectomy forcauses other than donation at the Cleveland
Clinic (women, 93%; white, 91%; black, 7%;
median age, 58 y)

External validation set comprising 16 studies
3896(women, 45%; white or other, 87%; black, 10%;Hispanic, 2%; Asian, 2%; mean age, 50 y;diabetes, 28%; donor, 16%; KTRs, 29%)

Patients, N
5238

United States

Population

Levey et al.87

Country

Adults who underwent an outpatient
iothalamate clearance at the Mayo Clinic in
Rochester, Minnesota (women, 45%; African
American, 2%; mean age, 56 y; donor or
potential donor, 13%; KTR, 26%)

Study

Murata et al.95 United States

Tc-DTPA (plasma)

Tc-DTPA (plasma)

99m

99m

Tc-DTPA (plasma)

I-Iothalamate (urine)

99m

125

I-Iothalamate (urine)

I-Iothalamate (urine)

125

125

I-Iothalamate (urine)

125

125
I-Iothalamate(urine) and others

I-Iothalamate (urine)

Reference standard
125

75 (IQR, 5 to 150)

39.6 (IQR, 11.8 to 82.9)

58 ( 22)56.8 (17.7)

55.5 (17.0)

73 ml/min (13)115 ml/min (20)78.2 ml/min (33.4)

50 (IQR, 29 to 69)

68 (36)55.9 (29.7)

Value (SD), ml/min per
1.73 m2

Measured GFREquation

MDRD
CKD-EPI

Roche Jaffe assay (Roche, Australia)
with demonstrated IDMS alignment

Jaffe assay on Dimension RxLTM
analyzer (Dade Behring, Marburg,
Germany); assay adjusted forcalibration with the IDMS method

MDRD
CKD-EPIMDRD
CKD-EPI

For the reexpressed MDRD Study and MDRD
CKD-EPICKD-EPI equations, SCr adjusted to
IDMS standard

MDRD
CKD-EPI

Measured by using a Jaffe CXRMDRDSynchron method and, later, an IDMS- CKD-EPI
traceable assay; Jaffe assay-based SCrconverted to IDMS-traceable values

MDRD
CKD-EPI

Roche enzymatic assay or Jaffe assay MDRD
on MEGA analyzer (Merck KGaA,CKD-EPI
Darmstadt, Germany); both methods
calibrated to reference standard at
the Cleveland Clinic

Hitachi enzymatic assay (Hitachi H911; MDRD
Boehringer Mannheim, Mannheim,
CKD-EPI
Germany) validated against IDMS

Measured at the Cleveland Clinic;
assay standardized against NIST

Roche enzymatic assay (Roche–Hitachi MDRD
P-Module instrument with RocheCKD-EPI
Creatininase Plus assay, Hoffman-La
Roche, Basel, Switzerland) recalibrated
to standardized SCr at the Cleveland
ClinicRoche Jaffe assay (Roche P- or DMDRD
Modular or Roche Cobas C501 withCKD-EPI
Roche Creatininase Plus assay; Roche
Diagnostics, Indianapolis, IN) withdemonstrated IDMS alignment

SCr calibration and assay

GFR estimation

Table 13 | Performance comparison of creatinine-based GFR estimating equations in North America, Europe, and Australia

3**1.5**

4.49
8.07

7.4
5.2

2.40
6.91

81
86

71.8
64.1

10.0z
10.9z

ND

79 (73 to 84)
84 (78 to 88)

14.4||
15.7||

75.0
66.7

71.7
58.5

17.9y
21.1y

15.8y
17.3y

71 (65 to 76)
89 (85 to 93)

12 (9 to 15)||
12 (10 to 16)||15 ml/min(14 to 16)
11 ml/min(9 to 11)
8.23
13.30

73 (68 to 79)
89 (85 to 93)

81.2
84.5

19.9z
12.1z

20 (14 to 26)||
18 (14 to 22)||758080.6 (79.5 to
82.0)
84.1 (83.0 to
85.3)

77.6
78.4

P30
(95% CI),%z

15.0||
13.8||

0.274 (0.265
to 0.283)y
0.250 (0.241
to 0.259)yND

Precision(95% CI)w

Results

22 ml/min(20 to 25)
14 ml/min(11 to 16)

14.6 ml/min
12.3 ml/min

1.0
1.7

5.5 (5.0 to5.9)
2.5 (2.1 to
2.9)

4.1
0.7

Bias (95% CI),
ml/min per
1.73 m2*

chapter 1

Kidney International Supplements (2013) 3, 19–62

Country

Continued

NorwayKidney International Supplements (2013) 3, 19–62

Population

Patients, N

Patients with cancer who were referred for
determination of GFR before chemotherapy(women, 57%; mean age, 62 y)

185

Patients participating in the 6th Tromsø
1621
population survey who had no previous
myocardial infarction, angina, stroke, diabetes,or renal disease (women, 51%; mean age, 57 y)

White adults with and without kidney disease 356(with kidney disease, 49%; women, 41%; meanage, 47 y; diabetic nephropathy, 26 cases;
glomerulonephritis, 40 cases; PKD, 15 cases)

Reference standard

85.1 (20.3)

51

Cr-EDTA (plasma)

91.7 (14.4)

71.5 (36.3)

Iohexol (plasma)

Inulin (plasma)

Value (SD), ml/min per
1.73 m2

Measured GFREquation

Jaffe (Abbott Architect C systems
MDRD
8000, reagent 7D64; Abbott Park,CKD-EPI
Illinois) method standardized to IDMS

Hitachi enzymatic method (CREA Plus; MDRD
Roche Diagnostics, Mannheim,
CKD-EPI
Germany) standardized against IDMS

Kinetic Jaffe assay (Bayer Express Plus; MDRD
Siemens, Munich, Germany)
CKD-EPI
standardized to NIST

SCr calibration and assay

GFR estimation

0.81 (IQR
1.56 to 3.19)
1.16 IQR(0.76 to
3.09)

1.3 (0.4 to 2.1)
2.9 (2.2 to 3.5)

5.2
0.9

Bias (95% CI),
ml/min per
1.73 m2*

93 (91 to 94)
95 (94 to 96)

88.6
89.7

16.49z13.37z

87.4
88.2

14.9z
13.2z

18.2 (17.2 to19.5)||
15.4 (14.5 to16.3)||

P30(95% CI),%z

Precision(95% CI)w

Results

Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CI, confidence interval; Cr-EDTA, chromium-ethylenediamine tetraacetic acid; GFR, glomerular filtration rate; IDMS, isotope-dilution mass spectrometry;
IQR, interquartile range; KTR, kidney transplant recipient; MDRD, Modification of Diet in Renal Disease; ND, not documented; NIST, National Institute of Standards and Technology; P30, percentage of estimated GFR values within
30% of measured GFR; PKD, polycystic kidney disease; SCr, serum creatinine; Tc-DTPA, technetium-diethylenetriamine pentaacetic acid.
*Computed as estimated GFR minus measured GFR. Positive numbers indicate overestimation and negative numbers indicate underestimation of measured GFR. Smaller absolute values indicate lesser bias.
wLower values indicate greater precision.
zHigher values indicate greater accuracy. Among the 3 studies99,101,104 that reported alternative measures of accuracy, results were consistent with P30 in all. In addition to P30, three references99,101,104 reported P10; Cirillo et al.104
also reported P20.
yEvaluated as the root mean squared error for the regression of estimated GFR on measured GFR.
||
Evaluated as the IQR for the differences between estimated and measured GFR.
z
Evaluated as the SD of the differences between estimated and measured GFR.
**Converted to raw scale by multiplying percentage of bias by measured GFR.
Reprinted with permission from Earley A, Miskulin D, Lamb EJ, et al.85 Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med 2012; 156(11): 785-795.

Redal-Baigorri Denmark
et al.106

Eriksenet al.105

Cirillo et al.104 Italy

Study

Table 13

chapter 145

chapter 1

eGFR (ml/min/1.73 m2) ¼ 40.7  (height/SCr)0.64  (30/
BUN)0.202, where height is in meters, SCr and BUN are in
mg/dl.
The additional recommendation for laboratory reportingof SCr is fully applicable in pediatrics.
When the individual clinician has information regarding
current and accurate height and applies the appropriate
pediatric formula, the recommendation to report anindividual child’s eGFRcreat value of less than 60 ml/min/
1.73 m2 as ‘‘decreased,’’ would be applicable in children over
the age of 2 years.
1.4.3.5: We suggest measuring cystatin C in adults witheGFRcreat 45-59 ml/min/1.73m2 who do not havemarkers of kidney damage if confirmation of CKD
is required. (2C)K
If eGFRcys/eGFRcreat-cys is also o60 ml/min/
1.73 m2, the diagnosis of CKD is confirmed.
K
If eGFRcys/eGFRcreat-cys is Z60 ml/min/1.73 m2,
the diagnosis of CKD is not confirmed.
RATIONALE

Figure 12 | Comparison of distribution of GFR and CKD
prevalence by age (NHANES 1999-2004). GFR was categorizedon the basis of the classification system established by the
NKF-KDOQI. Top. Distribution of estimated GFR, by 4-ml/min per
1.73 m2 categories. Values are plotted at the midpoint. Bottom.
Prevalence of CKD, by age. CKD, chronic kidney disease;
GFR, glomerular filtration rate; NKF-KDOQI, National Kidney
Foundation-Kidney Disease Outcomes Quality Initiative; NHANES,
National Health and Nutrition Examination Survey. Reprinted withpermission from Levey AS, Stevens LA, Schmid CH, et al.87 A newequation to estimate glomerular filtration rate. Ann Intern Med
2009; 150(9): 604-612.

A major foundation of this guideline is that CKD classification and staging should be influenced primarily by clinicalprognosis. As will be reviewed in the sections below,
abundant evidence has shown that GFR estimates based on
cystatin C are more powerful predictors of clinical outcomesthan creatinine-based eGFR. These findings have beenstrongest for mortality and CVD events, and the prognostic
advantage of cystatin C is most apparent among individuals
with GFR 445 ml/min/1.73 m2. In addition, new findings
show that using cystatin C in addition to SCr can lead to
improved accuracy of GFR estimation, including CKDclassification. In the opinion of the Work Group, these
considerations warrant new recommendations for GFR
estimation using cystatin C.
Evidence BaseAny eGFRcreat formula used in children will preferably bevalidated at the appropriate age and level of renal function,and the laboratory methods used locally will be calibrated orcomparable to those used in the process of developing theformula being applied. Currently the most robust pediatriceGFR formulas, derived using iohexol disappearance andcreatinine measurements which were measured centrally andcalibrated and traceable to international standards comefrom the CKiDs study.80
The two most common creatinine-based formulas
recommended for use in clinical practice include:
Updated ‘‘Bedside’’ Schwartz equation:eGFR (ml/min/1.73 m2) ¼ 41.3  (height/SCr), where heightis in meters and SCr is in mg/dl.
‘‘1B’’ Equation (include blood urea nitrogen [BUN] notcystatin C):
46

Evidence supports the use of cystatin C-based eGFR within
the population of persons diagnosed with CKD based on an
eGFRcreat 45-59 ml/min/1.73 m2 (G3a) but without albuminuria (A1) or other manifestations of kidney damage. This
group represents 3.6% of the US population and 41% of
people in the US estimated to have CKD based on eGFRcreatand urine ACR alone (Figure 8), and there has been
substantial controversy over whether or not these persons
have CKD. Data described below indicate that use of cystatin
C to estimate GFR in this population leads to more accurate
estimation of GFR and prediction of risk for future adverse
events.
In several studies, eGFRcys has been measured in
populations with and without eGFRcreat o60 ml/min/
1.73 m2, and participants were separated into those withand without eGFRcys o60 ml/min/1.73 m2 (Figure 14). Thosewith both eGFRcreat and eGFRcyso60 ml/min/1.73 m2, about
two-thirds of those with eGFRcreat o60 ml/min/1.73 m2, had
Kidney International Supplements (2013) 3, 19–62

chapter 1

All-cause mortality
No. ofCohorts

Favors
MDRD

Cardiovascular mortality

FavorsCKD-EPI

No. ofCohorts

Favors
MDRD

End-stage renal disease

FavorsCKD-EPI

No. ofCohorts

Overall

23

18

5

Sex
Female
Male

22
23

17
18

5
5

Race/ethnicity
White
Black
Asian

15
5
10

13
4
5

3
2
2

Age, y
<65
≥65

20
21

15
18

5
5

Diabetes
No
Yes

23
23

18
17

5
3

Hypertension
No
Yes

23
23

18
18
–0.1

0

0.1

0.2

NRI (95% CI)

FavorsMDRD

FavorsCKD-EPI

2
3
–0.1

0

0.1

0.2

NRI (95% CI)

–0.1

0

0.1

0.2

NRI (95% CI)

Figure 13 | Meta-analysis of NRI for all-cause mortality, CVD mortality, and ESRD. NRI summarizes the risk of clinical outcomes among
participants who are reclassified from one estimated GFR category using the MDRD Study equation to another estimated GFR category
using the CKD-EPI equation compared with those who are not reclassified. NRI greater than zero favors the CKD-EPI equation. NRI less thanzero favors the MDRD Study equation. The sizes of the data markers are proportional to the inverse of the variance of the NRIs. CKD-EPI,
Chronic Kidney Disease Epidemiology Collaboration; CVD, cardiovascular disease; ESRD, end-stage renal disease; GFR, glomerular filtration
rate; MDRD, Modification of Diet in Renal Disease; NRI, net reclassification improvements. Reprinted with permission from Matsushita K,
Mahmoodi BK, Woodward M, et al.107 Comparison of risk prediction using the CKD-EPI equation and the MDRD Study equation for
estimated glomerular filtration rate. JAMA 2012; 307(18): 1941-1951. Copyright & (2012) American Medical Association. All rights reserved.

markedly elevated risks for death, CVD, and ESRD end points
compared with persons with eGFRcreat 460 ml/min/1.73 m2.
The Work Group therefore considers this groupto have ‘‘confirmed CKD.’’ In contrast, about one-third of
those with eGFRcreato60 ml/min/1.73 m2 had eGFRcys460 ml/
min/1.73 m2 and this group were similar in risk for adverse
outcomes as persons with eGFRcreat460 ml/min/1.73 m2.
New data from CKD-EPI also showed improved accuracy
in GFR estimation using both creatinine and cystatin C(eGFRcreat-cys) compared to either marker alone. In thesubgroup with eGFRcreat 45-59 ml/min/1.73 m2, the combined equation correctly reclassified 16.8% of those witheGFR 45-59 ml/min/1.73 m2 to measured GFR Z60 ml/min/
1.73 m2.113
The consensus of the Work Group was therefore that thelarge group of persons with eGFRcreat 45-59 ml/min/1.73 m2
without markers of kidney damage, but with eGFRcys/
eGFRcreat-cys Z60 ml/min/1.73 m2 could be considered not tohave CKD. The removal of the diagnosis and label of CKD may
be reassuring to patients and may help clinicians to focus theirefforts on higher risk CKD patients.
The guideline statement suggesting the use of eGFRcys/
eGFRcreat-cys requires several important qualifiers. First,
clinicians may not want or need to confirm the diagnosis
of CKD in patients with eGFRcreat 45-59 ml/min/1.73 m2
without markers of kidney damage, either because thelikelihood of CKD is high because of the presence of risk
factors for CKD or presence of complications of CKD. Second,cystatin C is not universally available, so it may not be practicalfor a clinician to request a cystatin C blood test. Third, incertain clinical settings, the cost of measuring cystatin C (US$1–5) may be prohibitive. For all these reasons, the guideline
statement 1.4.3.5 is stated as a suggestion.
In addition to the population described above, eGFRcys
may be useful as a confirmatory test in situations where
Kidney International Supplements (2013) 3, 19–62

either the eGFRcreat may be inaccurate or biased, or when theclinical scenario warrants a secondary test (Recommendation
1.4.3.2). In these clinical situations, a clearance measurement
using an exogenous filtration marker may be optimal when it
is available. The measurement of eGFRcys/eGFRcreat-cys would
be a relatively low-cost, feasible alternative when GFR
measurement is not practical. The Work Group believed thatmeasured urinary CrCl was an inferior confirmatory test
relative to either GFR measurement or GFR estimation using
both creatinine and cystatin C.
If cystatin C testing is desired, it is very important thatclinicians understand principles of GFR estimation using cystatin
C. As with creatinine, GFR should be estimated from cystatin C
and an appropriate equation should be chosen for the specificclinical population (Recommendation 1.4.3.6), and an assay bechosen for measurement that is traceable to the international
standard reference material (Recommendation 1.4.3.7).
Pediatric Considerations

The utility of this specific statement to pediatrics is unclear as
the vast majority of children with significant reductions in
GFR, e.g., below 60 ml/min/1.73 m2, have either structuralabnormalities or findings of renal damage as evidenced byurinary or serum abnormalities. It is very unlikely thatisolated reduction in GFR would occur as in older adults. As
such, the confirmation of CKD will be made on criteria
beyond that of GFR alone.
1.4.3.6: If cystatin C is measured, we suggest that healthprofessionals (2C):K
use a GFR estimating equation to derive GFRfrom serum cystatin C rather than relying on theserum cystatin C concentration alone.
K
understand clinical settings in which eGFRcys
and eGFRcreat-cys are less accurate.
47

48

Japan

Japan

Korea

Matsuo et al.91

Horio et al.88

Yeo et al.110

South Africa

China, Japan, andSouth Africa

Stevens et al.109

van Deventer
et al.111

Country

Study

Patients, N

350

102

Black South African patients100(women, 49%; median age, 47 y;diabetes, 25%; donors, 7%; HIV,20%; hypertension, 36%)

Korean KTRs in the early
postoperative period (women,
43%; mean age, 42 y; diabetes,
16%)

51

51

Cr-EDTA (plasma)

Cr-EDTA (plasma)

Inulin (urine)

Inulin (urine)

61.5 (49.6)

76.8 (17.0)

45 (25)57.2 (34.7) (GFR
Z60, 41%; GFR
o60, 59%)

53 (31)675 Asian patients(China)Japanese patients (women, 42%; 350
mean age, 54 y; diabetes, 22%;
donors, 3%; KTRs, 1%;
hypertension, 58%)

Hospitalized Japanese patients;
external validation set (women,
42%; mean age, 54 y; diabetes,
44 cases; donors, 10; KTRs, 2;
glomerulonephritis, 176 cases;
PKD, 0 cases; lupus, 3 cases)

55 (35)MDRD
Japanese-modified MDRD
(equation 1)
JSN-CKDI equation (equation 2)
MDRD with Japanese coefficient(equation 3)
3-variable Japanese equation(equation 4)

Rate-blanked, Rochecompensated, kinetic Jaffe assay(Roche Modular analyzer; Roche
Diagnostics, Indianapolis,
Indiana) with calibration
traceable to IDMS, comparedwith Roche enzymatic assay(Creatinine Plus; Roche
Diagnostics, Indianapolis,
Indiana) at the Cleveland Clinicwith values adjusted byregression

MDRD with race or ethnicity
factor**
MDRD without race or ethnicity
factor**Rate-blanked, ToshibaMDRD
compensated kinetic Jaffe assay Japanese-modified MDRD
(Toshiba Medical Systems Tokyo,
Japan) using a Roche calibrator(Roche Diagnostics, Indianapolis,
Indiana) traceable to IDMS
reference method

Results

13.1 (5.5 to
18.3)
1.9 (0.8 to
4.5)

0.33
17.95

52
74

28.5||
16.6||

94.1
68.6

12.57z11.06z75 (70 to 79)

19.1||
2.1

73 (69 to 78)
75 (70 to 79)

73 (69 to 78)
73 (59 to 78)

20.3||
19.4||
7.9
1.3

19.4||
17.8||

59 (54 to 64)
72 (67 to 76)

73.2 (69.9 to
76.6)
72.1 (68.7 to
75.7)
25.2||
19.9||

0.325 (0.302
to 0.348)||0.318 (0.295
to 0.343)||

2.7 (3.7 to1.9)
1.3 (2.2 to0.6)

29.4 (23.8 to
35.1)
36.3 (30.6 to
42.3)

55.6 (46.5 to
64.6)
55.6 (46.5 to
64.6)

P30
(95% CI),
%z

12.0
5.9

0.469 (0.424
to 0.515)||
0.507 (0.463
to 0.553)||

0.326 (0.292
to 0.361)||
0.327 (0.292
to 0.362)||17.8 (14.7 to
20.1)
21.4 (18.2 to
23.3)

12.4 (7.6 to
18.3)
12.5 (7.6 to
18.4)Bias (95% CI),
ml/min per
Precision
1.73 m2*(95% CI)w

Enzymatic assay validated by
MDRD with Japanese coefficient 1.3
using the calibration panel of the CKD-EPI with Japanese0.4
Cleveland Clinic
coefficient

Hitachi enzymatic assay (Hitachi,
Tokyo, Japan) with excellent
agreement against Cleveland
ClinicCKD-EPI equation with 2-level
race or ethnicity coefficient
CKD-EPI equation with 4-level
race or ethnicity coefficient

CKD-EPI equation with 2-level
race or ethnicity coefficient
CKD-EPI equation with 4-level
race or ethnicity coefficient

CKD-EPI equation with 2-level
race or ethnicity coefficient
CKD-EPI equation with 4-level
race or ethnicity coefficient

Equation

GFR estimation

Calibrated to standardized SCr
measurements by using Roche(Roche-Hitachi P-Module
instrument with Roche
Creatininase Plus assay;
Hoffmann–La Roche, Basel,
Switzerland) enzymatic assay at
the Cleveland Clinic

Value (SD), ml/min
SCr calibration and assay
per 1.73 m2

125
I-Iothalamate (urine) 61 (32)and other filtration
markers

Reference standard

248 Asian patients(Japan)Populations from 3 studies in
99 black patients
China, Japan, and South Africa(South Africa)(women, 48%; Asian, 90%; black,
10%; mean age, 49 y; diabetes,
6%; KTRs, 0%)Population

Measured GFRTable 14. Performance comparison of creatinine-based GFR estimating equations outside of North America, Europe, and Australia

chapter 1

Kidney International Supplements (2013) 3, 19–62

Patients with CKD from 9 renal
institutes at university hospitals
located in 9 geographic regionsof China

Thai patients with CKD who were 100
in stable condition

China

Thailand

Ma et al.93

Praditpornsilpa
et al.90

Kidney International Supplements (2013) 3, 19–62
Tc-DTPA (plasma)

Tc-DTPA (plasma)99

Tc-DTPA (plasma)

99

99

Reference standard

51.1 (28.4)

ND

51.7 (27.5) (GFR
Z60, 69%; GFR
o60, 31%)

Roche enzymatic assay (Roche
Diagnostics, Indianapolis,
Indiana) with values adjusted to
IDMS reference serum SRM 967

Hitachi kinetic Jaffe assay withvalues adjusted by regression
analysis to Cleveland Clinic
Beckman CX3 assay (Beckman
Coulter, Fullerton, California)

Results3.0 (4.2 to1.7)
1.2 (2.7 to
0.3)

77.8

79.6

62.7
68.0
73.3
90.0

0.9 (9.6 to ND
7.4)

0.8 (9.7 to ND
7.4)
8.8z
7.8z
8.5z
6.3z

11.9
10.9
10.3
7.2

Original MDRD equation,
calibrated to Cleveland Clinic
creatinine measurements, with
Chinese coefficient (study
equation 4)ww
Chinese equation (study
equation 6)zz
MDRD
CKD-EPI
MDRD equation with Thai racial
factor correction
Thai estimated GFR equation

66.1

79.7 (74.6 to
84.9)
82.8 (77.9 to
87.6)

P30
(95% CI),%z

ND

12.2 (10.0 to14.4)y12.1 (9.0 to15.1)yBias (95% CI),
ml/min per
Precision
1.73 m2*(95% CI)w

Original MDRD equation,
7.8 (21.5
calibrated to the Cleveland Clinic to 1.8)
creatinine measurements (study
equation 2)ww

CKD-EPI

MDRD

Equation

GFR estimation

Siemens enzymatic assay(Siemens Advia 2400; Siemens,
Munich, Germany) calibrated
with manufacturer-provided
materials traceable tostandardized creatinine (NIST
SRM 967) measured by using
IDMS

Value (SD), ml/min
SCr calibration and assay
per 1.73 m2

Measured GFRCKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CI, confidence interval; Cr-EDTA, chromium-ethylenediamine tetraacetic acid; GFR, glomerular filtration rate; IDMS, isotope-dilution mass
spectrometry; JSN-CKDI, Japanese Society of Nephrology-Chronic Kidney Disease Initiatives; KTR, kidney transplant recipient; MDRD, Modification of Diet in Renal Disease; ND, not documented; NIST, National Institute of Standards
and Technology; P30, percentage of estimated GFR values within 30% of measured GFR; PKD, polycystic kidney disease; SCr, serum creatinine; SRM, standard reference material; Tc-DTPA, technetium-diethylenetriamine pentaaceticacid.
* Computed as estimated GFR minus measured GFR. Positive numbers indicate overestimation and negative numbers indicate underestimation of measured GFR. Smaller absolute values indicate lesser bias.
wLower values indicate greater precision.
z
Higher values indicate greater accuracy. Among the 5 studies90,91,93,110,112 that reported alternative measures of accuracy, results were consistent with P30 in 3. Of the studies reporting results consistent with P30, Praditpornsilpa
et al.90 reported P10 and P15, Yeo et al.110 reported P10, and Matsuo et al.91 reported P15. Two studies93,112 reported inconsistent results between P15 and P30.
yEvaluated as the interquartile range for the differences between estimated and measured GFR.
||
Evaluated as the root mean squared error for the regression of estimated GFR on measured GFR.
z
Evaluated as the SD of the differences between estimated and measured GFR.
**African American coefficient of the MDRD Study equation.
ww
Derived by using the original MDRD equation (with the 186 coefficient). For use with an SCr traceable to the SRM, the 186 coefficient should be replaced with the 175 coefficient from the reexpressed MDRD equation.
zz
Derived by using the original MDRD equation (with the 186 coefficient). For use with an SCr traceable to the SRM, the SCr should be replaced by SCr  0.95, which represents the calibration factor relating the SCr assay in the
Cleveland Clinic laboratory to the standardized SCr assay.
Reprinted with permission from Earley A, Miskulin D, Lamb EJ, et al.85 Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med 2012; 156(11): 785-795.

230

Outpatients with CKD in the232
nephrology clinic at National
University Hospital, Singapore(women, 48%; Chinese, 41%;
Malay, 31%; Indian or other, 28%;
median age, 58 y; diabetes, 23%;
hypertension, 50%)

Singapore

Patients, N

Teo et al.112

Population

Country

Continued

Study

Table 14

chapter 149

chapter 1

Figure 14 | Association of CKD definitions with all-cause mortality and ESRD. CKD, chronic kidney disease; ESRD, end-stage renal
disease. Reprinted with permission from Peralta CA, Shlipak MG, Judd S, et al.114 Detection of chronic kidney disease with creatinine, cystatin
C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA 2011; 305(15):1545-1552. Copyright & (2011) American Medical Association. All rights reserved.

Table 15 | Sources of error in GFR estimating using cystatin C
Source of error
Non-steady state
Non-GFR determinants of SCysC that differ from study populations in which
equations were developed
Factors affecting cystatin C generation

ExampleK

AKI

Race/ethnicity other than US and European black and white
Disorders of thyroid function
K Administration of corticosteroids
K Other hypothesized factors based on epidemiologic associations(diabetes, adiposity)
None identified
Increased by severe decrease in GFR
K Higher biological variability in non-GFR determinants relative to
GFR
K Higher measurement error in SCysC and GFR
K Heterophilic antibodies
K
K

Factors affecting tubular reabosrption of cystatin C
Factors affecting extra-renal elimination of cystatin C
Higher GFR

Interference with cystatin C assay

Abbreviations: AKI, acute kidney injury; GFR, glomerular filtration rate, SCysC, serum cystatin C.

RATIONALE

Cystatin C is licensed for use in some countries in
Europe and has been approved by the FDA as a measureof kidney function in the United States for nearly
10 years. In certain regions, notably Sweden and partsof China, eGFR is routinely estimated by both creatinineand cystatin C. As with creatinine, GFR estimates using
cystatin C are more accurate in estimating measured
GFR than the SCysC concentration alone. As with creatinine, sources of error in GFR estimation from SCysC
concentration include non-steady state conditions, nonGFR determinants of SCysC, measurement error at50

higher GFR, and interferences with the cystatin C assays(Table 15).
Pediatric Considerations

For Recommendation 1.4.3.6, this guideline is fully applicablein pediatrics. See Recommendation 1.4.3.7 for details.
In terms of clinical settings where eGFRcys might be lessaccurate, it should be noted that Schwartz et al. determinedthat the only variable that explained the outlier values of
estimated GFR (in both univariate and multivariate formulas) was heavier weight; race, high blood pressure,albumin levels and use of steroids did not contribute.115

Kidney International Supplements (2013) 3, 19–62

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1.4.3.7: We recommend that clinical laboratories thatmeasure cystatin C should (1B):K
measure serum cystatin C using an assay
with calibration traceable to the international standard reference material.
K
report eGFR from serum cystatin C in
addition to the serum cystatin C concentration in adults and specify the equation
used whenever reporting eGFRcys andeGFRcreat-cys.
Kreport eGFRcys and eGFRcreat-cys in adults
using the 2012 CKD-EPI cystatin C and2012 CKD-EPI creatinine-cystatin C equations, respectively, or an alternative cystatin
C-based GFR estimating equations if they
have been shown to improve accuracy of
GFR estimates compared to the 2012 CKDEPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations.
When reporting serum cystatin C:K
We recommend reporting serum cystatin C concentration rounded to thenearest 100th of a whole number when
expressed as conventional units (mg/l).
When reporting eGFRcys and eGFRcreat-cys:
KWe recommend that eGFRcys andeGFRcreat-cys be reported and rounded to
the nearest whole number and relative to abody surface area of 1.73 m2 in adults using
the units ml/min/1.73 m2.
KWe
recommend
eGFRcysandeGFRcreat-cys levels less than 60 ml/min/
1.73m2 should be reported as ‘‘decreased.’’RATIONALE

As for SCr, reporting eGFR using cystatin C in addition tocystatin C will facilitate clinician’s use of cystatin C for GFR
estimation. It is important to acknowledge that calibration of
assays is essential to interpretation of kidney function
measures. Cystatin C is measured by a variety of immunoassays and, as for creatinine, there can be variation among
methods in reported SCysC concentration but reported
analytic variation appears less common than with creatinine.
In June 2010 the Institute for Reference Materials andMeasurements (IRMM) released a reference material (ERMDA471/IFCC) for cystatin C measurement. Reagent manufacturers are in the process of recalibrating their assays
against this standard which will enable standardized reporting of cystatin C and eGFR results. This recommendation is
directed to laboratories with the intent to clarify the details ofsuch calibration and the use of specific equations so as tofacilitate international standardization.
Evidence Base

Numerous equations have been developed to estimate GFR.
Some equations include cystatin C as the only variable, while
Kidney International Supplements (2013) 3, 19–62

others include, age, sex, or race, but the magnitude ofcoefficients for these variables are smaller than in creatininebased equations, presumably reflecting less contribution ofmuscle to cystatin C generation than to creatinine generation.
Equations without race are a potential advantage for cystatin
C-based estimating equations in non-black, non-white
populations.
For our review of GFR estimating equations, we only
considered equations that were developed using assays thatwere traceable to the new reference methods and study
populations in which SCysC concentration was measured
using traceable assays. At this time, only the equations
developed by CKD-EPI are expressed for use with standardized SCysC (Table 16), including equations developed in
CKD populations in 2008116,117 and re-expressed for use withstandardized cystatin C in 2011, and equations developed indiverse populations in 2012.113 Equations using assays thatare not traceable to the the reference standard are listed in
Supplemental Table 3.
The 2012 creatinine-cystatin C equation is moreaccurate than equations using creatinine or cystatin C
separately (Figure 15), and more accurate than the2008 creatinine-cystatin C equation (Table 17). The averageof the GFR computed by the equations using creatinineand cystatin C separately is similar to the GFR computing
using the creatinine-cystatin C equations. The 2012
cystatin C equation has similar accuracy to the 2009
creatinine equation described above but does not require
use of race, and may be more accurate in non-black,non-white populations or in clinical conditions withvariation in non-GFR determinants of SCr. We anticipate the development of additional equations using cystatin
C in the future and recommend that they be compared with
the CKD-EPI 2012 cystatin C and creatinine-cystatin C
equations as well as with the CKD-EPI 2009 creatinine
equation.
Pediatric Considerations

For Recommendation 1.4.3.7 this set of statements would
need to be altered for application in pediatric practice in thefollowing way:
K Measure
SCysC using an immunonephelometricallydetermined method in which the assay is calibrated andtraceable to the international standard reference material.
K Report eGFRcys in addition to the SCysC concentration inchildren.
K Report
eGFRcys in children specifying the specificequation used.
Based on their recent work comparing particle-enhanced
nephelometric to turbidometric immunoassays for cystatin C
in a pediatric population with significant reduction in GFR(median GFR B45 ml/min/1.73 m2), Schwartz et al. demonstrated less bias for the nepholometric value and that its
reciprocal showed a substantially improved correlation to theiohexol GFR (0.87 versus 0.74) when compared to that of the51

52

135 x min(SCr/k, 1)a x max(SCr/k, 1)0.601 x
min(SCysC/0.8, 1)0.375 x max(SCysC/0.8,
1)0.711 x 0.995Age x 0.969 [if female] x 1.08
[if black] where SCr is serum creatinine, SCysC isserum cystatin C, k is 0.7 for females and 0.9 formales, a is -0.248 for females and -0.207 formales, min(SCr/k,1) indicates the minimum of
SCr/k or 1, and max(SCr/k,1) indicates the
maximum of SCr/k or 1; min(SCysC/0.8,1)
indicates the minimum of SCysC/0.8 or 1 andmax(SCysC/0.8,1) indicates the maximum of
SCysC/0.8 or 1

CKD-EPI creatinine-cystatin C
2012

GFR measurement method

5352 participants from 13 studies(7 RS and 6 CP)

125
I-Iothalamate (U) [Mean GFR 68 (39) ml/min/
1.73 m2 ; 51% GFR Z60 ml/min/1.73 m2; 49% GFR
o60 ml/min/1.73 m2]
Units for GFR in ml/min/1.73 m2

2,980 participants from pooled individual-level 125I-Iothalamate (U) [Mean GFR 51 ± 26 ml/min/patients data from the MDRD Study, African
1.73 m2]
American Study of Kidney Disease (AASK), and Units for GFR in ml/min/1.73 m2
Collaborative Study Group (CSG)

N, Development and internal validation
population
Reference

Inker LA, et al.113
All assays were performed at the Cleveland Clinic
Research Laboratory (Cleveland, OH). We calibrated
SCr assays or measured serum SCr directly by the
Roche enzymatic method (Roche-Hitachi P-Module
instrument with Roche Creatininase Plus assay,
Hoffman-La Roche, Ltd., Basel, Switzerland), that had
been confirmed to be traceable to National InstituteStandardized Technology (NIST) creatinine standard
reference material 967. We calibrated SCysC assays
or measured SCysC directly on the Siemens Dade
Behring Nephelometer. We recently reported
standardization of this assay to the recently released
certified reference materials for cystatin C from theInternational Federation for Clinical Chemists (IFCC)
Working Group for the Standardization of SCysC andthe Institute for Reference Materials andMeasurements (IRMM) at the University of
Minnesota.
SCr in mg/dl
SCysC in mg/l

Stevens LA, et al.117
SCr assays were calibrated to standardized SCrvalues at the Cleveland Clinic Research Laboratory Inker LA, et al.116(CCRL; Cleveland, OH). Results of the calibration
procedure for the MDRD Study, AASK, and CSG were
described previously. Samples for all studies had
been frozen at -701C until 2005 to 2006, when SCysC
was measured at the CCRL by using a particle
enhanced immunonephelometric assay (N Latex
Cystatin C; Dade Behring, Deerfield, IL). Interassay
coefficients of variation for the assay were 5.05%
and 4.87% at mean concentrations of 0.97 and1.90 mg/l (72.7 and 142.3 nmol/l), respectively.
SCr in mg/dl
SCysC in mg/l

SCr and/or SCysC method

Abbreviations: AASK, African American Study of Kidney Disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CP, clinical population; GFR, glomerular filtration rate; IDMS, isotope-dilution mass spectrometry;
IFCC, International Federation for Clinical Chemists; IRMM, Institute for Reference Materials and Measurements; MDRD, Modification of Diet in Renal Disease; NIST, National Institute Standardized Technology, RS, Research study;
SCr, serum creatinine; SCysC, serum cystatin C; U, urinary clearance.

133 x min(SCysC/0.8, 1)0.499 x max(SCysC/0.8,
1)1.328 x 0.996Age x 0.932 [if female] where
SCysC is serum cystatin C, min indicates theminimum of SCysC/0.8 or 1, and max indicatesthe maximum of SCysC/0.8 or 1

[127.7 * (-0.105 + 1.13 x standardized
SCysC)1.17 x age0.13 x 0.91 [if female] x 1.06 [ifblack]][177.6 * SCr0.65 x (-0.105 + 1.13 x standardized
SCysC)0.57 x age0.20 x 0.82 [if female] x 1.11
[if black]]

76.7 x (-0.105 + 1.13 x standardized SCysC)1.19

Equation

CKD-EPI cystatin C2012

CKD-EPI creatinine-cystatin C
2008
Re-expressed 2011

CKD-EPI cystatin C 2008
Re-expressed 2011

Cystatin C equations
CKD-EPI cystatin C (alone)
2008
Re-expressed 2011

Equation name

Table 16 | Equations based on IDMS traceable creatinine and IFCC traceable cystatin C assays

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date. The formula they use to obtain these values is: 70.69 (cystatin c)-0.931.
Of note, their final multivariate equation, when applied to
the validation set and using height/SCr, nepholemetriccystatin C, BUN, sex, and an adjusted height term
demonstrated the best accuracy reported in pediatric studies
to date, 91% and 45% within 30% and 10% of the true GFR,
respectively; with a bias of only 0.2 and correlation of 0.92.
1.4.3.8: We suggest measuring GFR using an exogenous
filtration marker under circumstances where moreaccurate ascertainment of GFR will impact on
treatment decisions. (2B)
RATIONALE

Figure 15 | Performance of three equations for estimating
GFR. Panel a shows the median difference between measured
and estimated GFR. The bias is similar with the equation using
creatinine alone, the equation using cystatin C alone, and the
combined creatinine–cystatin C equation. Panel b shows theaccuracy of the three equations with respect to the percentageof estimates that were greater than 30% of the measured
GFR (1 – P30). Whiskers indicate 95% confidence intervals. GFR,
glomerular filtration rate; P30, percentage of estimated GFR values
within 30% of measured GFR. From N Engl J Med, Inker LA,
Schmid CH, Tighiouart H, et al.113 Estimating glomerular filtration
rate from serum creatinine and cystatin C. 367: 20-29. Copyright& 2012 Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society.

turbidometric assay.115 This demonstrates the importance ofusing an assay calibrated and traceable to the international
standard reference material.
Numerous pediatric specific and derived eGFRcys formulas
have been published, the most current and recent by
Schwartz115 who derives the newest available from avalidation set from the CKiD study and compares thoseresults to 3 other well-recognized formulas from theliterature, namely Zapitelli et al.,118 Filler and Lepage,119
and Hoek et al.120
Their results demonstrate that the newest univariate
cystatin C formula derived from the CKiD cohort has
excellent accuracy with 82.6% of eGFRcys within 30% of thetrue measured iohexol GFR and 37.6% within 10% of thetrue measured iohexol GFR. Likewise the bias of 0.3% andcorrelation of 0.85 are the best of all formulas reported to
Kidney International Supplements (2013) 3, 19–62

In clinical practice, there may be a requirement to measure
GFR when the need for a ‘truer’ more precise value isidentified (such as for organ donation or for dosing of toxic
drugs). The intention of this statement is to recognize thatspecialty centers for kidney disease, usually tertiary referral
centers, should have the capacity to measure GFR using
exogenous filtration markers as a recognized specialist
service. We recognize that this ability does not currently
constitute the definition of specialty kidney referral centers
and that it may be problematic, but resources to ensure
accurate measurement ought to be made available. Given thatthese specific measurements require levels of rigor andreproducibility similar to those of laboratory calibration
issues, specialist centers would be the right place to suggestthat these facilities be made available.
Evidence BaseGFR is measured as the clearance of an exogenous filtration
marker. The ‘‘gold standard’’ method is the urinary clearance
of inulin during a continuous intravenous infusion. To
simplify the procedure there are a number of alternative
clearance methods and alternative filtration markers, withminor differences among them.79 For all measurement
methods, measured GFR should be reported as describedfor eGFR.
Table 18 summarizes the strengths and limitations ofclearance methods and filtration markers for clearance
measurements. Thus measured GFR may also be associatedwith error, and in evaluation of GFR estimating equations,random error in GFR measurement is a source of some of theimprecision in GFR estimating equations.27,121 In principle,
the magnitude of random error in GFR measurements islikely to be smaller than errors in GFR estimation using
creatinine and cystatin C due to conditions listed in Tables 11
and 15.
International RelevanceThe calculation of eGFR using these equations usuallyrequires computer programming and some processes for
quality monitoring. Nonetheless the statements are here toserve as ‘best practice’ recommendations so that these can be53

54
mGFR (SD)Cr-EDTA51

34 (17)

Exogenous
70 (41)
filtration
markers otherand urinary
iothalamate (U)ReferencestandardmGFR

Y (IFCC SRM 967)

Y (IFCC SRM 967)

Serum creatinine (SCr)calibration and assay
detailY (IRMM)Y (IRMM)-6.0 (-7.1, -4.9)-4.9 (-5.9, -4.2)-3.7 (-4.6, -2.8)-3.4 (-4.4, -2.3)-3.9 (-4.5, -3.2)

CKD-EPI cystatin C 2011
CKD-EPI creatinine-cystatin C
2011
CKD-EPI creatinine 2009

CKD-EPI cystatin C 2012
CKD-EPI creatinine-cystatin C
2012
Average of CKD-EPI creatinine
2009 and CKD-EPI cystatin C2012

2 (1, 2)CKD-EPI cystatin C 2011

0 (0, 1)3 (2, 3)CKD-EPI cystatin C (alone) 2011

CKD-EPI creatinine-cystatin C
2011-2 (-3, -1)

Re-expressed MDRD

-3.5 (-4.1, -2.8)-6.3 (-7.8, -5.4)

Bias ml/min/
1.73 m2*

Results

Re-expressed MDRD

Cystatin C
Equationscalibration andassay detail

GFR estimate

0.264(0.239,0.289)
0.248(0.223,0.271)
0.193(0.174,0.211)

0.229(0.210,0.247)

16.4 (14.8,
17.8)
13.4 (12.3,
14.5)
13.9 (12.9,
14.7)

18.7 (17.5,
20.0)
15.3 (14.0,
16.3)
15.4 (14.3,
16.5)

19.4 (17.4,
21.1)

Precisionw

90%(89, 91)

79%(78, 80)73%(72, 74)

84%(83, 85)

92%

92%

86%

87%

92%

84%

83%

Accuracyz

Abbreviations: CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CP, clinical population; Cr-EDTA, chromium-ethylenediamine tetraacetic acid; DM, diabetes mellitus; GFR, glomerular
filtration rate; IFCC, International Federation of Clinical Chemistry; IQR, interquartile range; IRMM, International Reference Materials and Measurements; MDRD, Modification of Diet in Renal Disease; mGFR, measured glomerular
filtration rate; RMSE, root mean square error; RS, Research study; SCr, serum creatinine; SRM, standard reference material; U, urine; Y, yes
Footnotes:*Bias is computed as estimated GFR minus measured GFR. A positive number indicates estimated GFR overestimates measured GFR. A negative number indicates estimated GFR underestimates measured GFR. A smaller absolutevalue indicates lesser bias. A lower value for RMSE, IQR, or SD indicates greater precision.
wPrecision is evaluated as IQR for the differences between estimated and measured GFR.
zHigher values for P30 indicate greater accuracy. Values in parenthesis are 95% confidence intervals.

438
Stevens, LA et al.117 CP: Clinical population in Paris,
FranceFrance [29% women, 79% white, 8%
black, 13% other, Mean age 59y,
22% DM, 16%]

RS/CP: 5 studies (2 RS and 3 CP)
using equations developed indiverse dataset [3% black, Mean age
50y, 53% DM]

RS/CP: 5 studies (2 RS and 3 CP)
1119
using equations developed in CKD
population [3% black, Mean age 50y,
53% DM]

Inker LA et al.113
Multi

N

Population (subgroup)

AuthorStudy description

Table 17 | Performance comparison of cystatin C-based estimating equations in North American and European populations

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Table 18 | Strengths and limitations of GFR measurement methods and markers
ApproachStrengths

Limitations

Methods
Urinary clearance
Bladder catheter and continuous
intravenous infusion of marker
Spontaneous bladder emptying

K

Gold standard method

K

Invasive

K

Patient comfort
Less invasive
Shorter duration

K

Possibility of incomplete bladder emptying
Low flow rates in people with low levels of GFRRapidly declining plasma levels at high levels of GFRLonger equilibration time in extracellular volume expansion
Cumbersome
Prone to error

K

Bolus administration of marker

K

K
K
K

24 h urinary collection

K
K

Plasma clearanceK
K

No urine collection required
Potential for increased precision

K
K
K

Nuclear imaging

K
K

No urine collection or repeatedblood samples required
Relatively short duration

K

Gold standard
No side effects

K

Overestimation of GFR in extracellular volume expansion
Inaccurate values with 1-sample technique, particularly at
lower GFR levels
Longer duration of plasma sampling required for low GFRLess accurate

Markers
InulinK
K

K
KCreatinine

K
K

Iothalamate

K
K

Endogenous marker, no needfor administration
Assay available in all clinicallaboratories
Inexpensive
Long half life

K

K
K
K
K

IohexolK

Not radioactive
Inexpensive
Sensitive assay allows for low doseK

Widely available in Europe

K
K

K
K
K
K

EDTA

K
K

DTPA

K
K

Widely available in the US
New sensitive and easy to
use assay for gadolinium

K
K
K
K

Expensive
Difficult to dissolve and maintain into solution
Short supply
Secretion can vary among and within individuals

Probable tubular secretion
Requirement for storage, administration, and disposal ofradioactive substances when 125I used as tracer
Use of non-radioactive iothalamate requires expensive assay
Cannot be used in patients with allergies to iodine
Possible tubular reabsorption or protein binding
Use of low doses requires expensive assay
Cannot be used in patients with allergies to iodine
Nephrotoxicity and risk for allergic reactions at high doses
Probable tubular reabsorption
Requirement for storage, administration, and disposal ofradioactive substances when 51Cr is used as tracer
Requirement for storage, administration, and disposal ofradioactive substances when 99mTc used as tracer
Requires standardization for 99mTc
Dissociation and protein binding of 99mTc
Concern for NSF when gadolinium is used as the tracer

Abbreviations: DTPA, diethylenetriamine pentaacetic acid; EDTA, ethylenediamine tetraacetic acid; GFR, glomerular filtration rate; NSF, nephrogenic systemic fibrosis.

aspired to over time in those locations where theserecommendations are currently not able to be implemented.
The Work Group appreciated that not all laboratories havecapabilities to assay cystatin C. Different countries andregions will have different availabilities for measurement of
GFR. The statement about GFR measurements mostly applies
to countries with tertiary care services such as kidneytransplantation and oncology.
Implications for Clinical Practice and Public Policy

It is important for clinicians to understand various methods
for estimating and measuring kidney function and thesituations in which specific methods may be superior inclinical decision making about treatment and referral.
Kidney International Supplements (2013) 3, 19–62

Standardized assays and robust equations are importantfor epidemiological and planning purposes so that public
policy can be informed by more accurate estimates of CKD,
which may be possible with improved standardization ofboth assays and equations.
In different parts of the world, different assays are usedand equations for estimating eGFR may differ. Thus,
appreciating and understanding local standards is importantfor individual patients who may travel, and for comparative
research across countries or regions.
In the event that a clinician requires measurement of GFR
instead of an estimate, knowledge of these different tests andavailability of them is important. Situations in whichmeasurement would be required are likely quite infrequent55

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but include donor evaluation in kidney transplantation anduse of toxic drugs which have a narrow therapeutic range. We
acknowledge that drug development and clinical observation
programs may not define the various thresholds with
sufficient granularity to require greater accuracy than isprovided by eGFRcreat. Guidance is evolving regarding kidney
function evaluation during drug development programs.13
There are no direct implications for public policy for thestatement about GFR measurement.
Areas of Controversy, Confusion, or Non-consensus

The Work Group recognizes that no single creatinine-based
estimating equation will perform optimally in all clinicalcircumstances and that there may be changes in theperformance of estimating equations over time and indifferent regions. However, for the purpose of eGFR
reporting, it is important to select a single equation withina region or country. At the writing of this guideline, inNorth America, Europe, and Australia, the advantages of the
CKD-EPI equation at higher GFR make it more applicablethan the MDRD Study equation for general practice andpublic health.
While cystatin C offers some advantages over SCr as thebasis of estimating equations, the cost of the assay andpotential lack of standardization across laboratories for this‘newer’ test limit our ability to recommend it as a preferredor even usual second test after creatinine. We recognize thatthese factors may lead to variations in implementation. The
recommendation to consider confirmatory or additional
testing if there is a need for more accurate determination of
GFR is important. That there are other laboratory markers toestimate GFR (i.e., cystatin C) is stated here as there has been
accumulating data to support its use in these situations. We
have specifically mentioned cystatin C because of these data.

1.4.4 Evaluation of albuminuria
1.4.4.1: We suggest using the following measurements
for initial testing of proteinuria (in descendingorder of preference, in all cases an earlymorning urine sample is preferred) (2B):(1) urine albumin-to-creatinine ratio (ACR);(2) urine protein-to-creatinine ratio (PCR);(3) reagent strip urinalysis for total proteinwith automated reading;(4) reagent strip urinalysis for total proteinwith manual reading.
1.4.4.2: We recommend that clinical laboratories report
ACR and PCR in untimed urine samples in
addition to albumin concentration or proteinuria concentrations rather than the concentrations alone. (1B)
1.4.4.2.1: The term microalbuminuria should
no longer be used by laboratories.
(Not Graded)
1.4.4.3: Clinicians need to understand settings that
may affect interpretation of measurements ofalbuminuria and order confirmatory tests as
indicated (Not Graded):
K
Confirm reagent strip positive albuminuria
and proteinuria by quantitative laboratory
measurement and express as a ratio tocreatinine wherever possible.
K
Confirm ACR Z30 mg/g (Z3 mg/mmol) on
a random untimed urine with a subsequent
early morning urine sample.
K
If a more accurate estimate of albuminuria
or total proteinuria is required, measure
albumin excretion rate or total protein
excretion rate in a timed urine sample.

Clarification of Issues and Key Points

It is important for clinicians to appreciate the need forstandardized assays and standardized equations for laboratory reporting of eGFR. Changes in laboratory assays or
calculation methods should be reported to clinicians in order
to avoid confusion when serially following individuals. Thisis because values in an individual might indicate a worsening
or improvement in eGFR which may be attributable todifferent assays or calculation methods, rather than areflection of true change.
When precise information about GFR is required, direct
measurement using reliable methods should be pursued.
Pediatric Considerations

For Recommendation 1.4.3.8 this guideline is fully applicablein pediatrics.

56

RATIONALE

We recommend measurement of urinary albumin because itis relatively standardized and because it is the single mostimportant protein lost in the urine in most chronic kidneydiseases. Use of urinary albumin measurement as thepreferred test for proteinuria detection will improve thesensitivity, quality, and consistency of approach to the early
detection and management of kidney disease.
By contrast, laboratory tests purporting to measureurinary total protein are commonly flawed, often being
standardized against, and predominantly sensitive to, albumin. They have poor precision at low concentrations anddemonstrate poor between-laboratory agreement while being
insensitive, non-specific, and susceptible to a range of falsepositive and false-negative problems. There may occasionally

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Opportunistic findingof positive reagent
strip result for albuminor total protein

Yes
Inspect urine

Yes
Cloudy?

Repeatreagent strip
positive?

No

MSU for C&S
Treat infection if positive

No
Patient requires testingfor proteinuria as part ofCKD detectionor
surveillance program

Measure urinary ACR

Yes
ACR >300 mg/g(>30 mg/mmol)?

Severely increased
proteinuria

No

No

ACR ≥30 mg/g(≥3mg/mmol)?

Refer for specialist
assessment e.g.,
possible biopsy

Yes
Send 2 further EMU samples for ACR
within the next 2 months

Yes
EMU
ACR ≥30 mg/g(≥3 mg/mmol) in atleast 1of 2
subsequent
samples?

Yes
Hematuria?

No
No

Moderately increased
albuminuria

Continue routine
observation

Figure 16 | Suggested protocol for the further investigation of an individual demonstrating a positive reagent strip test foralbuminuria/proteinuria or quantitative albuminuria/proteinuria test. Reagent strip device results should be confirmed using
laboratory testing of the ACR on at least two further occasions. Patients with two or more positive (Z30 mg/g or Z3 mg/mmol) tests onearly morning samples 1-2 weeks apart should be diagnosed as having persistent albuminuria. The possibility of postural proteinuria should
be excluded by the examination of an EMU. PCR measurement can be substituted for the ACR but is insensitive in the detection ofmoderately increased albuminuria/proteinuria. Approximate PCR equivalent to an ACR of 30 mg/mmol is 50 mg/mmol. ACR, albumin-tocreatinine ratio; C&S, culture and sensitivity; CKD, chronic kidney disease; EMU, early morning urine; MSU, mid-stream urine; PCR, protein-tocreatinine ratio. aConsider other causes of increased ACR (e.g., menstrual contamination, uncontrolled hypertension, symptomatic urinary
tract infection, heart failure, other transitory illnesses, and strenuous exercise), especially in the case of type 1 diabetes present for less than
5 years. The presence of hematuria may indicate non-diabetic renal disease. This figure was published and adapted from Lamb EJ, Price
CP.122 Kidney function tests, in Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, eds Burtis CA, Ashwood E, Bruns DE, 5thedition, pp 669-708, 2012. Copyright Elsevier.

be clinical reasons for a specialist to use PCR instead of
ACR to quantify and monitor significant levels of proteinuria(e.g., in patients with monoclonal gammopathies).
Commonly used reagent strip devices measuring total
protein are insufficiently sensitive for the reliable detection ofproteinuria, do not adjust for urinary concentration, and are
only semi-quantitative. Furthermore, there is no standardization
between manufacturers. The use of such strips should be
discouraged in favor of quantitative laboratory measurements ofalbuminuria or proteinuria. When used, reagent strip results
should be confirmed by laboratory testing (Figure 16).
The combination of reagent strips with automated reader
devices can improve inter-operator variability. More recently
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launched reagent strip devices capable of producing albuminor total protein results as a ratio to urinary creatinine require
further evaluation to provide evidence that they haveequivalent sensitivity and specificity to laboratory tests andare economically advantageous.
Although the reference point remains the accurately timed
24-hour specimen, it is widely accepted that this is a difficult
procedure to control effectively and that inaccuracies inurinary collection may contribute to errors in estimation ofprotein losses. In practice, untimed urine samples are areasonable first test for ascertainment of albuminuria.
An EMU (‘first pass’) sample is preferred since it correlates
well with 24-hour protein excretion, has relatively low
57chapter 1

intra-individual variability, and is required to exclude the diagnosis of orthostatic (postural) proteinuria. However, a random
urine sample is acceptable if no EMU sample is available.
The concentration of protein or albumin in a urine sample
will be affected by hydration (i.e., how diluted or concentrated a urine sample is). Creatinine excretion is considered
to be fairly constant throughout the day and it has become
customary to correct for urinary concentration by expressing
either the protein or albumin concentrations as a ratio to thecreatinine concentration in the same sample.
Timed urine collections may be used for confirmatory
purposes but are not required except in circumstances inwhich untimed urine ACR is less accurate. It is worthwhile
noting that albumin and protein excretion display considerable biological variability and may be increased by a variety ofpathological and non-pathological factors. Consequently,
confirmation of increased excretion rates is recommended.
Evidence Base
Why is albumin measurement being recommended insteadof total protein? Urine albumin measurement provides amore specific and sensitive measure of changes in glomerularpermeability than urinary total protein.123–125 There issubstantial evidence linking increased albuminuria tooutcomes of CKD4,30 (e.g., CKD Prognosis Consortium2–5,
Nord-Trøndelag Health Study [HUNT 2]125a, Prevention of
Renal and Vascular Endstage Disease [PREVEND]125b). Thereis also evidence that urinary albumin is a more sensitive test
to enable detection of glomerular pathology associated withsome other systemic diseases including diabetes, hypertension and systemic sclerosis.126–129
In health, relatively small amounts of albumin (o30 mg/
24 hours) are lost in the urine. Because of this, andadditionally because total protein assays are imprecise andinsensitive at low concentrations, relatively large increases inurine albumin excretion can occur without causing asignificant measurable increase in urinary total protein.125
Total protein measurement is problematic in urine due to:large sample-to-sample variation in the amount andcomposition of proteins; high and variable concentrationsof non-protein interfering substances relative to the protein
concentration; and high inorganic ion content. All thesefactors affect the precision and accuracy of the various
methods. Most laboratories currently use either turbidimetry
or colorimetry130 to measure total protein and as with urine
reagent strip analysis, these methods do not give equal
analytical specificity and sensitivity for all proteins which cancontribute to diverse estimates of proteinuria prevalence.131,132 Most methods tend to react more strongly with
albumin than with globulin and other non-albumin proteins.34,133–135 There are significant interferences causing
falsely high results.136–138. There is no reference measurement
procedure and no standardized reference material for urinary
total protein listed by the JCTLM. The variety of methods
and calibrants in use means that there is inevitably significant
58

between-laboratory variation.139–141 Since a variable mixtureof proteins is measured, it is difficult to define a standardized
reference material.
How should albumin be measured and reported?

Albumin should be measured using immunological assays
capable of specifically and precisely quantifying albumin at
low concentrations and of producing quantitative results overthe clinically relevant range. Currently urinary albumin is
predominantly measured by diagnostic laboratories using
turbidimetric assays.130 At present there is no reference
measurement procedure or standardized reference material
for urine albumin listed by the JCTLM, although the NKDEPand the International Federation of Clinical Chemistry andLaboratory Medicine have recently established a jointcommittee to address these issues.142,143 At present, mostassays are standardized against a serum-based calibrant (CRM470) distributed by the IRMM of the European Commission,as has previously been recommended by KDIGO.31
Albumin concentration should be reported as a ratio tourinary creatinine concentration (mg/mmol or mg/g). ACR
results should be expressed to one decimal place (mg/mmol) or
whole numbers (mg/g). Both enzymatic and Jaffe assays are
suitable for the measurement of creatinine in urine. We suggestthat the term ‘microalbuminuria’ no longer be used because it
can be misleading in suggesting that the albumin may be small or
different in some way. The proposed albuminuria categories
A1-3 are a more clinically meaningful way to express information
about categories within the continuum of albumin excretion.
Reagent strip point-of-care testing devices capable ofmeasuring low concentrations of albumin are also available
producing both semi-quantitative and fully quantitative ACR
results. Reasonable analytical144–147 and diagnostic performance has been demonstrated.148–150 While studies of thesedevices have been somewhat limited in size, they demonstrate
their potential to play a significant role in the care pathway ofpatients suspected of having CKD.
Why are reagent strip devices for protein measurement
considered less accurate than laboratory measurement?

Reagent strip devices for proteinuria detection have been in use
for more than 50 years. As discussed earlier, a positive reagent
strip result is also associated with outcomes of CKD. Suchdevices have been used to support screening programs in somecountries,151–153 although there appears to be no evidence
supporting such screening of unselected populations.154
Although purporting to measure total protein, the reagent
pad is most sensitive to albumin.155–157 There is evidence that
strips from different manufacturers perform differently at thecutoff (‘ þ ’) concentration of 300 mg/l and degrees of ‘plusness’ between different manufacturers don’t always correspond to the same nominal concentration of protein in
urine.124 Concentrated urines may give a color change in thepositive range of a reagent strip device even though protein
loss remains normal and vice versa. False-positive results may
occur if the urine is alkalinized (e.g., due to urinary tract
Kidney International Supplements (2013) 3, 19–62

chapter 1

infection) or in the presence of quaternary ammonium
compounds that alter the pH of the urine. The performanceof reagent strips is operator-dependent158 and affected by thepresence of colored compounds such as bilirubin and certain
drugs (e.g., ciprofloxacin, quinine, and chloroquine).159
Reagent strips cannot reliably distinguish between proteinuria categories124,157 and show relatively poor diagnostic
accuracy for proteinuria detection.160,161 In the Australian
Diabetes, Obesity and Lifestyle (AusDiab) study, a reagent
strip reading of þ or greater had 58% and 99% sensitivity
for detecting ACR Z30 mg/g (Z 3 mg/mmol) and Z300 mg/
g (Z30 mg/mmol), respectively. 47% of individuals who
tested þ or greater had an ACR Z30 mg/g (Z 3 mg/mmol)on laboratory testing.162
Automated devices capable of reading the color changes ofreagent strips using reflectance spectrometry are available.
These reduce inter-operator variability and improve diagnostic accuracy.150,158,163 A creatinine test pad has been added
to some reagent strip systems to enable a PCR to be reported
and so reduce the intra-individual variation seen withrandom urine collections. Such devices have been shown tobe suitable for ruling out significant proteinuria (4300 mg/
24 hours) in an outpatient setting.149
Correcting for urinary dilution. Since creatinine excretionin the urine is fairly constant throughout the 24-hour period,
measurement of ACR (or PCR) allows correction forvariations in urinary concentration.164,165 ACR is a suitable
alternative to timed measurement of urine albuminloss.143,166–170 PCR on random or early morning untimed
samples shows good diagnostic performance and correlation
with 24-hour collection.160,163,171–177

Expressing albumin as a ratio to creatinine reduces intraindividual variability: lowest variability for the ACR has beenreported in EMU samples as opposed to other untimed
samples or timed collections.142,178 In one study albumin
variability was reduced from 80% to 52% when expressed as
an ACR rather than an albumin concentration.179 The
within-subject biological variation for urinary ACR in an
EMU has been reported to be 31%, compared to 36% forurinary albumin concentration.180 The same study reported
variability for ACR of 103% and 85% in random and timed
24-hour collections, respectively.180 Intra-individual variation
for protein loss is also significantly reduced when reported asa PCR compared to protein concentration in random urine
samples collected throughout the day (a mean reduction
from 97% to 39%).179
Why and how should a finding of albuminuria be confirmed?

Given the high biological variation and other pathologicaland physiological causes of albuminuria (Table 19),143 repeat
testing to confirm albuminuria, ideally using an EMU andlaboratory testing, is recommended (Figure 16).
There has been extensive discussion in the literature about
the appropriate urine sample to use for the investigation ofprotein loss. It is generally recognized that a 24-hour sample
is the definitive means of demonstrating the presence ofproteinuria. However, overnight, first void in the morning(i.e., EMU), second void in the morning, or random sample
collections can also be used. In a systematic review random
urine PCR was shown to have better performance as a test forruling out significant proteinuria than as a ‘‘rule-in’’ test; theauthors suggested that positive PCR results may still require

Table 19 | Factors affecting urinary ACR
FactorExamples of effectPreanalytical factors
Transient elevation in albuminuria

Intraindividual variability
Preanalytical storage conditions
Non-renal causes of variability in creatinine
excretion

Changes in creatinine excretion

Menstrual blood contamination
Symptomatic UTI181
Exercise182
Upright posture (orthostatic proteinuria)41,183
Other conditions increasing vascular permeability (e.g., septicemia)
Intrinsic biological variability180
Genetic variability184
Degradation of albumin before analysisa
Age (lower in children and older people)
Race (lower in Caucasian than black people)
Muscle mass (e.g., lower in people with amputations, paraplegia, muscular dystrophy)
Gender (lower in women)Non-steady state for creatinine (AKI)

Analytical factors
Antigen excess (‘prozone’) effectSamples with very high albumin concentrations may be falsely reported as low or normal using someassays124

Abbreviations: ACR, albumin-to-creatinine ratio; AKI, acute kidney injury; UTI, urinary tract infection.
aSamples for urinary albumin (or total protein) measurement may be analyzed fresh, stored at 41C for up to one week, or stored at -701C for longer periods. Freezing at -201C
appears to result in loss of measurable albumin and is not recommended. When analyzing stored samples, they should be allowed to reach room temperature andthoroughly mixed prior to analysis.142

Kidney International Supplements (2013) 3, 19–62

59chapter 1

confirmation with a 24-hour collection.185 If an EMU isunavailable, subsequent samples can give a reliable indicationof the 24-hour urine protein loss.174
International RelevanceThe recommendation to replace urinary total protein with
albumin as the test of choice in testing for proteinuria isconsistent with most,1,31,130,186,187 but not all,188,189 current
national and international guidance. It is accepted that costpressures may affect implementation of this recommendationand may differ across the world.
Most international guidelines have also discouraged theuse of reagent strip analysis for proteinuria detection.186,189–191 Nevertheless, in the present guideline we
acknowledge that these devices may have a role, particularly
in settings where access to laboratory services may be limited.
ACRs in North America tend to be reported in mg/g
whereas in other parts of the world usage of mg/mmol
predominates. This difference appears unlikely to be resolvedin the foreseeable future. When publishing data authors
should ensure either that both units are cited or that a
conversion factor is provided.
There is increasing adoption of the term ‘albuminuria’
instead of microalbuminuria by international and national
laboratory and some clinical organizations.
Implications for Clinical Practice and Public Policy

Direct reagent costs of total protein measurement are
generally lower than those of albumin measurement, which
requires antibody-based reagents. It is often considered thatreagent strip analyses are a cheaper option. Therefore somehealth-care systems may struggle to justify the recommendations in this guideline.
Costs of diagnostic tests vary depending on local financial
agreements between hospitals and suppliers. In England,
the National Institute for Health and Clinical Excellence (NICE)
sampled a small random number of laboratories and estimatedthe average cost of an ACR to be d2.16 whereas a PCR cost
d1.42.186 It is acknowledged that increased use of ACR testing
may reduce the unit cost on the basis of economies of scale. In
Canada, laboratory analysis costs (Canadian dollars) of $2.81
for reagent strip, $11.67 for PCR, and $29.23 for ACR have been
cited.192 In relation to albumin-specific reagent strips, a cost of
approximately $4 for a Micral test II (Roche Diagnostics)
compared to $2 for a laboratory ACR has been reported.193
The cost- and clinical-effectiveness of an approach
utilizing reagent strip testing followed by laboratory measurement compared to an approach in which samples are
submitted directly to the laboratory (for either albumin orprotein measurement) has recently been evaluated in a healtheconomics model.186 The model favored abandoning the useof reagent strips for identification of proteinuria.
Areas of Controversy, Confusion, or Non-consensus

Some data suggest that ACR is a poorer predictor of 24-hour
total protein loss than PCR194 and has no advantage over60

PCR as a predictor of renal outcomes and mortality inpatients with CKD.195,196 In the prediction of futuretransplant rejection, PCR has been reported to have equal
utility to ACR,192 although in a separate study ACR was
found to be a better predictor.197
In the setting of preeclampsia, proteinuria is generally
defined as Z300 mg/24 hours or a PCR Z300 mg/g
(Z30 mg/mmol).175 Currently, there is insufficient evidence
to substitute urine albumin measurement for total protein inthis setting.172
Creatinine excretion is affected by a variety of non-renal
influences (Table 19) and it therefore follows that different
cutoffs for ACR (and PCR) may be required in different
individuals.194,198 While age-related cutoffs have not generally been applied in clinical practice, clinicians should bear
this in mind when interpreting urine ACR data in older
individuals or those with very low body mass, as these will
impact the urine creatinine excretion.
While most guidelines agree that an ACR greater thanapproximately 3 mg/mmol (30 mg/g) is pathological in thesetting of diabetes, in the non-diabetic population a higher
threshold has commonly been used to define proteinuria. In the
NICE guideline in England and Wales, proteinuria in nondiabetic individuals was defined as Z30 mg/mmol (Z300 mg/g),
with higher level proteinuria being 470 mg/mmol (4700 mg/
g).186 Confirmation of results lying between 30 and 70 mg/mmol(300-700 mg/g) was recommended.186 The present guideline
proposes a lower threshold definition for albuminuria for use inboth diabetic and non-diabetic individuals.
A study from Italy in type 2 diabetes has reported that,
although intra-individual biological variation of albuminuria
is large, a single sample (either ACR or timed collection) canaccurately classify patients into albuminuria categories,
negating the need for multiple collections.178
Some data suggest that a significant proportion ofalbumin present in urine may be non-immunoreactive,199–202
although this finding has been questioned.203,204
There is a substantial existing literature using the term
microalbuminuria and many existing guidelines use this term
especially in the context of diabetes and cardiovascular risk,
as its presence confers risk. Nonetheless, the Work Group
believes that it is important for this international guideline tofoster ‘best practices’ and clarity of communication, andsince the risk of adverse events is continuous throughout the
spectrum of albuminuria, we encourage adoption of the term
‘albuminuria’ with subsequent quantification of the level oramount.
Pediatric Considerations

For Recommendation 1.4.4.1, this set of statements would need
to be altered for application in the pediatric practice as follows:
We suggest using the following measurements for initial
testing of proteinuria in children (in descending order ofpreference):(1) urine PCR, EMU sample preferred;(2) urine ACR, EMU sample preferred;
Kidney International Supplements (2013) 3, 19–62

chapter 1(3) reagent strip urinalysis for total protein with automatedreading;(4) reagent strip urinalysis for total protein with manual
reading.
For Recommendations 1.4.4.2 and 1.4.4.3, this set ofstatements would need to be altered for application in thepediatric practice as follows:
Currently the urinary PCR should be favored over theurine ACR in children. Unlike in adults where powerfulevidence exists in support of the use of measures of albuminrather than total protein to predict adverse outcomes, thislevel of evidence is currently lacking in children.205 However,current longitudinal trials such as CKiD55 and European 4C78
may eventually shed light on this issue.
In children the underlying conditions associated with thediagnosis of CKD are also important considerations as towhich form of testing is most valuable. Unlike adults where
the majority of patients with CKD are attributed to anunderlying glomerular disease or hypertensive damage, thevast majority of children have underlying developmental
abnormalities often referred to as CAKUT (congenital
anomalies of the kidney and urinary tract).70 This relative
paucity of glomerular conditions makes the use of albumin
excretion a less sensitive test for diagnostic purposes as many
children will have underlying tubular conditions and hence
tend to excrete more Tamm-Horsfall protein and other lowmolecular-weight proteins that will not be captured by thealbumin-to-creatinine (or formal albumin excretion) assay.
For Recommendations 1.4.4.2 and 1.4.4.2.1 this guideline
is fully applicable in pediatrics. The recommendation thatclinical laboratories report ACR and PCR in untimed
urine samples in addition to albumin concentration orproteinuria concentrations rather than the concentrations
alone is valid and useful in the pediatric population. As per
Recommendation 1.2.4, however, note should be madethat age-related normal values for urinary protein losses
must be considered when laboratories choose to report either
ACR or PCR.
Albuminuria in children, whether measured as an absolutevalue per day, an excretion rate, or as an albumin tocreatinine ratio is fraught with more uncertainity than in
adults as they are known to vary across categories of age, sex,
height, weight, and Tanner staging.206
In two recent reviews by Rademacher206 and Tsioufis et al.,205
both groups examined the results of all relevant studies on
normative values of AER or ACR. Rademacher’s paper inparticular provides detailed information on the mean AERvalues (with SD) across a variety of studies, ages, sex, and race,and provides a normative estimate for overnight AER of
between 2-6 mg/minute or a 95th percentile value from 4.5–28 mg/
minute. Similarly, they summarize results for ACR in normalchildren and suggest that the mean for children older than 6
years would seem to fall between 8-10 mg/g (0.8-1.0 mg/mmol).
For Recommendation 1.4.4.3, this guideline is fully
applicable in pediatrics.
Kidney International Supplements (2013) 3, 19–62

1.4.4.4:

If significant non-albumin proteinuria is suspected, use assays for specific urine proteins(e.g., a1-microglobulin, monoclonal heavy or
light chains, [known in some countries as‘‘Bence Jones’’proteins]). (Not Graded)

RATIONALE

Testing for tubular proteinuria using a total protein approachalmost certainly has very poor sensitivity for detecting
tubular disease. When an isolated tubular lesion is suspected(Table 3), this is probably best investigated by measuring a
specific tubular protein (e.g., a1-microglobulin) using an
immunoassay approach.
Evidence Base

There have been concerns that replacing urinary total protein
measurement with albumin measurement may cause nonalbuminuric (effectively tubular and overproduction) proteinuria to be missed. Low-molecular-weight proteinuria is adefining feature in some uncommon kidney diseases (e.g.,
Dent’s disease).207 However, for some of the reasons alreadydiscussed, total protein assays will also be poor at detecting
tubular proteinuria. When investigating patients for tubular
proteinuria, it is advisable to use assays targeted at specifictubular proteins.
In the AusDiab study, of those with proteinuria (2.4% of thegeneral population, defined as a PCR 423 mg/mmol [230 mg/g]) 92% had albuminuria (defined as an ACR 43.4 mg/mmol[34 mg/g]); 8% had an ACR within the reference range.208 These
individuals were less likely to have diabetes than those with bothproteinuria and albuminuria, but no further information isavailable as to the nature of the proteinuria in these individuals
or its likely significance. The authors speculate that these
individuals could have had light chain proteinuria or interstitialnephropathies. Using albuminuria testing to identify proteinuria had a specificity of 95%. The negative predictive value was
99.8% and the positive predictive value was 32.4%. The authors
concluded that testing for albuminuria rather than proteinuria
was supported.
As discussed above, quite significant increases in urinary
albumin loss have to occur before such an increase isdetectable on the background of a total protein assay. The
situation is even more extreme for tubular proteins which, in
health, are present in urine at lower concentrations thanalbumin (e.g., normal daily losses of retinol binding protein,
a1-microglobulin and b2-microglobulin are 0.08, 3.6, and
0.1 mg/d, respectively).209 This problem will be exacerbatedby the fact that the recognition of tubular proteins by sometotal protein assays is poor.210
In disease states concentrations of tubular proteins, at least
collectively, can reach levels detectable by total protein assays.
For example, among patients with tubulointerstitial disease
but without renal insufficiency, median concentrations of a1microglobulin were 37 mg/l, with concentrations up to 100 mg/l
being observed; higher concentrations were seen in patients withdecreased GFR.211 Among a group of patients with acute61chapter 1

tubular necrosis requiring dialysis treatment, median a1microglobulin concentration was 35 mg/mmol of creatinine.212
However, although tubular proteinuria is characterized by arelative increase in low-molecular-weight protein concentrations, generally albumin still remains a significant component of
the total protein concentration. Indeed, it is thought thattubular disease results in an increase in albumin loss as a resultof decreased tubular reabsorption of filtered albumin. For
example, it has been estimated that when tubular absorption
fails completely, b2-microglobulin loss increases to 180 mg/24
hours (approximately 1800-fold normal) but there will also be
an increase in urinary albumin loss to about 360 mg/24 hours(approximately 20-fold normal).209 In a series of patients with
Dent’s disease, a classical tubular disorder, 21 of the 23 patientsdemonstrating increased urinary a1-microglobulin and b2microglobulin loss also had increased urinary albumin loss:
those who did not had borderline increases in tubular protein
losses that would not have been detectable using a total protein
measurement approach.207 The authors comment that in thosepatients in whom proteinuria was marked (41 g/d), urinary
albumin loss was also markedly increased. In some situations,however, tubular proteinuria in the absence of albuminuria has
been reported (e.g., in some children with type 1 diabetes213 andin kidney scarring in reflux nephropathy214).

Areas of Controversy, Confusion, or Non-consensus

Testing for proteinuria using a urine albumin rather than
total protein first-line approach may occasionally miss casesof tubular proteinuria but the significance of this problem isprobably overestimated and should be the subject of further
research.
Earlier guidance from KDOQI1 suggested that proteinuria
in children should be detected with total protein rather thanalbumin assays due to the higher prevalence of nonglomerular diseases in this group of patients. For the reasons
outlined above, we do not think total protein assays are
suitable for this purpose and would ideally recommend
testing for albumin and for specific tubular proteins when
non-glomerular disease is suspected.
Pediatric Considerations

For Recommendation 1.4.4.4, this statement is fully applicable in pediatrics. In children the likelihood of any form of
overflow proteinuria such as seen in conditions of heavy or
light chain production is extremely low; however a significant
number of underlying genetic tubular disorders do exist andprotein electrophoresis can assist the practitioner in determining the presence of such a condition or the concurrent
finding of severe tubular injury in addition to a glomerularcondition.

International Relevance

There is no reason to believe that there are significant
differences around the world with respect to incidence or
prevalence of conditions in which measurement of nonalbumin proteins would be required. The availability of
reliable tests for these alternative proteins, however, may bedifferent in different regions.
Implications for Clinical Practice and Public Policy

The incidence and prevalence of tubular disorders will vary
geographically with the clinical setting (e.g., adult or
pediatric practice) and factors such as occupational exposure.
Clinicians should agree with their local laboratories a suitableapproach to the detection of tubular proteinuria andlaboratories should be able to advise on suitable sample
handling procedures. It is acknowledged that many laboratories do not currently offer assays of tubular proteins.
In patients with suspected myeloma, monoclonal
heavy or light chains (known in some countries as BenceJones) protein should be sought in concentrated urine using
electrophoresis with immunofixation of any identified
protein bands in accordance with current myeloma guidelines.215 Simultaneous albumin measurement is needed when
the possibility of immunoglobulin light chain (AL) amyloid
or light chain deposition disease is suspected.
Non-albumin proteinuria may also be suspected inpatients with disorders of tubular function (see Table 3).

62

DISCLAIMER

While every effort is made by the publishers, editorial board,
and ISN to see that no inaccurate or misleading data, opinion
or statement appears in this Journal, they wish to make it
clear that the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board andtheir respective employers, office and agents accept noliability whatsoever for the consequences of any suchinaccurate or misleading data, opinion or statement. While
every effort is made to ensure that drug doses and otherquantities are presented accurately, readers are advised thatnew methods and techniques involving drug usage, anddescribed within this Journal, should only be followed inconjunction with the drug manufacturer’s own publishedliterature.

SUPPLEMENTARY MATERIAL

Supplemental Table 1: Search strategy.
Supplemental Table 2: Equations based on serum creatinine assays inadults that are not traceable to the standard reference material.
Supplemental Table 3: Equations based on serum cystatin C assays inadults that are not traceable to standard reference material.
Supplementary material is linked to the online version of the paper at
http://www.kdigo.org/clinical_practice_guidelines/ckd.php

Kidney International Supplements (2013) 3, 19–62

chapter 2

http://www.kidney-international.org& 2013 KDIGO

Chapter 2: Definition, identification, and predictionof CKD progression
Kidney International Supplements (2013) 3, 63–72; doi:10.1038/kisup.2012.65

2.1: DEFINITION AND
PROGRESSION
2.1.1:IDENTIFICATION

OF

CKD

Assess GFR and albuminuria at least annuallyin people with CKD. Assess GFR andalbuminuria more often for individuals at
higher risk of progression, and/ or where
measurement will impact therapeutic decisions (Figure 17). (Not Graded)

RATIONALE

The statement is worded this way to remind the practitioner
to use both GFR and albuminuria in order to assess
progression and is consistent with the definition offered in
Chapter 1 regarding definitions of CKD which include bothparameters. There is increasing evidence which supports thatboth parameters are valuable. Lower GFR and greater

albuminuria are both associated with an increased rate ofprogression and are synergistic.
More frequent measures of eGFR and albuminuria should beconsidered in patients with a lower GFR and greater
albuminuria as these people are more likely to progress.
Frequency of measurement should also be individualized basedon the patient history and underlying cause of kidney disease.
In specific conditions (e.g., GN or increased levels ofalbuminuria), frequent (every 1–3 months) assessment may
guide therapeutic decisions. Regular monitoring of stablepatients may include more frequent monitoring thanannually, but will be dictated by underlying cause, history,
and estimates of GFR and ACR values obtained previously.
Evidence Base

There is variability in the presence of or rate of declineof kidney function in those with CKD. The rate at which

Persistent albuminuria categories
Description and range

GFR categories (ml/min/1.73 m2)
Description and range

Guide to Frequency of Monitoring(number of times per year) by
GFR and Albuminuria Category

A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30–300 mg/g
3–30 mg/mmol>300 mg/g>30mg/mmol

G1

Normal or high≥90

1 if CKD

1

2

G2

Mildly decreased

60–89

1 if CKD

1

2

G3a

Mildly to moderately
decreased

45–59

1

2

3

G3b

Moderately toseverely decreased

30–44

2

3

3

G4

Severely decreased

15–29

3

3

4+

G5

Kidney failure

<15

4+

4+

4+

Figure 17 | GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep
red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). Green reflects stable disease, withfollow-up measurements annually if CKD is present; yellow requires caution and measurements at least once per year; orange requires
measurements twice per year; red requires measurements at 3 times per year while deep red may require closest monitoring approximately
4 times or more per year (at least every 1–-3 months). These are general parameters only based on expert opinion and must take into
account underlying comorbid conditions and disease state, as well as the likelihood of impacting a change in management for any
individual patient. CKD, chronic kidney disease; GFR, glomerular filtration rate. Modified with permission from Macmillan Publishers Ltd:
Kidney International. Levey AS, de Jong PE, Coresh J, et al.30 The definition, classification, and prognosis of chronic kidney disease: a KDIGO
controversies conference report. Kidney Int 2011; 80: 17–28; accessed http://www.nature.com/ki/journal/v80/n1/full/ki2010483a.html
Kidney International Supplements (2013) 3, 63–72

63chapter 2

Table 20 | Decline in kidney function in various populations (longitudinal studies only)
Reference

Population

Slack TK216
Rowe JW et al.217
Lindeman RD218
Halbesma N et al.219
Imai E et al.220
Matsuchita K et al.221
Kronborg J et al.222

Healthy
Healthy kidney donors
Healthy males
Healthy males
PREVEND cohort (all participants)
Annual health exam participants in Japan
Atherosclerosis Risk In Communities Cohort
Healthy adults from Norway

Lindeman RD218
Lindeman RD218
Halbesma N et al.219
Halbesma N et al.219
Imai E et al.220
Imai E et al.220

Hemmelgarn B et al.223
Hemmelgarn B et al.223
Hemmelgarn B et al.223
Hemmelgarn B et al.223
Keller C et al.224

N
141
293
254
6894
120,727
13,0294441

With comorbidity
Males with renal/urinary tract disease
Males with hypertension
PREVEND cohort – adults with macroalbuminuria (4300 mg/24 hours)
PREVEND cohort - Adults with impaired renal function(5% lowest CrCl/MDRD GFR)
Annual health exam participants in Japan with hypertension
Annual health exam participants in Japan with proteinuria(X1+ dipstick proteinuria)
Older adults
Males age 465 with diabetes
Males age 465 without diabetes
Females age 465 with diabetes
Females age 465 without diabetes
Cardiovascular Health StudyGFR decline
0.40 ml/min/year
0.90 ml/min/1.73 m2/year (CrCl)
0.75 ml/min/year (CrCl)
0.55 ml/min/1.73 m2/year
0.36 ml/min/1.73 m2/year
0.47%/year (median)
1.21 ml/min/1.73 m2/year (men)1.19 ml/min/1.73 m2/year (women)

118
74
86
68

1.10 ml/min/year (CrCl)
0.92 ml/min/year (CrCl)
1.71 ml/min/1.73 m2/year
0.05 ml/min/1.73 m2/year

16,7222054

0.3 to 0.5 ml/min/1.73 m2/year
0.6 to 0.9 ml/min/1.73 m2/year

490
2475
445
3163
4128

2.7 ml/min/1.73 m2/year
1.4 ml/min/1.73 m2/year
2.1 ml/min/1.73 m2/year
0.8 ml/min/1.73 m2/year
1.83 ml/min/1.73 m2/year (based on
cystatin C-based eGFR)

Abbreviations: CrCl, creatinine clearance; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; PREVEND, Prevention of Renal and Vascular End-Stage
Disease.

this decline occurs also varies based on the underlying
population, cause of CKD, presence of albuminuria/proteinuria, comorbidities and age. The Work Group searched theliterature for longitudinal studies that evaluated decline
in kidney function. As outlined in Table 20 the study
populations included healthy adults, those with comorbidity,
as well as a subgroup of adults aged 65 and older.
Data from the PREVEND study, a prospective, population-based cohort study, provides important information
on decline in kidney function at the population level.219
The PREVEND study evaluated 6894 people over a 4-year
period and reported loss in eGFR of 2.3 ml/min/1.73 m2/
4 years in the whole population, 7.2 ml/min/1.73 m2/4 years
in participants with macroalbuminuria (4300 mg/24 hours)
and 0.2 ml/min/1.73 m2/4 year in participants with impaired
renal function. The yearly decline in eGFR among a Japanesegeneral population over 10 years was slightly lower at
0.36 ml/min/1.73 m2/year.220 The rate of eGFR decline wasapproximately two times higher in participants withproteinuria, and about 1.5 times higher among participants
with hypertension.220 Among adults aged 65 and older,
progression (median follow-up 2 years) varied by sex andpresence of diabetes.223 In general these studies suggest
progression rates of approximately 0.3 to 1 ml/min/1.73 m2/
year among participants without proteinuria or comorbidity and rates of approximately two to three times higher
among participants with proteinuria or comorbidity. The
somewhat surprising finding that eGFR had low rates ofprogression among the group with impaired renal function64

at baseline219 has been shown in other studies225 and may
relate to the statistical phenomenon of regression to themean. There is also a concern that it is hard to maintainconsistent calibration of the SCr assay over time andprogression results are highly sensitive to drift in thecreatinine assay.
Studies evaluating rate of decline in eGFR among
populations with CKD specifically are outlined in Table 21
and typically demonstrate a slightly more rapid rate of
decline in this subgroup, thus requiring more frequentassessment of GFR and albuminuria.
Data from the MDRD Study during a mean 2.2 year
follow-up showed that the average rate of decline in GFR
ranged from 2.3 to 4.5 ml/min/year, depending on thebaseline GFR and protein/MAP treatment assignments.227
Similarly, a more recent study of 4231 patients with GFR
categories G3a-G5 (GFRo60 ml/min/1.73 m2) referred to anephrologist showed a mean decline in GFR of 2.65 ml/min/
1.73 m2/year,231 and variability in the rates of decline in thisreferred cohort.
Note that there have been no studies which evaluate theutility of more or less frequent monitoring in CKD cohorts.
International Relevance

Frequency of measurements of GFR and albuminuria mayvary by country and so are economic resources available
to support such testing, and the ability to implement
therapeutic strategies to address changes. Nonetheless, given
the availability of simple monitoring tools like urine reagent
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chapter 2

Table 21 | Decline in kidney function in CKD populations

Study

Study population

MDRD Study
Group226
227

Klahr S et al.

Wright J et al.228

Eriksen B229
Jones C et al.230
Levin A et al.231

N

Baseline GFR
ml/min/1.73 m2

Mean Follow-up
years

GFR decline
Mean (SD) or(95% CI) ml/min/1.73 m2/year

1.2

3.7 (7.6)

2

Study A: GFR 25-80 ml/min/1.73 m

28

Mean (SD)37.1 (8.7)

Study B: GFR 7.5-24 ml/min/1.73 m2
Study 1: GFR 25-55 ml/min/1.73 m2- Usual protein, usual MAP- Usual protein, low MAP- Low protein, usual MAP- Low protein, low MAP

6315.0 (4.5)
Mean (SD)37.6 (9.0)
38.2 (8.6)
38.9 (8.8)
39.7 (9.1)

Study 2: GFR 13-45 ml/min/1.73 m2- Low protein, usual MAP- Low protein, low MAP- Very low protein, usual MAP- Very low protein, low MAP
African Americans withhypertension and
GFR 20-65 ml/min/1.73 m2- Low MAP
- Usual MAP

GFR categories G3a and G3b(GFR 30–59 ml/min/1.73 m2)
Nephrology referrals withGFR categories G3a-G5(GFRo60 ml/min/1.73 m2)
Nephrology referrals withGFR categories G3a-G5(GFRo60 ml/min/1.73 m2)

145
149
140
151

62
67
61
65

18.7 (3.1)
18.8 (3.3)
18.3 (3.7)
18.4 (3.5)
Mean (SD)380374

46.0 (12.9)
45.3 (13.2)

3047

Median (IQR)
55.1 (50.8 – 57.9)
Median (IQR)
29 (18-38)

726

4231

Median33 ml/min/1.73 m2

4.3 (4.7)
2.2 years
4.5 (3.7 – 5.3)
3.3 (2.5 – 4.1)
3.3 (2.5 – 4.2)
2.3 (1.5 – 3.0)

4 years

4.9 (3.8 – 5.9)
3.9 (3.2 – 4.7)
3.6 (2.8 – 4.4)
3.5 (2.6 – 4.5)
Mean (SE)2.21 (0.17)
1.95 (0.17)

Median 3.7 years
Median (IQR)
2.9 years (1.3 – 4.1)
Median (IQR)
2.6 years(1.6-3.6)

Mean
1.03 ml/min/1.73 m2/year
Median0.35 ml/min/1.73 m2/year
Mean
2.65 ml/min/1.73 m2/year

Abbreviations: CI, confidence interval; CKD, chronic kidney disease; GFR, glomerular filtration rate; IQR, interquartile range; MAP, mean arterial pressure; MDRD, Modification ofDiet in Renal Disease; SD, standard deviation; SE, standard error.

strips, consideration may be given to implementation of thisassessment in high-risk groups.

ments should be performed based on their ability to inform
strategies which prevent adverse outcomes (e.g., progressionof kidney disease and death).

Implications for Clinical Practice and Public Policy

Practitioners must incorporate underlying category of
GFR and albuminuria as well as cause of kidney disease
and individual patient characteristics in determining thefrequency of ongoing assessment. The implications forpractice include the incorporation of regular monitoringof both GFR and albuminuria into clinical care for patientswith CKD.
There are no immediate implications for public policy ofthis statement.
Areas of Controversy, Confusion, or Non-consensus

There are many who would like more definitive guidance on
frequency of measurement according to specific categories ofrisk. However this is not possible at the current time given
the lack of evidence to guide such statements and the extreme
number of individual circumstances that would mitigate any
proposed protocol.
We recommend further research to more accurately define
the frequency with which GFR and albuminuria measureKidney International Supplements (2013) 3, 63–72

Clarification of Issues and Key Pointsa) Assessment of both GFR and albuminuria should beundertaken to evaluate progression.
b) More frequent assessment is required as kidney diseaseprogresses.
c) Not all individuals with CKD require close surveillance
and monitoring; clinical context remains an important
modifier for all recommendations.
d) While cause of CKD is an important predictor ofprogression, it is the values of GFR and albuminuriathat are used to assess progression.
Pediatric Considerations

Currently there is no evidence as to the value of increasing thefrequency of assessment of either GFR or proteinuria inchildren with CKD. Eventually more complete longitudinal
data from the CKiD cohort55 and hence better granularity of
individual and group rates of decline in GFR may provide thedata required to strengthen proof of this guideline in children.
65chapter 2

As described in detail in the Pediatric Considerations for
Recommendation 1.3.1, there is good observational evidence acknowledging the importance of level of GFR andproteinuria at baseline on predicting rates of progression andit may be that interventional opportunities would exist if
closer monitoring and earlier recognition of worsening inthese values for the individual were available. Future studies
may examine this.
2.1.2: Recognize that small fluctuations in GFR arecommon and are not necessarily indicative of
progression. (Not Graded)
2.1.3: Define CKD progression based on one of more of
the following (Not Graded):
K Decline in GFR category (Z90 [G1], 60-89[G2], 45-59 [G3a], 30-44 [G3b], 15-29 [G4],o15 [G5] ml/min/1.73 m2). A certain drop in
eGFR is defined as a drop in GFR category
accompanied by a 25% or greater drop in eGFR
from baseline.
K Rapid progression is defined as a sustained decline
in eGFR of more than 5 ml/min/1.73 m2/year.
K The confidence in assessing
progression isincreased with increasing number of serum
creatinine measurements and duration offollow-up.

RATIONALE

This statement serves to inform clinicians that some consistentdefinition of progression is required and should be implemented based on an appreciation of baseline values for anindividual. There is considerable controversy as to what
constitutes normal progression of CKD. The potential forbiological and analytical variation associated with use of SCr
measurements should be taken into account as they represent
reversible fluctuations in GFR and are not necessarily
indicative of progression. Further, it is important to recognizethat the degree of precision with which progression is able tobe estimated is highly dependent upon two factors: thenumber of SCr measurements used to define progression andthe duration of follow-up. Estimating risk of ESRD based on
extrapolation of the previous rate of change in GFR required
substantial information (Z4 measurements over Z3 years
in most cases) to add to the risk information in the mostrecent GFR. Further, it should be recognized that somereno-protective treatments (e.g., BP lowering and RAAS
antagonists) result in a slower rate of GFR decline longterm but often lower GFR in a stepwise fashion as a result of
hemodynamic effects. Even substantial (5-25%) reductions in
GFR may be protective, complicating the interpretation ofprogression in these individuals. Finally, underlying diseaseactivity should be considered when assessing patients for
progression of kidney dysfunction.
The importance of determining the rate of decline in
kidney function over time is to identify individuals who are
66

progressing at a more rapid rate than anticipated, which is
associated with increased morbidity and mortality. Individuals who are ‘‘rapid progressors’’ should be targeted toslow their progression and associated adverse outcomes.
A progressive decline in kidney function is influenced bybaseline GFR category and albuminuria category.
Evidence Base

Unfortunately few studies are available to guide us regarding
the optimal definition of ‘‘rapid progression.’’ Such studies
require serial follow-up of patients to calculate change in
GFR over time, with more frequent measurements and longer
duration of follow-up providing more accurate estimates.
The Work Group reviewed cohort studies of the general
population that have evaluated rapid progression of kidney
function (Table 22).
Approaches to define decline in kidney function included
absolute rate of loss232,233,235 as well as percent change.221,234
Studies consistently demonstrate that a more rapid rate ofloss of kidney function was associated with an increased riskof adverse clinical outcomes including death and vascular
related events. These studies have been limited however by
relatively few patients with GFR levelso60 ml/min/1.73 m2,
few measurements of SCr, and relatively short duration offollow-up to obtain accurate estimates of the rate of decline
in kidney function. The precision of the estimate of the slope
depends on a number of factors including the number ofmeasurements of kidney function, biological variability,
measurement error, and duration of follow-up. In general
at least three measures of kidney function are required topermit an estimate of slope.1
None of these studies assessed the impact of albuminuria
on rate of ‘‘rapid decline’’ in kidney function. However as
noted in Recommendation 2.1.1, the presence of proteinuria
has been associated with a faster rate of kidney function
decline compared with people without proteinuria.236–238
Two of the largest prospective cohort studies have shown anapproximate two-fold increase in the rate of decline in GFR
in the presence of proteinuria.219,220 Further evidence
regarding the potential adverse effects of albuminuria on
outcomes has been reported among patients with diabetes.
The AER is one of the best indicators of diabetic nephropathy
risk in both type 1 and type 2 diabetes, and patients withmicroalbuminuria have been reported to have 200 to 400%higher risk for progression to proteinuria than patients withnormal albuminuria.239,240 Long-term follow-up studies havealso demonstrated the increased risk of ESRD associated with
albuminuria among patients with both type 1 and type 2
diabetes.241,242
Given the recognized limitations in defining rapid
progression, the Work Group aimed to provide options fordetermination of progression, based on their clinical utility,and ease of use. One approach included an assessment ofchange in GFR category, combined with a minimal percent
change. A criterion requiring both a change in GFR category(e.g., change from G2 to G3a) and percent change would
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232

Kidney International Supplements (2013) 3, 63–72

Cardiovascular
Health Study- Age 65þ- eGFR
measurements atbaseline, years
3 and 7

Rifkin et al.235
4380

7968

13,029

4378

4171

N

Rapid decline: eGFR
43 ml/min/1.73 m2/yr
Not rapid decline:o3 ml/min/1.73 m2/yr

Quartiles of % annualchange in eGFR:
Q1 (-52.76 to -5.65)
Q2 (-5.65 to -0.47)
Q3 (-0.47 to -0.33)
Q4 (-0.33 to 42.94)% decrease:o20% decrease
Z20% decrease

Rapid decline: eGFR
43 ml/min/1.73 m2/yr
Not rapid decline:
r3 ml/min/1.73 m2/yr

No decline: eGFR 0 ml/min/yr
Mild decline: 0 to 1
Moderate decline: 1 to 4
Severe decline: 44

Categories for decline in
kidney function

All cause,
CVD,
CHD,
& strokemortality
All cause,& CVD
mortality

CHD & allcausemortality

Incident:
HF
MI
StrokePAD

Death

OutcomeMean follow-up
9.9 yrs

Up to Dec 31,
2005(Baseline 1989-94)

Up to Jan 1, 2006
(Baseline 1987-89)

Subsequent
8 years after
enrollment inyear 75.7 yrs (median)

Follow-up

HR (multivariate):
CHD:
Q1: 1.30 (1.11-1.52)
Q2: 1.16 (1.00-1.35)
Q3: Reference
Q4: 1.04(0.90-1.22)
HR (multivariate):
All death: 1.45 (1.13-1.86)
CVD death: 2.48 (1.58-3.89)
CHD death: 2.14 (1.07-4.29)
Stroke death: 2.79 (1.45-5.36)
HR (multivariate):
All death: 1.73 (1.54-1.94)
CVD death: 1.70 (1.40-2.06)

HR (multivariate):
HF: 1.40 (1.20-1.65)
MI: 1.42 (1.14-1.76)
Stroke: 1.11 (0.89-1.37)
PAD: 1.67 (1.02-2.75)

HR (multivariate):
No decline: 1.15 (0.99-1.24)
Mild: Reference
Moderate: 1.10 (0.98-1.30)
Severe: 1.54 (1.30-1.82)

Results (95% CI)

Mortality:
Q1: 1.22 (1.06-1.41)
Q2: 1.05 (0.92-1.21)
Q3: Reference
Q4: 1.10 (0.96-1.27)

Abbreviations: ARIC, Atherosclerosis Risk in Communities; CHD, coronary heart disease; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HF, heart failure;HR, hazard ratio; MI, myocardial infarction; PAD, peripheral arterial disease; yr, year.

Taiwanese civil
servant & school
teachers

Veterans Affairs- GFR categories G3aand G3b (GFR 30–59
ml/min/1.73 m2) withZ2 eGFR
measurements
Cardiovascular
Health Study- Age 65þ- eGFR
measurements atbaseline, years
3 and 7
ARIC study- eGFR
measurements atbaseline and 3 years

Study population

Cheng et al.234

Matsushita et al.221

Shlipak et al.233

Al-Aly Z et al.

Study

Table 22 | Studies evaluating rapid progression (general population studies only)

chapter 267chapter 2

ensure that small changes GFR from 61 to 59 ml/min/1.73 m2
for example, which represents a change in category but aminimal change in GFR, would not be misinterpreted torepresent progression. A change of o25% in a pair of GFRestimates may reflect physiologic variation rather than true
progression.
Additional work to inform this definition has been
undertaken, using data from the Alberta Kidney Disease
Network (AKDN).243 In this analysis 598,397 adults with atleast two out-patient measures of SCr spaced at least 6months apart were included. Progression was defined as‘‘certain’’ (rise or drop) if during the median follow-up timeof 2.4 years there was a change in GFR category combinedwith a 25% or greater change in GFR from the baseline
measurement (constituting a certain rise or a certain drop).
Participants who changed GFR category but did not meet thecriterion of 25% change in GFR were categorized as‘‘uncertain’’ rise or drop. The reference group was comprisedof participants who did not change GFR category over thefollow-up period. As outlined in Table 23, compared toparticipants with stable eGFR, those with a certain drop had
an almost two-fold increase in the risk of all-cause mortality
Table 23 | CKD progression and risk of all-cause mortality and
ESRD using baseline (first) eGFRDefinition ofprogression

All-cause mortality
HR** (95% CI)

ESRD*
HR** (95% CI)

1.51 (1.46–1.56)
1.12 (1.08–1.16)
Ref
0.98 (0.95–1.01)
1.89 (1.83–1.95)

0.33 (0.26–0.42)
0.39 (0.30–0.51)
Ref
2.13 (1.84–2.47)
5.11 (4.56–5.71)

Certain rise
Uncertain rise
Stable (reference)
Uncertain drop
Certain drop

Abbreviations: CI, confidence interval; eGFR, glomerular filtration rate; ESRD, endstage renal disease; HR, hazard ratio.
Data from Turin et al.244,245*ESRD defined as requiring renal replacement therapy.
**Adjusted for age, gender, hypertension, diabetes, proteinuria, Charlson comorbidities and baseline (first) eGFR.

(HR 1.89; 95% CI 1.83–1.95)244 and a five-fold increase in therisk of ESRD (HR 5.11; 95% CI 4.56–5.71).245 Lesser degreeof risk was present for those with an uncertain drop
(reflecting a change in category only). It is worth notingthat once progression occurs, the last eGFR which has a lower
level often contains much of the information about risk of
ESRD and extrapolation of progression using informationfrom prior progression and the most recent eGFR is only
useful if the information about progression is precise and thepatient’s trajectory is linear.
The second approach to define progression takes into
account the rate of change in kidney function based on aslope analysis. In this approach the rate of loss is defined byboth the absolute rate of change and the percent change, as
determined among a cohort of 529,312 adults who had atleast 3 outpatient SCr measurements over a four year period(AKDN databases). Two indices of change in eGFR were
estimated: the absolute annual rate of change (categorized as:increase, stable and -1, -2, -3, -4, and Z -5 ml/min/1.73 m2/
year decline); and the annual percentage change (categorized
as: increase, stable, -1 to -2, -3 to -4, -5 to -6, and Z-7
percent decline/year). The adjusted ESRD risk associatedwith each category of change in eGFR was estimated, using
stable eGFR (no change in eGFR) as the reference. The results
were adjusted in two ways: for eGFR and covariates at thetime of the first eGFR measurement, and at the time of thelast eGFR measurement. As outlined in Table 24, the risk of
ESRD increased almost two-fold for every 1 ml/yr decline ineGFR, when adjusted for covariates and eGFR at the time of
the first eGFR measurement. The risk remained significant,but was less pronounced, when adjustments were performedat the time of the last eGFR measurement. This suggeststhat extrapolation of kidney function beyond the lastmeasurement of eGFR is still informative, but identifies alesser risk. Similar results were obtained when change ineGFR was defined by a percentage.

Table 24 | Association between absolute and percentage change in kidney function and risk of ESRD*, based on adjustment foreGFR at the first and last measurement
Absolute rate of change(over a median of 3.5 years)
Increasing eGFR
Stable (0 ml/min/1.73 m2/year)-1 ml/min/1.73 m2/year-2 ml/min/1.73 m2/year-3 ml/min/1.73 m2/year-4 ml/min/1.73 m2/year-5 ml/min/1.73 m2/year or more
Percentage Change:
Increasing
Stable-1 to -2%/year-3 to -4%/year-5 to -6%/year-7%/year or more

Adjusted for eGFR at firstcreatinine measurement HR** (95% CI)

Adjusted eGFR at last creatinine
measurement HR** (95% CI)

0.64 (0.48–0.86)
Ref
2.05 (1.56–2.69)
2.71 (2.08–3.53)
3.98 (3.06–5.17)
5.82 (4.45–7.61)
12.49 (10.04–15.53)

1.20 (0.90–1.61)
Ref
1.45 (1.11–1.90)
1.58 (1.21–2.06)
1.63 (1.25–2.13)
1.90 (1.45–2.48)
1.70 (1.36–2.12)

0.76 (0.55–1.07)
Ref
1.17 (0.81–1.68)
1.79 (1.25–2.56)
2.26 (1.55–3.29)
11.30 (8.53–14.97)

1.11 (0.80 – 1.55)
Ref
0.97 (0.67–1.40)
1.19 (0.83–1.71)
1.21 (0.83–1.78)
2.17 (1.60–2.93)

Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stge renal disease; HR, hazard ratio.
Data from the Alberta Kidney Disease Network.
*ESRD defined as requiring renal replacement therapy.
**Adjusted for age, gender hypertension, diabetes, proteinuria, Charlson comorbidities and eGFR at the first or last measurement.

68

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chapter 2

Figure 18 | Distribution of the probability of nonlinearity (top) with three example trajectories demonstrating different
probabilities of nonlinearity (bottom). Reprinted from Li L, Astor BC, Lewis J, et al. Longitudinal Progression Trajectory of GFRAmong Patients With CKD. Am J Kidney Dis 2012; 59: 504-512 with permission from the National Kidney Foundation.247; accessed
http://download.journals.elsevierhealth.com/pdfs/journals/0272-6386/PIIS0272638611017896.pdf

With respect to the impact of changes in albuminuria overtime, a study from the Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint trial (ONTARGET) investigators showed that a greater than or equal to
twofold increase in albuminuria from baseline to 2 years
associated with a nearly 50% higher mortality (HR 1.48; CI
1.32-1.66), while a greater than or equal to twofold decrease
in albuminuria associated with 15% lower mortality (HR0.85; CI 0.74-0.98) compared with those with lesser changes
in albuminuria, after adjustment for baseline albuminuria,
BP, and other potential confounders. Increases in albuminuria also significantly associated with renal outcomes, definedas ESRD or doubling of SCr (HR 1.40; CI 1.11-1.78), while adecrease in albuminuria was associated with a decrease of the
combined renal outcome (HR 0.73; CI 0.57-0.95).246
However, preliminary analysis of cohort studies is limited
and suggests that further research is required to moreaccurately determine the change in albuminuria associatedwith an increased risk of kidney disease progression.
There is accumulating evidence that the trajectories of
GFR decline are non-linear, and may take a number ofdifferent courses over time. The longer an individual isfollowed over time, the more likely they are to experience
non-linear change in trajectory.247,248 The non-linearityof a trajectory may be due to intercurrent illness, changes
in medication, intrinsic to the disease process, or any
combination of these factors. Li et al.247 described individual
GFR progression trajectories over twelve years of follow-up
among participants in the African American Study of Kidney
Disease (AASK) (Figure 18). The authors reported that
41.6% of patients exhibited a greater than 90% probability
Kidney International Supplements (2013) 3, 63–72

of having a non-linear trajectory; in 66.1% the probability of
non-linearity was 450%.
International RelevanceStudies to date evaluating rapid progression of kidney disease
have been limited to North American (White and African
American), European, and Asian populations. Given the
differences in the prevalence of CKD by ethnic group, there
may also be variations in rate of progression by ethnicity, andin particular ethnic groups with high rates of comorbid
conditions leading to ESRD such as the Aboriginal population. Thus, the definition of rapid progression may vary
according to country or region. However, by using a generaldefinition of progression, which includes change of categoryof eGFR or albuminuria or both, as well as a numeric changeover an established period of time, we believe that thedefinition of progression can be used in all cohorts.
Implications for Clinical Practice and Public Policy

Practitioners should monitor the GFR and albuminuria at
regular intervals to identify rates of decline which exceed that
normally demonstrated. The rate of GFR decline may berelatively constant over time in an individual; however therate of GFR decline is highly variable among people and overlong periods of observation, within individuals. Thus
clinicians are encouraged to evaluate changes in GFR or
albuminuria in the context of multiple observations overtime, and with attention to clinical events which may have
impacted the change. A number of factors influenceassessment of rate of progression including frequency andduration of GFR and albuminuria measurements as well as
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chapter 2

factors related to the patient (e.g., baseline GFR, comorbidities, age etc.).
There are no implications for public policy at this time.
Areas of Controversy, Confusion, or Non-consensus

The practical issue in clinical practice and clinical trials is
how to define progression (as inferring true deterioration in
kidney function) with meaningful thresholds that are easy
to understand for the non-nephrologist. While changes inproteinuria may signify change in clinical condition, there are
no data yet to suggest that change in proteinuria is itself
reliably associated with progression of CKD per se. This may
be confusing to practitioners, since a change in quantity ofproteinuria is an indication for referral.
We recommend research to confirm rates which can beclassified as slow, moderate, and rapid progression of kidneydisease. The rate to define ‘‘rapid progression’’ may varydepending on the outcome considered, such as kidney failure
versus mortality for example. It will be important for
researchers to determine methods by which reproducibleclassification systems for describing rates of progression canbe developed. There are increasing data to suggest the nonlinearity of progressive disease in many individuals. This
makes extrapolation risky and warrants continued assessmentof the slope on a regular basis.
Clarification of Issues and Key Points

Small fluctuations in GFR are common and should not be
misinterpreted to represent progressive decline in kidney
function. Many factors can cause a small change in GFR
including medications, volume status, measurement error,
and biological variability. Assessment of progressive decline
in GFR needs to take into account the number ofmeasurements considered and time period of assessment.
In pediatrics, information about utilty of serial creatinine
measurements over periods of time during which growth(and muscle mass increase) is occurring, for the diagnosis ofprogression or regression, remains problematic.
Pediatric Considerations

Applying strict GFR criteria in order to develop cutoff values
associated with ‘true’ progression in terms of any one
individual child is not currently possible. Conceptually the
movement from various levels of renal function downward,
in particular if that movement is associated with increasing
comorbidities or intensity of such, is a reasonable approach.
The most informative data available in children comes fromthe longitudinal GFR data from CKiD.72 Examination of thewhole cohort reveals an annual decline in GFR of 4.2%;
median GFR decline was 1.8 ml/min/1.73 m2 (interquartile
range [IQR] 6.6 to 1.6); this can be expressed as a medianabsolute decline in GFR of 4.3 ml/min/1.73 m2 (IQR 11.9 to1.1) and 1.5 ml/min/1.73 m2 (IQR 5.0 to1.8).
Given that the lower IQR in each of the overall cohort andboth sub-groups is equal to or exceeds the suggested declineof 5 ml/min/1.73 m2 as stated here, we suggest that it is70

reasonable to adopt this definition at least for the purpose ofclassification as it relates to ‘rapid’ progression; note theabove values all relate to measured GFR.
Increasing numbers of any given measurement of an event
generally allow for greater precision and accuracy. However,the simple repeated measurements of creatinine over time areless likely to be valuable in children than in adults with CKD.
Unlike adults with static muscle mass and hence expectedstability in creatinine values, or adults with expected
declining muscle mass and hence expectations of declining
creatinine if renal function has remained stable, pediatricpopulations have a situation of increasing muscle mass withexpectation of increasing creatinine in the otherwise normalchild without CKD. In a child with CKD who is growing
therefore, and in particular one going through puberty, thesimple comparison of creatinine values over time will likely
not be sufficient to presume CKD progression or regression
has occurred. The two exceptions to this would be a) a seriesof creatinine measurements demonstrating significant
increase over a short period of time wherein there is nodemonstrable or expected gain of muscle mass; b) values ofcreatinine that over time demonstrate an increase to levels
above that which is expected of the child’s age and sex basedon population normative value for the lab and method of
measurement.
2.1.4: In people with CKD progression, as defined in
Recommendation 2.1.3, review current management, examine for reversible causes of progression,and consider referral to a specialist. (Not Graded)
RATIONALE

This statement intends to reassure patients and practitioners
that not all patients necessarily require referral to specialists,
but that this should be considered in the event that thepatient or clinician requires further guidance or prognostic
information. CKD progression, contextualized for theindividual circumstance, does not always require referral,and earlier guidelines may not have been so overt in stating
this. Faster or unusual trajectories of progression should alert
the patient and physician to assess for potentially reversible
causes of progression.
Progressive kidney disease requires the need for moreaggressive assessment and treatment, which may include
referral to a nephrologist or specialist (if they are notcurrently being managed by a nephrologist).
Evidence Base

Decline in GFR may not be constant, with acute decline
superimposed on CKD (see Chapter 2.2 for discussion offactors associated with progression of a more chronic
nature). The most common risk factors identified for acutedecline in GFR for patients with established CKD include:
obstruction of the urinary tract; volume depletion; nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX 2) inhibitors; select antimicrobial agents
Kidney International Supplements (2013) 3, 63–72

chapter 2such as aminoglycosides and amphotericin B; radiocontrast
agents; and angiotensin-converting enzyme inhibitors(ACE-Is) and angiotensin-receptor blockers (ARBs).249–252
Readers are also referred to the KDIGO Clinical Practice
Guideline for Acute Kidney Injury7 which contains additional
relevant details regarding risk factors for rapid progression
and management strategies.
Rapid sustained decline in GFR could also be considered
an indication for referral once potentially reversible factors as
outlined above have been assessed and treated. The principles
guiding referral include additional input from a nephrologist
into management of CKD and preparation for RRT, such asthat which may be required with rapidly declining GFR. The
NICE guidelines for CKD also recommend referral for‘‘rapidly declining GFR’’ although the definition of rapidly
declining is not provided.186 Most studies assessing nephrology referral have focused on early versus late referral, and notconsidered the impact or implications of nephrology referralin situations associated with rapid decline in GFR.253 The
evidence that such referral will change outcomes is not clear
but given that nephrologists often have access to educationand specialized services, which are essential for optimal
preparation for RRT, referral to a specialist is recommended.
Additional discussion of when to consider a referral to anephrologist can be found in Chapter 5.
International Relevance

Risk factors for acute deterioration in kidney function may varyslightly by country of origin, although the common categories
in general (e.g., medications, volume depletion and urinary
tract obstruction) would be relevant irrespective of country.
This set of statements serves to ensure that attention to changes
in kidney function in those identified with kidney disease is partof the usual care of these individuals.
Implications for Clinical Practice and Public Policy

Practitioners should be aware of the common risk factors for
acute-on-chronic kidney disease resulting in a rapid loss ofkidney function. Acute rapid deterioration in kidney function
should alert the practitioner to assess for these potentiallyreversible causes of progression. This assessment would include
an evaluation for potential urinary tract obstruction as well as a
volume assessment and detailed medication review.
Areas of Controversy, Confusion, or Non-consensus

Readers are referred to the KDIGO Clinical Practice Guideline
for Acute Kidney Injury7 for a detailed discussion of issues
related to definition, diagnosis, and treatment of rapid
progression of kidney dysfunction, as defined by AKI.
Clarification of Issues and Key Points

There are no specific numeric values to define ‘‘rapid loss’’ asthis varies within and between disease states, individuals, andpopulations. The key point for practitioners is to seriallyreview individual trajectories of changes in kidney function
so as to determine stability or not, identify changes in
Kidney International Supplements (2013) 3, 63–72

previous stable trajectories, and to be aware of theimportance of circumstances where AKI changes the courseof CKD. Further studies are required to determine the rate ofloss of GFR that constitutes rapid loss of kidney function. In
children, interpretation of serial changes in SCr requires
understanding of normative value ranges and drivers ofchange in SCr which are different than in adults.
2.2: PREDICTORS OF PROGRESSION
2.2.1: Identify factors associated with CKD progression to inform prognosis. These include cause of
CKD, level of GFR, level of albuminuria, age,sex, race/ethnicity, elevated BP, hyperglycemia,
dyslipidemia, smoking, obesity, history of
cardiovascular disease, ongoing exposure tonephrotoxic agents, and others. (Not Graded)
RATIONALE

The rationale for estimating the risk of kidney failure is thatit may inform referral, care plans, and other therapeuticstrategies, including frequency of monitoring and follow-up.
Previous guidelines have not been able to suggest risk
equations or relative and absolute risks of specific outcomesbut with the data currently available, this is now possible.
There are several factors that influence the likelihood and rateof CKD progression including GFR and albuminuria category,the degree of albuminuria, the cause of kidney disease, ongoing exposure to nephrotoxic agents, obesity, hypertension,age, race/ethnicity and laboratory parameters such as Hb(hemoglobin), albumin, calcium, phosphate, and bicarbonate.
As some of these risk factors are modifiable they should be
actively identified and, if present, be treated as they may
impact long-term outcomes including cardiovascular conditions, QOL, and progression of CKD.
It is not yet clear what the relative weight of each of thesefactors is in predicting in an individual whether he/she will
have progressive CKD.
Evidence BaseAs progression of CKD is defined as either a progressive
decrease in GFR or a progressive increase in albuminuria, weshould consider separately whether different factors would
predict these two components of CKD differently. Given thelimited evidence, this will not be discussed separately. It is
however clear that a subject with a lower GFR to start withwill progress more rapidly to a GFR o15 ml/min/1.73 m2,
just as a subject with already elevated albuminuria will
progress more rapidly to an ACR 4300 mg/g (430 mg/mmol). Similarly, it is well-known that a subject withmembranous glomerulopathy is more likely to progress tonephrotic syndrome, while a subject with adult polycystic
kidney disease is more likely to progress to ESRD.
Although there are many cross-sectional studies that describe
factors associated with a low GFR and factors associated with ahigh albuminuria, the number of studies evaluating which71chapter 2

factors are associated with progressive decreases in GFR andprogressive increases in albuminuria are more limited. In
general, it can be argued that most of the above-mentioned
factors are associated with a more progressive rise in albuminuria
and a more progressive fall in GFR. Most recently, studies havefocused on the development of risk scores for identifying
progressive decreases in GFR and progressive increases inalbuminuria. It has not yet been established which prediction
formula could best be used. Some formulas use just simple
demographic and clinical measures, while others also include
laboratory tests. Some were developed for high-risk populations,such as people with known underlying CVD,254 with CKD ingeneral,255 or with specific causes of CKD, such as IgA
nephropathy,256 diabetic nephropathy,257 or renal artery stenosis.258 Others developed a risk prediction model in the general
population.259 This latter model included age, race, gender, andin dichotomized version, the presence of anemia, hypertension,
diabetes, and CVD history. More recently, two studies used moreaccurate laboratory parameters in addition to demographic
characteristics. The first study was in patients with an eGFR of
15-60 ml/min/1.73 m2/year, and included age, gender, eGFR,
albuminuria, and serum calcium, phosphate, bicarbonate andalbumin.260 The second study was in subjects from the general
population and included age, eGFR, albuminuria, measured
levels of BP and C-reactive protein (CRP).261 The results fromthese predictive models require validation in future studies but
they demonstrate the potential and the capabilities of developing
clinically meaningful classification of risk for individual patients.
Further research is required to establish whether prediction
formulas may differ for different ethnicities.
International RelevanceStudies describing factors associated with lower GFR andhigher ACR have been described from all over the world. In
general, there is much overlap between these data. It may bethat in different parts of the world the relative weight of eachof the factors predicting progressive increases in albuminuria
or decreases in GFR may substantially differ.
Implications for Clinical Practice and Public Policy

It is important to realize that some factors predicting
progression of CKD are modifiable. This holds true forlifestyle measures such as cessation of smoking and prevention of obesity. It also subtends to lowering of BP, lowering ofalbuminuria and prevention of hyperglycemia. A further
factor that may be modifiable is the underlying cause of
CKD. As various causes may respond to targeted treatment,
finding the cause of CKD is the starting point of the work-up
of a subject with CKD. If this causal disease is modifiable, forexample by immunosuppressive treatment, then suchtreatment is the first step to consider. Management of72

patients with CKD and delay of progression are dealt with in
Chapter 3 and more fully in other guidelines (see KDIGOClinical Practice Guideline for Glomerulonephritis8 andKDOQI Clinical Practice Guideline for Diabetes and CKD:
2012 Update.262)
Areas of Controversy, Confusion, or Non-consensus

While there are prediction equations available using combinations of eGFR, albuminuria, cause of CKD, and some or all of
the laboratory abnormalities listed, they have not been used inclinical practice to guide therapy as yet. Furthermore, while theassociated abnormalities clearly increase in severity withworsening kidney function, normalizing them in some instances
has not changed progression to ESRD. The need for prediction
equations to take into account changes over time (trajectories)and stability or instability of specific factors has been raised bymany. Nonetheless, the ability to determine progression versus
stability should be of value for patients and clinicians.
Clarification of Issues and Key Points

Clinicians should attempt to determine stability or progression of patients with CKD for the purposes of informing care.
Further research is required to determine which formula best
predicts who will have progressive increases in albuminuria
and progressive decreases in GFR. The key components ofprediction equations for ESRD may well be different than
prediction equations for cardiovascular events or death.
Pediatric Considerations

A more complete discussion of the evidence in children
supporting these factors as potentially related to risk ofprogression, in addition to the pediatric specific risk ofgrowth/puberty, can be found in the Pediatric Considerations
for Recommendation 1.3.1.
DISCLAIMER

While every effort is made by the publishers, editorial board,
and ISN to see that no inaccurate or misleading data, opinion
or statement appears in this Journal, they wish to make it
clear that the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contributor,
copyright holder, or advertiser concerned. Accordingly, thepublishers and the ISN, the editorial board and their respective
employers, office and agents accept no liability whatsoever forthe consequences of any such inaccurate or misleading data,
opinion or statement. While every effort is made to ensure that
drug doses and other quantities are presented accurately,
readers are advised that new methods and techniques
involving drug usage, and described within this Journal,
should only be followed in conjunction with the drug
manufacturer’s own published literature.

Kidney International Supplements (2013) 3, 63–72

chapter 3

http://www.kidney-international.org& 2013 KDIGO

Chapter 3: Management of progression andcomplications of CKD
Kidney International Supplements (2013) 3, 73–90; doi:10.1038/kisup.2012.66

DELAYING PROGRESSION OF CKD

The following section describes key recommendations andguidance for people with CKD with respect to delaying
progression of CKD. General lifestyle recommendations areprovided as well as caveats given for those with diabetes.
Cardiovascular risk reduction including management ofhypertension, dyslipidemia, and hyperuricemia is further
addressed. Unless otherwise stated, the guidance is intended
to apply to adults with CKD.
For the practicing clinician, ideally working with a team of
health-care professionals, it is important to institute general
lifestyle modification practices in people with CKD so thatthey may gain the benefit of these in addition to morekidney-specific strategies. Often these general measures areoverlooked or disregarded in people with CKD, thus theirutility is underscored here.

3.1 PREVENTION OF CKD PROGRESSION

The management of progression of CKD is aimed ataddressing a multiplicity of factors known to be associatedwith progression. There are general measures which havebeen shown to address cardiovascular health and CKD
together, or each separately. Addressing CVD risk factors may
indirectly and directly impact CKD progression. Strategies
include general lifestyle measures which improve cardiovascular health, BP control, and interruption of the RAAS.
In addition, control of other metabolic parameters such as
blood sugar, uric acid, acidosis, and dyslipidemia may also be
important. This section deals with management of BP, RAAS
interruption, glycemic control and dietary/lifestyle manipulations which have been examined in the context ofdelaying progression of CKD.
BP and RAAS interruption

The following statements are excerpted and where
necessary, condensed, from the KDIGO Clinical Practice
Guideline for the Management of Blood Pressure in CKD.10
3.1.1: Individualize BP targets and agents according to age,coexistent cardiovascular disease and other comorbidities, risk of progression of CKD, presence or absenceof retinopathy (in CKD patients with diabetes), andtolerance of treatment as described in the KDIGO
2012 Blood Pressure Guideline. (Not Graded)
Kidney International Supplements (2013) 3, 73–90

3.1.2:

Inquire about postural dizziness and check forpostural hypotension regularly when treating CKD
patients with BP-lowering drugs. (Not Graded)
3.1.3: Tailor BP treatment regimens in elderly patients withCKD by carefully considering age, comorbidities andother therapies, with gradual escalation of treatment
and close attention to adverse events related to BP
treatment, including electrolyte disorders, acute
deterioration in kidney function, orthostatic hypotension and drug side effects. (Not Graded)
3.1.4: We recommend that in both diabetic and nondiabetic adults with CKD and urine albumin
excretion o30 mg/24 hours (or equivalent*) whose
office BP is consistently 4140 mm Hg systolic or
490 mm Hg diastolic be treated with BP-loweringdrugs to maintain a BP that is consistently r140 mm
Hg systolic and r90 mm Hg diastolic. (1B)
3.1.5: We suggest that in both diabetic and non-diabetic
adults with CKD and with urine albumin excretion of Z30 mg/24 hours (or equivalent*) whose
office BP is consistently 4130 mm Hg systolic or
480 mm Hg diastolic be treated with BP-loweringdrugs to maintain a BP that is consistently r130 mm
Hg systolic and r80 mm Hg diastolic. (2D)
3.1.6: We suggest that an ARB or ACE-I be used in diabetic adults with CKD and urine albumin excretion
30-300 mg/24 hours (or equivalent*). (2D)
3.1.7: We recommend that an ARB or ACE-I be used inboth diabetic and non-diabetic adults with CKD
and urine albumin excretion 4300 mg/24 hours(or equivalent*). (1B)
3.1.8: There is insufficient evidence to recommend combining an ACE-I with ARBs to prevent progressionof CKD. (Not Graded)
3.1.9: We recommend that in children with CKD, BPlowering treatment is started when BP is consistently
above the 90th percentile for age, sex, and height. (1C)
3.1.10: We suggest that in children with CKD (particularly
those with proteinuria), BP is lowered to consistently
achieve systolic and diastolic readings less than orequal to the 50th percentile for age, sex, and height,
unless achieving these targets is limited by signs or
symptoms of hypotension. (2D)
*Approximate equivalents for albumin excretion rate per 24 hours—
expressed as protein excretion rate per 24 hours, albumin-to-creatinine
ratio, protein-to-creatinine ratio, and protein reagent strip results— are given
in Table 7, Chapter 173chapter 3

3.1.11: We suggest that an ARB or ACE-I be used in children
with CKD in whom treatment with BP-loweringdrugs is indicated, irrespective of the level of proteinuria. (2D)
These statements are worded to maintain consistency with
the KDIGO Clinical Practice Guideline for the Management of
Blood Pressure in CKD,10 where the full rationale andevidence behind the statements may be found. In detailing
BP targets, we recognize that we have not made recommendations or suggestions concerning lower limits of BP. The
risks of overtreatment should be specifically considered when
making decisions about BP lowering and this is encapsulated
in the first two guideline statements.
CKD and risk of AKI

3.1.12: We recommend that all people with CKD are
considered to be at increased risk of AKI. (1A)
3.1.12.1: In people with CKD, the recommendations
detailed in the KDIGO AKI Guideline
should be followed for management of
those at risk of AKI during intercurrent
illness, or when undergoing investigationand procedures that are likely to increase
the risk of AKI. (Not Graded)
RATIONALE

Observational data suggest a strong association between preexisting CKD and AKI. The appreciation that CKD patients
may be more susceptible to AKI is the purpose of the above setof statements. However, methodological issues such as how
CKD and AKI are defined in clinical studies and the statisticaladjustments for non-uniformity of comorbidities among
various studies may affect the validity of observed associations.
These statements would be applicable in pediatrics, though thedata are not available for this specific issue.
Evidence BaseCKD is designated as a risk factor for AKI because of theepidemiological association between the two.263,264 A number ofstudies in a variety of settings report an association between
pre-existing CKD and AKI.265–271 CKD is a potent predictor of
acute decline in kidney function following exposure to radiocontrast,272 major surgery,273 and other medical conditions.274
Hsu et al.14 compared the pre-hospitalization MDRD GFR
of 1764 adult members of the Kaiser Permanente Northern
California health-care system who developed dialysis-requiring AKI during hospitalization with 600,820 individuals who
did not. Compared with a reference baseline GFR of Z60 ml/
min/1.73 m2, a baseline GFR of 45–59 ml/min/1.73 m2 wasassociated with an adjusted odds ratio (OR) of in-hospital
AKI of 1.66 (95% CI 1.40–1.97). For GFR values of 15–29 ml/
min/1.73 m2, the adjusted OR for in-hospital AKI was 20.42(95% CI 17.40–23.96). The presence of diabetes, hypertension, and proteinuria increased the likelihood of developing74

in-hospital AKI, with adjusted OR of 1.99 (95% CI
1.78–2.23), 1.55 (95% CI 1.37–1.76) and 2.84 (95% CI
2.52–3.19), respectively. The authors concluded that CKD is
the main risk factor for AKI during hospitalization. A
contrasting approach by Singh et al. defined AKI as dialysisrequiring acute renal failure.275 Because the clinical decision
to dialyze a patient is frequently influenced by a higher
overall SCr, presence of hemodialysis access, or considerationof inevitable progression to ESRD, this definition of AKI
could bias toward capturing more AKI cases in CKD patients.
Moreover, in patients with advanced CKD, the progression of
CKD to ESRD may sometimes be difficult to separate fromacute-on-chronic renal failure. A cohort study by Lafrance
et al. followed a referred CKD population in British
Columbia for a median of 19.4 months after achieving a
GFR of r30 ml/min/1.73 m2. Forty-five percent had at least
one episode of AKI.276 In another cohort study of 920,985
adults in Alberta, Canada with at least one outpatientmeasurement of SCr and proteinuria and not requiring
chronic dialysis, risk of admission with AKI increased withheavier proteinuria and reduced GFR.16
International Relevance

The incidence of AKI in CKD populations may be different
around the world, or have different etiologies. It is not yet
clear what the recovery rates from AKI are in the CKD
population, and how these vary around the world dependent
on cause and duration of AKI.
Areas of Controversy, Confusion, or Non-consensus

Interpretation of published data examining the influenceof pre-existing CKD on the increased likelihood of AKI
is potentially confounded by a number of issues. These
include the comorbidities associated with CKD, influenced
by repeated exposure to various nephrotoxic insults or
in-hospital errors,57,277 or primarily due to the alteredphysiology in CKD. There are also methodological issues
such as how CKD and AKI are defined in clinical studies andthe varying statistical adjustments for comorbidities.
A further important issue to clarify is whether pre-existing
CKD influences the outcome of AKI. Currently, there is no
single biomarker that can differentiate ‘acute’ from ‘chronic’
kidney disease and help to address this issue. Several large
observational and database studies report, surprisingly, lower
in-hospital mortality in patients with AKI superimposed on
CKD compared with controls.278–283 Data from the Programto Improve Care in Acute Renal Disease (PICARD) reveal
lower in-patient mortality and median length of stay inintensive-care unit (ICU) subjects with acute-on-chronic
renal injury compared with non-CKD subjects with AKI,
though the post-discharge dialysis rates were higher insubjects with pre-existing CKD.284
Clarification of Issues and Key Points

AKI is relatively common in CKD populations and impacts
progression adversely. Clinicans should attempt to minimize
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chapter 3

avoidable episodes of AKI (see Chapter 4 for more details) as
part of a holistic approach to delaying progression.
RESEARCH RECOMMENDATIONSProspectively designed clinical studies with a clear anduniform definition of CKD and AKI and adjusted forcomorbidities are needed to determine the:K frequency of AKI events in a CKD population;
K outcome of AKI in patients with CKD;
K importance of proteinuria in addition to low GFR in therisk of AKI.
Protein intake

3.1.13: We suggest lowering protein intake to 0.8 g/kg/day
in adults with diabetes (2C) or without diabetes(2B) and GFR o30 ml/min/ 1.73 m2 (GFR categories G4-G5), with appropriate education.
3.1.14: We suggest avoiding high protein intake (41.3 g/
kg/day) in adults with CKD at risk of progression. (2C)RATIONALE

These statements are worded to reflect the potential benefits
and dangers of varying dietary protein intake (DPI) in people
with CKD. Excess dietary protein leads to the accumulationof uremic toxins, conversely insufficient protein intake maylead to loss of lean body mass, and malnutrition (the latter
more frequent in the elderly). The benefits of dietary protein
restriction include reduction of accumulation of metabolic
waste products that may suppress the appetite and stimulate
muscle protein wasting. The role of dietary protein restriction in slowing progression of CKD is more controversial andadvanced CKD is associated with a protein wasting syndrome
which is directly correlated with morbidity and mortality.
Note that statements about reduction in dietary protein do
not apply to pediatric populations given issues related to
growth and nutrition.
Evidence Base

A number of systematic reviews and meta-analyses havepooled the available RCT data.285–289 Pedrini et al.288
compared a low-protein diet (LPD), defined as a DPI of
0.4 to 0.6 g/kg/day, with a usual diet (5 RCTs, N ¼ 1413) overa period of follow-up ranging between 18-36 months inpeople with non-diabetic CKD and GFR o55 ml/min/1.73 m2.
Fouque et al.285 updated this analysis to include 8 RCTs
in people with non-diabetic CKD (N ¼ 1524). DPI in
their low-protein group was between 0.3-0.6 g/kg/day andfollow-up ranged from 12-24 months (5 of 8 studies were inpeople with GFR categories G4-G5 (GFR o30 ml/min/
1.73 m2). Roberston et al.289 compared diabetic subjects(8 studies in type 1 diabetes, N ¼ 322; 1 study in type 2
diabetes, N ¼ 263). DPI in the low-protein subjects was
0.3-0.8 g/kg/day and usual protein intake ranged from 1-2
g/kg/day. Mean follow-up ranged from 4.5 months to 4 years.
In all studies, compliance with a low DPI was poor. There was
Kidney International Supplements (2013) 3, 73–90

no convincing or conclusive evidence that long-term protein
restriction delayed the progression of CKD.
The largest RCT to date was the MDRD Study.227 The
MDRD Study compared the effects of LPD and BP control on
the progression of CKD in over 800 subjects split into
2 groups. Study A compared a DPI of 1.3 g/kg/day (usual
protein intake) with 0.58 g/kg/day (LPD) in 585 subjects witha measured GFR of 25-55 ml/min/1.73 m2 and the actual
DPIs were 1.11 and 0.73 g/kg/day, respectively. Study B
randomized 255 patients with a measured GFR 13-24 ml/
min/1.73 m2 to DPIs of 0.58 g/kg/day (LPD) or 0.28 g/kg/day
supplemented by keto-aminoacids (denoted by VLPD-KA),actual DPIs were 0.69 and 0.46 g/kg/day, respectively. In eachof the randomization groups ACE-Is were allowed and wereused by 32-44% of patients. Mean follow-up was 2.2 years
and the loss of GFR was estimated by the slope of
125
I-iothalamate clearance measured over 2 years. There wasno difference in GFR decline between groups in Study A andin Study B. Although there was a somewhat faster decline in
GFR in the LPD group compared with the VLPD-KA group,
this was not significant.
A follow-up study of the original MDRD Study followed
those subjects recruited to Study B between 1989-1993 up
until the year 2000. Median duration of follow-up until
kidney failure, death, or administrative censoring was 3.2
years and median time to death was 10.6 years.290 The
authors concluded that assignment to a very LPD did notdelay progression to kidney failure, but appeared to increase
the risk of death in the long-term. The chief limitation of thisfollow-up study was the lack of measurements of DPI andnutritional measurements during the course of the long-term
follow-up period and it is therefore not known how many
patients continued with the LPD or the VLPD-KA diets
after the study concluded.
There is some evidence to suggest that higher protein
diets above the recommended daily intake may accelerate
renal functional decline in people with early CKD. In a
study of 1624 women enrolled in the Nurses0 Health Study,
Knight et al. described the effect of protein intake over an
11-year period in women with eGFR Z80 ml/min/1.73 m2(normal renal function) at baseline and those with eGFR
55-80 ml/min/1.73 m2.291 DPI was measured twice during
the study period at intervals of 4 years using a semiquantitative food-frequency questionnaire that inquired about
the average intake of specified foods and beverages during
the previous year. In women with normal renal function
at baseline high protein intake was not significantly
associated with change in eGFR. However in those witheGFR 55-80 ml/min/1.73 m2 at baseline, protein intake
was significantly associated with a change in eGFR of1.69 ml/min per 1.73 m2 (95% CI, 2.93 to 0.45 ml/
min per 1.73 m2) per 10 g increase in protein intake.
The effect was greatest in those with the highest intake ofnon-dairy animal protein.
Dietary protein restriction of o0.80 g/kg/day appears tooffer no advantage and any dietary protein restriction should75

chapter 3

include careful monitoring of clinical and biochemicalmarkers of nutritional deficiencies. A high total protein
intake, particularly high intake of non-dairy animal protein,
may accelerate renal function decline in people with CKD
and should be avoided.

in 2012. The first three recommendations below are
reproduced verbatim from this guideline.

Clinicians should be aware of different sources of protein, andif lowering of protein is recommended, education andmonitoring for malnutrition should be implemented. Appropriate dietary counseling for CKD patients may have healthcare resource implications, although as part of a combined
strategy to manage obesity, salt intake, and diabetes may beconsidered cost-effective on a population basis in certain
countries. Avoidance of malnutrition is important.

3.1.15: We recommend a target hemoglobin A1c (HbA1c)of B7.0% (53 mmol/mol) to prevent or delay
progression of the microvascular complications ofdiabetes, including diabetic kidney disease. (1A)
3.1.16: We recommend not treating to an HbA1c target of
o7.0% (o53 mmol/mol) in patients at risk ofhypoglycemia. (1B)
3.1.17: We suggest that target HbA1c be extended above
7.0% (53 mmol/mol) in individuals with comorbidities or limited life expectancy and risk ofhypoglycemia. (2C)
3.1.18: In people with CKD and diabetes, glycemic control
should be part of a multifactorial intervention
strategy addressing blood pressure control andcardiovascular risk, promoting the use of angiotensin-converting enzyme inhibition or angiotensin receptor blockade, statins, and antiplatelet
therapy where clinically indicated. (Not Graded)

Areas of Controversy, Confusion, or Non-consensus

RATIONALE

Data are mixed on the value of protein restriction, the values
which are achievable in general populations, and the level of
GFR at which they should be instituted. Nonetheless, theWork Group felt that on balance there is enough data to
support a reduction in dietary protein in selected individuals.
It is important to avoid this advice in those with evidence ofor at risk of malnutrition.

These statements are included to reflect the current evidence
that achieving a hemoglobin A1c (HbA1c) level of B7.0%(53 mmol/mol) is able to prevent the microvascular complications of diabetes, although recognizing that the major riskfor patients attaining HbA1c levels o7.0% (o53 mmol/mol)is hypoglycemia, and that this risk will be higher in people
with lower levels of kidney function.

Pediatric Considerations

Evidence BaseA Cochrane review addresses this issue in children292 byexamining two RCTs with a total of 250 children to
determine the effect of protein restriction on a number ofvariables. The RR of progression to ESRD in the low-protein
restricted versus normal group was 1.12 (95% CI 0.54-2.33).
At two years, progression of kidney disease was not
significant as measured by change in CrCl: mean difference
1.47 ml/min/1.73 m2 (95% CI 1.19–4.14) or growth asmeasured by mean weight difference: 0.13 kg (95% CI
1.10–0.84) or mean height difference: 1.99 cm (95% CI
4.84–0.86). The conclusion of the authors was that a lowprotein diet did not delay progression to kidney failure inchildren, but it may be detrimental to growth.

The evidence base for these statements is reviewed in the
NKF KDOQI Clinical Practice Guideline for Diabetes andCKD: 2012 Update293 and will not be reiterated in full here. It
should be noted that the evidence that intensive glycemic
control reduces the microvascular complications of diabetes
is based almost exclusively on prevention of development ofalbuminuria (ACR 430 mg/g or 43 mg/mmol) and prevention of increasing albuminuria. Evidence from the three mostrecent studies, Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE),294 Action to Control Cardiovascular Risk
in Diabetes (ACCORD),295 and the Veterans Affairs Diabetes
Trial (VADT),296 is summarized in Table 25.
ADVANCE, ACCORD, or VADT did not show significant
benefits of more intensive glycemic control on creatininebased estimates of GFR. However, in the Diabetes Control
and Complications Trial (DCCT)/Epidemiology of Diabetes
Interventions and Complications (EDIC) follow-up study,
1.4% of participants in the previously intensive treatmentgroup and 3.6% of those in the previously conventional
treatment group developed SCr concentrations 42.0 mg/dl(177 mmol/l) (P ¼ 0.01) and 0.6% versus 1.9% required
kidney replacement therapy (P o0.03).297 For patients with
type 2 diabetes, intensive treatment in the United Kingdom

International RelevanceStudies on protein restriction have not been widely tested indifferent ethnicities or within cultures with low baseline
proten intake or purely vegetarian diets. Thus, the applicability of statements to all regions of the world is limited.
Implications for Clinical Practice and Public Policy

Glycemic control

Diabetes is the leading cause of CKD worldwide. Diabetic
nephropathy occurs in 25–40% of patients with type 1 or type2 diabetes within 20–25 years of disease onset and is anindependent risk factor for early death due to CVD. The
mortality rate in people with diabetes and urinary
ACR 430 mg/g (43 mg/mmol) is more than twice that inthose with normal urinary albumin levels.
The National Kidney Foundation (NKF) KDOQI Clinical
Practice Guideline for Diabetes and CKD293 has been updated
76

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chapter 3

Table 25 | Intensive versus normal glycemic control and albuminuria outcome
Study

Intensified treatment versus normal treatment HbA1C goals

Albuminuria outcome

ADVANCE294

6.5% (48 mmol/mol) versus 7.3% (56 mmol/mol)

ACCORD295

6.3% (45 mmol/mol) versus 7.6% (60 mmol/mol)

VADT296

6.9% (52 mmol/mol) versus 8.4% (68 mmol/mol)

9% k in new ACR 3-30 mg/mmol (30-300 mg/g)
30% k in ACR progression to 430 mg/mmol (4300 mg/g)
21% k in new ACR 3-30 mg/mmol (30-300 mg/g)
32% k in ACR progression to 430 mg/mmol (4300 mg/g)
32% k in new ACR 3-30 mg/mmol (30-300 mg/g)
37% k in ACR progression to 430 mg/mmol (4300 mg/g)

Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACR, albumin-to-creatinine ratio; ADVANCE, Action in Diabetes and Vascular Disease: Preterax andDiamicron Modified Release Controlled Evaluation; HbA1C, hemoglobin A1C; VADT, Veterans Affairs Diabetes Trial.

Prospective Diabetes Study (UKPDS) was associated with a
67% risk reduction for a doubling of plasma creatinine levels
at 9 years (0.71% of the intensive group and 1.76% of theconventional group, P ¼ 0.027).298
International Relevance

The incidence and prevalence of diabetes is rising around theworld and at rapid rates in developing countries. Glycemic
control is therefore one of the most important strategies
for delaying progression of CKD, irrespective of region or
country. It is recognized that not all hypoglycemic strategies
or treatments are available in all countries.

span of 90 days. In people with CKD the RBC life span isshortened, even if receiving erythropoiesis-stimulating agents(ESAs). As such, measurement may only reflect glycemic
control over a shorter time period than the presumed 3
months and thus, HbA1C measurements may be falsely low.
Awareness of this may alter clinicians’ reliance on thismeasurement as a long-term measure.299–304 Ongoing
research intitiatives comparing HbA1C with glycated albumin
using continuous glucose monitoring suggest that glycatedalbumin may provide a more reliable index of glycemic
control in people with advanced CKD.
Pediatric Considerations

Implications for Clinical Practice and Public Policy

Practitioners should encourage glycemic control in all people
with CKD and diabetes, including referral to education
sessions and diabetic clinics where available. Public healthpolicies and diabetic strategies should include screening in
high-risk populations such as those with diabetes, as thepresence of CKD would confer higher risk of adverse events,
and could represent an opportunity for intensified intervention with large implications for health-care.
Areas of Controversy, Confusion, or Non-consensus

Recommendations on the use of specific medications forglycemic control (e.g., metformin and glyburide) remainvariable depending on different perspectives. These are covered
more fully in Chapter 4 on medication dosing and AKI.
Clarification of Issues and Key Points

Glycemic control improves outcomes in people with diabetes,with or without CKD. Those with diabetes and CKD havehigher risk of adverse outcomes and therefore presumed
higher benefit from control. Many agents are renally excreted
and therefore adjustments to doses may be necessary as GFRdeclines or if patients are acutely unwell (see Chapter 4 on
medication dosing).
Caveats in measuring glycemic control with HbA1C

HbA1C may not be reflective of glucose control in people
with CKD who have reduced red cell life span, and thus
should be interpreted with caution. Review of blood sugar
daily logs may be more reliable.
Clinicians should be aware that HbA1C measurements that
inform glycemic control are based on an assumed red cell life
Kidney International Supplements (2013) 3, 73–90

It is recommended that the Guidelines of the American
Diabetes Association305 or similar national guidelines fordiabetes management in children and adolescents, bereviewed to address issues related to management of diabetic
children either with, or at risk of, CKD.
Salt intake

3.1.19: We recommend lowering salt intake to o90 mmol
(o2 g) per day of sodium (corresponding to 5 g of
sodium chloride) in adults, unless contraindicated(see rationale). (1C)
3.1.19.1: We recommend restriction of sodium intake
for children with CKD who have hypertension(systolic and/or diastolic blood pressure 495th
percentile) or prehypertension (systolic and/or
diastolic blood pressure 490th percentile ando95th percentile), following the age-based
Recommended Daily Intake. (1C)
3.1.19.2: We recommend supplemental free water andsodium supplements for children with CKD
and polyuria to avoid chronic intravasculardepletion and to promote optimal growth. (1C)RATIONALE

In subjects with CKD, impaired excretion of sodium is often
present. High sodium intake increases BP and proteinuria,
induces glomerular hyperfiltration and blunts the response
to RAAS blockade. Lowering salt intake not only reduces BP,
but also lowers albuminuria. The importance of salt intake
in the general management of CKD patients cannot be
overemphasized, hence the need for specific statements here.
We appreciate that there are some conditions in which salt
77

chapter 3

restriction may be harmful, and hence the qualifier ‘‘unlesscontraindicated.’ These conditions include salt losing nephropathies and those prone to hypotension and volume
contraction who do not have heart failure.
Evidence Base

A systematic review of 16 studies addressing salt intake andkidney disease set out to establish whether variations in
dietary sodium consumption influence renal outcomes inpeople with CKD.306 Despite marked heterogeneity, thereview suggested that increased salt intake was associatedwith worsening albuminuria and an increased likelihood of
reduction of GFR. Although the quality of the studies
included was insufficient to support the authors’ hypothesisthat increased salt intake is nephrotoxic, the results werestrong enough to suggest modest dietary avoidance of salt
should be encouraged in people with CKD, especially thosewith hypertension and/or proteinuria. In a randomized,
double-blind, placebo-controlled trial of salt reduction in 40
Afro-Caribbean hypertensives, a salt-restricted diet (approximately 5 g daily) significantly reduced 24-hour urinary
protein excretion by 19% and led to a fall in systolic anddiastolic BP of 8 mm Hg and 3 mm Hg, respectively.307 The
fall in urinary protein excretion correlated with a reduction
in urinary sodium excretion, not with BP reduction.
Individuals with metabolic syndrome may be especiallysensitive to the effects of sodium intake. Hoffman and
Cubeddu examined the role of salt intake in increased BP in
109 subjects with metabolic syndrome.308 Salt restriction
from an average usual intake of 8.2 g/day to nearly 2.3 g/day
reduced the percentage of hypertensive patients from 23.8%
to 8.2%. In a six-month prospective controlled trial, 110
patients with GFR categories G4 or G5 (GFRo30 ml/min/
1.73 m2) followed a low-sodium (circa 1 g/day) diet as part ofeither a LPD (0.6 g/kg/day) or very low-protein diet (VLPD)
supplemented with essential amino acids (0.35g/kg/day), or afree diet.309 BP fell significantly in the VLPD group from143±19/84±10 to 128±16/78±7 mm Hg (Po0.0001),
despite reduction of antihypertensive drugs. The improved
BP correlated with decreased urinary sodium and the authors
concluded that the antihypertensive effect was due toreduction of salt intake independent of actual protein intake.
Finally, a randomized controlled crossover trial in 52 nondiabetic subjects with CKD compared the effects of a lowsodium diet (target 50 mmol [1.15 g] sodium per day) versus
a regular sodium diet (target 200 mmol [4.60 g] sodium perday) on lowering of proteinuria through RAAS blockade.310
The reduction of proteinuria by the addition of a low-sodium
diet to angiotensin-converting enzyme inhibition was
significantly larger (Po0.001) than the addition of angiotensin receptor blockade to angiotensin-converting enzyme
inhibition and similarly the reduction of systolic BP by theaddition of a low-sodium diet was significantly larger (P ¼
0.003) than the addition of angiotensin receptor blockade.
The authors concluded that sodium restriction to a levelrecommended in guidelines was more effective than dual
78

renin-angiotensin blockade for reduction of proteinuria andBP in non-diabetic nephropathy.
International Relevance

Salt intake has been identified as an important driver of highBP in all countries and in adults, thus this recommendation
is of international relevance and applicability. The relevanceand caveats to children in different situations around theworld merits further review.
Implications for Clinical Practice and Public Policy

In most developed countries, a reduction in salt intake can beachieved by a gradual and sustained reduction in the amountof salt added to foods by the food industry. In other countries
where most of the salt consumed comes from salt added
during cooking or from sauces, a public health campaign isneeded to encourage consumers to use less salt. The range of
sodium intake associated with improved long-term outcomesis easily achievable and may have the potential to greatly
improve health outcomes in patients with CKD around theworld.
Areas of Controversy, Confusion, or Non-consensus

While salt restriction is of benefit on a population-basis, andin most people with hypertension and CKD, there may be
individual conditions in which salt restriction might be
detrimental (e.g., those with salt wasting tubular disorders;those either hypotensive in the absence of heart failure or
those prone to volume contraction). Thus while this generalstatement applies to the majority of people, individualizationis required based on clinical circumstance. This may beparticularly relevant to children.
Pediatric Considerations

The suggested relative salt restrictions for children with CKD
and/or hypertension are age-based with consideration given
to both average intakes and upper limit values. The
recommended upper limit for sodium intake from which a
reduced intake could be derived is provided in Table 26.
It must also be recognized that children with CKD often
have underlying tubular conditions that predispose tonumerous electrolyte losses, including sodium. For thesechildren a supplemental rather than restricted sodium intake
will be required.

Table 26 | Recommended Daily Intake of sodium for healthy
childrenAgeUpper Limit

0-6 months
7-12 months
1-3 years
4-8 years
9-13 years
14-18 years

No data
No data
1500 mg1900 mg
2200 mg
2300 mg

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chapter 3

Hyperuricemia

3.1.20: There is insufficient evidence to support or refute
the use of agents to lower serum uric acidconcentrations in people with CKD and either
symptomatic or asymptomatic hyperuricemia inorder to delay progression of CKD. (Not Graded)
Hyperuricemia is common in people with CKD and isdefined by urate concentrations above 7.0 mg/dl (420 mmol/l)as measured by automated enzymatic (uricase) laboratory
methods. Concentrations obtained with colorimetricmethods are approximately 1 mg/dl (60 mmol/l) lower.
The Work Group believe it important to acknowledge theaccumulating body of evidence describing the association of
hyperuricemia with CKD and adverse cardiovascular outcomes, and thus list hyperuricemia as a potential contributor
to progression. However, at the time of current writing, there
is not a reliable body of evidence from which to recommend
treatment of hyperuricemia for the specific goal of delaying
progression of CKD. Thus, the wording of this ungradedstatement is very deliberate.
RATIONALE

Observational data had implicated uric acid in the progression of CKD suggesting that adverse outcomes in people withCKD may be improved by specific uric acid lowering therapy.
Small studies using appropriate RCT design have shown
reduced left ventricular mass, improved endothelial function,and reduced progression of CKD in people with either
symptomatic or asymptomatic hyperuricemia and CKD.
Thus, the specific statement is intended to ensure and foster
RCTs to properly assess the risk and benefits of uric acidlowering strategies in people with CKD.
Evidence Base

Published data implicate elevated serum uric acid (SUA)
concentrations in the progression of CKD.311–315 Reductionof SUA by allopurinol has been reported to delay progressionof CKD in people with both diabetic and nondiabetic
CKD.316,317 Treatment of asymptomatic hyperuricemia has
also been reported to improve kidney function even in
subjects with normal levels of GFR.318,319 Both GFR andendothelial function significantly improved in asymptomatic
hyperuricemic subjects randomly assigned to 300 mg/day ofallopurinol in comparison to placebo.318 A separate doubleblind, placebo-controlled, parallel-group study in 67 people
with CKD (GFR 30-60 ml/min/1.73 m2) and left ventricular
hypertrophy (LVH) randomly assigned subjects to treatment
with allopurinol (300 mg/day) or placebo for 9 months.320
In comparison to placebo, the allopurinol-treated subjects
had significant reductions in left ventricular mass assessedby magnetic resonance imaging (MRI), and improvements
in endothelial function assessed by flow-mediated dilationof the brachial artery and in central arterial stiffness
assessed by pulse-wave analysis. Another study randomized
70 subjects with known hyperuricemia or SUA concentraKidney International Supplements (2013) 3, 73–90

tions Z7.0 mg/dl (Z420 mmol/l) to treatment with either
allopurinol monotherapy (100-200 mg/day) or a combination of allopurinol and a citrate preparation (3 g/day).321
SUA concentrations were decreased in both groups but to asignificantly lower level by combination treatment. GFR
assessed by CrCl increased in the combination therapy groupbut remained unchanged in those treated with allopurinol
alone. Other uric acid lowering agents have also beenreported to improve outcomes in people with CKD. In an
8-week, placebo-controlled group comparison of rasburicase
and placebo, a single 4.5 mg dose of rasburicase significantly
lowered SUA and resulted in a significant improvement inkidney function assessed by CrCl.322 In a post hoc analysis of1342 patients with type 2 diabetes mellitus and nephropathy
participating in the Reduction of Endpoints in Non-InsulinDependent Diabetes Mellitus with the Angiotensin II
Antagonist Losartan (RENAAL) trial, Miao et al. examined
the relationship between change in SUA concentration after 6
months of treatment with losartan and doubling of SCr or
ESRD.323 Baseline SUA was 6.7 mg/dl (400 mmol/l) in placeboand losartan-treated subjects. During the first 6 months,
losartan lowered SUA by 0.16 mg/dl (9.5 mmol/l) [95% CI
0.30-0.01; P ¼ 0.031] as compared with placebo. The risk of
doubling of SCr or ESRD was decreased by 6% (95% CI 10%3%) per 0.5-mg/dl (30-mmol/l) decrement in SUA during thefirst 6 months. This effect was independent of other risk
markers, including albuminuria.
International Relevance

There are no data to support or refute the importance ofhyperuricemia in different geographical reasons or ethnic
groups. Further study is needed.
Implications for Clinical Practice and Public Policy

There is insufficient evidence to recommend the use of uricacid lowering agents in asymptomatic individuals for the
specific purpose of delaying CKD progression. Further large
trials are required to better understand the potential benefitof uric acid lowering for this purpose.
Lifestyle3.1.21: We recommend that people with CKD be encouraged to undertake physical activity compatible withcardiovascular health and tolerance (aiming for atleast 30 minutes 5 times per week), achieve ahealthy weight (BMI 20 to 25, according to country
specific demographics), and stop smoking. (1D)RATIONALE

People with CKD have self-reported reduced physicalfunctioning and are not as aerobically fit as the general
population. Frailty, impaired physical performance, disability, and geriatric syndromes are common among older adults
even with mild kidney disease. Reduced physical functioning
and inactivity are associated with increased mortality andpoor QOL. Obesity is associated with increased morbidity,
79chapter 3

mortality, and reduction in life expectancy and leads to anincrease in the incidence of diabetes, hypertension, anddyslipidemia. Associations between smoking and CKD
suggest that smoking increases the risk of kidney failure
and that smoking cessation decreases that risk. Thus, thisstatement reflects the importance of ensuring lifestyle
recommendations.
Evidence BaseCKD patients have a reduced exercise capacity and impaired
physical functioning.324–326 Moreover, reduced physicalactivity is associated with increased mortality and poor
QOL in people with CKD.327–329 Regular exercise leads toincreased exercise capacity, decreased morbidity, and improved health-related QOL.330–332 Exercise may reduce
cardiovascular risk through its beneficial effects on BP,
triglycerides, high-density lipoprotein cholesterol (HDL-C),
insulin resistance, and glycemic control. In ESRD, exercise
has been shown to improve arterial stiffness, BP, cardiorespiratory function, and QOL.333–339 Less data are available
on the beneficial effects of exercise on early CKD. However, as
cardiovascular risk gradually increases with both a lower GFR
and a higher ACR, it is expected that exercise will also help toprevent progressive CVD in less severe CKD. Indeed, in
subjects with GFR categories G3a-G4 (GFR 15–59 ml/min/
1.73 m2), long-term exercise training improved physicalimpairment, arterial stiffness, and health-related QOL.340 It
has therefore been argued that exercise training is imperative
in CKD patients341 and that support programs including selfmonitoring, verbal reinforcement, and motivation should beapplied342–344 in an attempt to prevent the high cardiovascular risk in CKD. A prospective study compared the benefitsof 6 months of regular walking in 40 predialysis patients withGFR categories G4-G5 (GFRo30 ml/min/1.73 m2) (20 in an
exercising group and 20 patients who continued with usualphysical activity for comparison). Improvements noted after
1 month were sustained to 6 months in the 18 of 20 who
completed the exercise study. These included improvements
in exercise tolerance (reduced exertion to achieve the sameactivity), weight loss, improved cardiovascular reactivity,
avoiding an increase in BP medication and improvements inquality of health and life and uremic symptom scores asassessed by questionnaire.345
In the absence of diabetes, hypertension or othercardiovascular risk factors there has been a lack of evidence
to support a causal link between obesity and CKD.
Observational studies suggest that obesity is an independentrisk factor for CKD.346–348 The evidence in population studies
is conflicting; some studies have failed to link obesity withdecreased GFR,349,350 possibly because BMI in isolation is apoor measure, while others suggest that CKD is independently associated with BMI.351 It has been known for sometime that obesity is associated with secondary focal andsegmental glomerulosclerosis,352 yet significant associations
between obesity and CKD in large observational studies suchas The Framingham Heart Study disappear after adjustment
80

for age, gender, and cardiovascular risk factors.353 However,systematic review and meta-analysis of weight loss interventions in CKD have shown weight loss to be associated withsignificant decrease in proteinuria and systolic BP with nofurther decrease in GFR in people with CKD during a meanfollow-up of 7.4 months.354 A further systematic review drew
very similar conclusions. Weight loss interventions wereassociated with decreased proteinuria and albuminuria by
1.7 g (95% CI 0.7-2.6 g) and 14 mg (95% CI 11-17 mg),respectively (Po0.05).355 Each 1-kg weight loss was associated with 110 mg (95% CI 60-160 mg; Po0.001) decreasein proteinuria and 1.1 mg (95% CI 0.5-2.4 mg; P ¼ 0.011)
decrease in albuminuria, respectively, independent of reduction in BP.
Multiple studies document a clear association between
smoking and renal damage in the general population,
patients with diabetes, and hypertensive patients.356 Smoking
is causally linked to cardiovascular events in the general
population and is also associated with an increased risk for
cardiovascular events in patients with CKD.357–360 Studies
investigating the beneficial effects of smoking cessation on
kidney function have all been positive.361–365
International Relevance

Exercise, weight loss and smoking cessation in CKD are
equally important in all countries and thus this recommendation is of international relevance and applicability.
Implications for Clinical Practice and Public Policy

Implementation of this recommendation has no publichealth cost but has the potential to make far-reaching publichealth gains both in terms of population health and healthcare economics.
Additional dietary advice

3.1.22: We recommend that individuals with CKD receive
expert dietary advice and information in thecontext of an education program, tailored toseverity of CKD and the need to intervene on salt,
phosphate, potassium, and protein intake whereindicated. (1B)
RATIONALE
International Relevance

The importance of lifestyle recommendations and dietary
counseling cannot be overstated. It is however recognizedthat within the context of different countries, health-caresystems and jurisdictions, the degree to which these can be
implemented is variable. These recommendations serve as a‘best practice’ suggestion.
3.2 COMPLICATIONS ASSOCIATED WITH LOSS OF KIDNEY
FUNCTION

People with CKD are prone to develop a variety of complications which reflect loss of endocrine or exocrine function of
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chapter 3

Table 27 | Prevalence of CKD complications by GFR category*
derived from CKD cohorts
Complication

GFR category (ml/min/1.73 m2)
30-44

o30

Anemia
4.0% 4.7% 12.3% 22.7%
Hypertension2
18.3% 41.0% 71.8% 78.3%
25(OH) Vit D deficiency3 14.1% 9.1%
10.7%
Acidosis4
11.2% 8.4% 9.4% 18.1%
5
Hyperphosphatemia
7.2% 7.4% 9.2% 9.3%
Hypoalbuminemia6
1.0% 1.3% 2.8% 9.0%
Hyperparathyroidism7
5.5% 9.4% 23.0% 44.0%

51.5%
82.1%
27.2%
31.5%
23.0%
7.5%
72.5%

Z90

60-89

45-59

1

Reference
366
366
367
366
366
366
366

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.
*Note that modification of prevalence according to albuminuria categories data is
not yet available to inform this table adequately, though there are limited data tosuggest increasing prevalence of hypoalbuminemia, hypertension, anemia, andacidosis as albuminuria category increases
1
Defined as hemoglobin levels o12 g/dl (120 g/l) for women; o13.5 g/dl (135 g/l)
for men
2
Defined as a systolic blood pressure Z140 mm Hg, diastolic blood pressure
Z90 mm Hg, or self-reported use of antihypertensive medication
3
Less than 15 ng/ml [37 nmol/l] (as defined in Study for the Evaluation of Early
Kidney disease [SEEK])
4Defined as serum bicarbonate less than 21 mEq/l
5Defined as serum phosphate Z4.5 mg/dl (Z1.5 mmol/l)
6Defined as serum albumin less than 3.5 g/dl (35 g/l)
7
Defined as PTH levels Z70 pg/ml; (Z7.4 pmol/l)the kidneys. The incidence and prevalence of these complications increase with severity of CKD as defined predominantly
by GFR categories (Table 27).
It is beyond the scope of this guideline to describe eachof the complications and the proposed treatment options
for them in detail as guidance for these conditions canbe found in other documents. However, for the purpose ofcompleteness, the key complications and management
recommendations for people with CKD are addressed inthis section.
In addition to these complications, we have describedstrategies to delay progression of CKD which are in part
predicated on the identification and management of theclinical, metabolic, and hematologic complications. Note that
not all people with CKD will have all of the complications
and complications may not occur at the same rate or to thesame degree in individuals with the same categories of GFR
or albuminuria. Nonetheless knowledge of the common
complications and treatment options is important in the care
of CKD.

Management of Complications
Anemia in CKD. Anemia is an important complication of

CKD because it contributes significantly to the heavy
symptom burden of CKD. It has a major impact on the livesof people with CKD but it is potentially reversible withappropriate treatment. The guideline statements included
here are those we consider to be the key considerations forpeople with non-dialysis CKD. Interested readers are referredto the KDIGO Clinical Practice Guideline for Anemia in
CKD11 for comprehensive guidance on this topic.
Kidney International Supplements (2013) 3, 73–90

Table 28 | Hemoglobin thresholds used to define anemia
Age or gender groupChildren
6 mo-5 yr
5-12 yr
12-15 yr
Non-pregnant females 415 yr
Pregnant females 415 yr
Men 415 yr

Hemoglobin threshold: g/dl (g/l)
11.0 (110)11.5 (115)12.0 (120)12.0 (120)11.0 (110)13.0 (130)Abbreviations: mo, month; yr, year.
Reproduced with permission from World Health Organization. Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia.368 In: de Benoist
B, McLean E, Egli I and Cogswell M (eds), 2008; accessed: http://whqlibdoc.who.int/
publications/2008/9789241596657_eng.pdf.

Definition and identification of anemia in CKD

3.2.1: Diagnose anemia in adults and children 415 years
with CKD when the Hb concentration is o13.0 g/
dl (o130 g/l) in males and o12.0 g/dl (o120 g/l) in
females. (Not Graded)
3.2.2: Diagnose anemia in children with CKD if Hbconcentration is o11.0 g/dl (o110 g/l) in children
0.5-5 years, o11.5 g/dl (115 g/l) in children 5-12
years, and o12.0 g/dl (120 g/l) in children 12-15
years. (Not Graded)

RATIONALE

These statements reflect the need to measure Hb inpeople with CKD in order to detect if anemia is present,
given its association with poor outcomes and its use inprediction models. Anemia is a common occurrence in CKD
patients, though variable in its time of presentation andseverity within individuals. Thus, the guidelines stress that
evaluation and treatment of anemia in people CKD should beundertaken as in other individuals, and emphasize thatanemia due to CKD is a diagnosis of exclusion. Furthermore, the guidelines stress that laboratory values used for
diagnosis do not imply therapeutic thresholds or targets.
For details, consult KDIGO Clinical Practice Guideline for
Anemia in CKD.11
Evidence Base

Conventionally anemia is defined as a Hb concentration
lower than the established cutoff defined by the WHO.368
Different biological groups have different cutoff Hb values
below which anemia is said to be present, ranging from
11 g/dl (110 g/l) for pregnant women and for children
between 6 months and 5 years of age, to 12 g/dl (120 g/l)
for non-pregnant women, and to 13 g/dl (130 g/l) for men(Table 28).
International Relevance

Globally the prevalence of anemia is 24.8% of the population,much of this is linked to nutritional deficiency exacerbated by81chapter 3

infectious disease. However, altitude, race, and smoking will
each also have an impact on Hb concentration. Hbconcentration can be expected to increase by about 0.6 g/dl
(6 g/l) in women and 0.9 g/dl (9 g/l) in men for each 1000 mof altitude above sea level.369 Hb concentrations also vary
between races, with African-American individuals consistently showing concentrations 0.5 to 0.9 g/dl (5 to 9 g/l)
lower than those of whites or Asian populations.370–372
Smoking is associated with elevated carboxyhemoglobin
levels, which are associated with a compensatory increase
in total Hb concentration. Hence, the US Centers for Disease
Control and Prevention have recommended a downwards
adjustment of 0.3 g/dl (3 g/l) for smokers.373 Thus, specific
Hb levels expected for different levels of eGFR should becontextualized within the normal distribution of the
population.
Implications for Clinical Practice and Public Policy

The recommended thresholds for diagnosis and evaluationof anemia should not be interpreted as being thresholds
for treatment of anemia but simply for the identification ofthis complication. Practice preferences with respect totreatment strategies should be directed according to local
resources.
Evaluation of anemia in people with CKD

3.2.3: To identify anemia in people with CKD measure Hbconcentration (Not Graded):
K when clinically indicated in people with GFR
Z60 ml/min/1.73 m2 (GFR categories G1-G2);
K at least annually in people with GFR 30-59 ml/
min/1.73 m2 (GFR categories G3a-G3b);
K at least twice per year in people with GFRo30 ml/min/1.73 m2 (GFR categories G4-G5).
RATIONALE

The recommendation that patients be evaluated at least
annually rests on observations from clinical trials that (in theabsence of ESA therapy) the natural history of anemia inpatients with CKD is a gradual decline in Hb concentration
over time.374–376 The exact frequency of monitoring of Hbconcentration will be influenced by kidney function, underlying disease process, the initial Hb concentration, and therate of change in Hb concentration. The latter will also be
influenced by whether or not anemia is being treated andwhat type of treatment is undertaken. The statements
specifically address the need to measure Hb concentrations
at a minimum and are not intended to deter the clinician
from more frequent measurements as required for individual
circumstances.
The initial evaluation of anemia in CKD is geared towards
the exclusion of causes other than those directly related tokidney disease (relative iron and erythropoietin deficiency);
see KDIGO Clinical Practice Guideline for Anemia in CKD11
for details.
82

Evidence Base

Anemia as defined above is found in people with CKD in
increasing proportions as GFR declines (Table 27). This isdue to a number of reasons, including loss of erythropoietic
hormone efficacy, production, substrate deficiency (mostnotably iron), and other conditions which may contribute to
the lack of effective erythropoiesis. For a full description of
the evidence behind this statement please refer to the KDIGOClinical Practice Guideline for Anemia in CKD.11
International Relevance

Frequency of Hb concentration monitoring and the initial
evaluation of anemia should not differ by country, exceptthat causes of anemia other than those related to CKD dodiffer. Nutritional deficiencies in resource-poor areas arecommon, particularly iron deficiency, which is frequently
exacerbated by infectious diseases.
Implications for Clinical Practice and Public Policy

Anemia is associated with increased morbidity, mortality,
and consumption of health-care resources. The major healthconsequences include poor pregnancy outcome, impaired
physical and cognitive development, increased risk ofmorbidity in children, and reduced work productivity inadults.
Treatment of anemia in CKD. The last 30 years have seen amajor transition in approach to the treatment of anemia in
people with CKD beginning with the introduction oferythropoietin therapy into clinical practice and the subsequent resurgence of interest in iron therapies. The promiseof early intervention with anemia treatment in non-dialysis
CKD suggested by observational study has been temperedwith the reality of risks of adverse cardiovascular outcomes in
RCTs. Nevertheless treatment of anemia with iron and ESAs
has an important positive role to play in the lives of people
with CKD. For the treatment of anemia in people with CKD,
we suggest clinicians refer to the KDIGO Clinical Practice
Guideline for Anemia in CKD for further details.11
The key points for practitioners to remember include thefollowing:
1. Work-up for anemia in CKD should include assessment of secondary causes including iron deficiency.
2. Iron replacement is often effective in anemia of CKD as
initial therapy and routes of administration (intravenous or oral) will be determined by clinicians, patient
preferences, and local available resources.
3. ESA therapy is not recommended in those with active
malignancy, or recent history of malignancy.
4. In most people with CKD, ESAs should not be used tointentionally increase the Hb concentration above 11.5
g/dl (115 g/l)
5. For pediatric patients, the selection of Hb concentration at which ESA therapy is initiated should be
individualized after taking into account the potential benefits (e.g., improvement in QOL, school
Kidney International Supplements (2013) 3, 73–90

chapter 3

attendance/performance, and avoidance of transfusion)and potential harms.

3.3 CKD METABOLIC BONE DISEASE INCLUDINGLABORATORY ABNORMALITIES

Changes in bone mineral metabolism and alterations in calcium
and phosphate homeostasis occur early in the course of CKD
and progress as kidney function declines (Table 27). Thesechanges are grouped under the umbrella term Chronic Kidney
Disease-Mineral and Bone Disorder (CKD-MBD) which
includes renal osteodystrophy and extraskeletal (vascular) calcification related to abnormalities of bone mineral metabolism.
Renal osteodystrophy is the component of CKD-MBD that is
identified and quantified through bone biopsy histomorphometry and includes osteitis fibrosa (hyperparathyroidism),osteomalacia, and adynamic bone disease.
The evidence on which existing recommended guideline
treatment targets for serum concentrations of calcium,
phosphate, and parathyroid hormone (PTH), and thestrategies to achieve these targets, is exclusively observational
and thus problematic for that reason. Furthermore, very littleof the evidence is derived from patients with non-dialysis CKD.
Nevertheless we feel it is important to include here some of the
key statements relating to mineral metabolism abnormalities inpatients with non-dialysis CKD from the KDIGO Clinical
Practice Guideline for the Diagnosis, Evaluation, Prevention,
and Treatment of Chronic Kidney Disease-Mineral and Bone
Disorder (CKD-MBD) published in 2009.9 These statements
will be qualified where new data since the publication of
the CKD-MBD guidance have become available.
3.3.1: We recommend measuring serum levels of calcium,
phosphate, PTH, and alkaline phosphatase activity
at least once in adults with GFR o45 ml/min/
1.73 m2 (GFR categories G3b-G5) in order todetermine baseline values and inform prediction
equations if used. (1C)RATIONALE

As kidney function declines, abnormalities of serum calcium,
phosphate, and circulating hormones related to CKD-MBD
progress. These include PTH; 25-hydroxyvitamin D(25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), andother vitamin D metabolites; fibroblast growth factor-23(FGF-23); and growth hormone. At the tissue level there isdown regulation of vitamin D receptors and resistance to theactions of PTH. Immunohistochemical abnormalities in bonealso occur early and generally precede changes in mineral
homeostasis. Extraskeletal calcification may result fromderanged mineral and bone metabolism and from thetherapies used in an attempt to correct these abnormalities.
Associations between disorders of mineral metabolism and
CVD have widened the focus of CKD-MBD to include
abnormal mineral metabolism, abnormal bone, and extraKidney International Supplements (2013) 3, 73–90

skeletal calcification. Once baseline values have beenobtained, the subsequent frequency of testing will be
determined on an individual basis by the actual value andany intervention that may be introduced.
Evidence Base

There are observational studies which describe the abnormalities of each of these parameters at relatively high values of
eGFR in general and high-risk population cohorts.367,377,378
Importantly, abnormalities of calcium and phosphate appear
to occur relatively later in the course of CKD than doabnormalities in values of 1,25(OH)2D, 25(OH)D, and PTH.
Thus, the recommendation is to evaluate these parameters
relatively early in the trajectory of CKD, as an assessment ofburden of illness. In dialysis patients, the highest risks for
mortality have been reported with combinations of highserum phosphate and calcium together with either high
PTH (RR 3.71; 95% CI 1.53-9.03; P ¼ 0.004) or low PTH(RR 4.30; 95% CI 2.01-9.22; Po0.001) compared with the
combination of high PTH with normal serum calcium andphosphate which had the lowest mortality and was used as
the index category.379 The importance of examining combinations of parameters of mineral metabolism is likely to be
no different in patients with less severe CKD, but this has notbeen tested in non-dialysis populations.
There are also racial differences in the parameters ofmineral metabolism. In a multicenter cohort of 227 black and1633 non-black patients with early CKD, blacks had similar
1,25(OH)2D levels compared with non-blacks but significantly lower levels of 25(OH)D with higher levels of calcium,
phosphate, and PTH, and were significantly more likely tohave hyperphosphatemia than non-blacks.380 In multivariable analyses adjusted for age, gender, eGFR, BMI, anddiabetes, blacks had significantly lower 25(OH)D and higher
PTH levels than non-blacks. Examining the relationships
between 25(OH)D and PTH in 8415 adult participants (25%
black and 24% Mexican-American) in NHANES 2003–2004
and 2005–2006, and the relationship between 25(OH)D andbone mineral density (BMD) in 4206 adult participants (24%black and 24% Mexican-American) in the 2003–2004
NHANES sample, Guitierrez et al. found significant racialdifferences.381 Blacks and Mexican-Americans had significantly lower 25(OH)D and higher PTH concentrations thanwhites (Po0.01 for both). Bone mineral density significantly
decreased (Po0.01) as serum 25(OH)D and calcium intake
declined among whites and Mexican-Americans, but notamong blacks (P ¼ 0.2).
International Relevance

The association between black race and Hispanics andsecondary hyperparathyroidism, independent of known risk
factors, suggests that novel mechanisms may contribute tosecondary hyperparathyroidism in non-whites with CKD.
Testing for these parameters would therefore be informed by
the demographics of the population. In different countries
and regions, the ability to measure these parameters may
83chapter 3vary, thus the authors of the guideline statements appreciatethat implementation of regular measurements of all theseparameters may not be possible in all jurisdictions.
Implications for Clinical Practice and Public Policy

Given there remains no clear recommendation as to‘expected’ values in CKD nor consensus on thresholds
regarding treatment, the testing of PTH, and vitamin D
parameters would lead to substantial costs to the health-caresystem. Abnormal values lead to repeat testing. There are nodata to suggest how effective or useful repeated monitoring ofabnormal values is, nor what an acceptable interval ofmonitoring should be to inform care. Laboratory testing forphosphate and calcium is relatively inexpensive, but treatment and ongoing monitoring may be expensive. At thecurrent time, recommendations for testing frequency may beproblematic for clinical practice.
Areas of Controversy, Confusion, or Non-consensus

The inter-relationship of calcium, phosphate, and PTH, andthe potential impact of vitamin D on these mineralmetabolites and extraskeletal calcification remains an areaof research and debate among clinicians. Newer research
examining the role of FGF-23, an important molecule inphosphate, PTH, and vitamin D homeostasis, has caused
many to question the previous focus on PTH values asmisplaced. The questions of whether vitamin D therapies are
toxic in some or all patients and what values of phosphate arepathologic have yet to be resolved.
Pediatric Considerations

clinician the fact that the information gained from BMD in
those with reduced GFR may be false, leading to either
under- or over-treatment. Although fractures rates andfracture-related mortality are elevated in CKD, bonedensitometry does not reliably predict fracture risk inpatients with GFR o45 ml/min/1.73 m2 and neither does it
predict the type of renal osteodystrophy. Thus, BMD
measurements do not provide the information usually soughtfrom such testing, which is usually the basis of interventions.
Evidence Base

Decreased bone mass and changes in bone microarchitecture
occur early in CKD and worsen with progression of diseasesuch that patients with CKD are at increased risk of bone
fracture.383 Bone strength is determined by the density andquality of the bone. Dual-energy x-ray absorptiometry(DXA) scanning measures density of bone but is not able
to determine bone quality (cortical and trabecular microarchitecture). Studies using high-resolution peripheral quantitative computed tomography (HR-pQCT) demonstrateabnormalities in the cortical and trabecular microarchitecture of patients with early CKD compared with healthy
control subjects.384 Although abnormalities of both DXA andHR-pQCT associate with fractures in patients with CKD,
receiver operator characteristic curve analysis suggests thatneither technique is predictive of fracture (area under the
curve o0.75), although this improved for patients withlonger duration of CKD.385 In a cross-sectional study, thecombination of these imaging techniques with markers ofbone turnover improved prediction of fracture.386

Application of guidelines related to bone health, growth, andCKD in children is extremely complex. Numerous issues
arise, including age-related variation in normative values,
comparisons across age, sex, size, and the need to account for
pubertal changes etc., when one considers the options andtargets for evaluation and treatment.
It is recommended that in the application of any of these
specific guidelines, the reader carefully reviews the publications as they relate to pediatrics, starting with the following
two documents and then accessing the most currently
available pediatric CKD resources for the topic(s).
Recommended primary pediatric CKD-MBD resources:
K KDOQI
Clinical Practice Guideline for Nutrition inChildren with CKD: 2008 Update382
K KDIGO Clinical Practice Guidelines for the Diagnosis,
Evaluation, Prevention, and Treatment of CKD-MBD9

Implications for Clinical Practice and Public Policy

3.3.2: We suggest not to perform bone mineral density
testing routinely in those with eGFR o45 ml/min/
1.73 m2 (GFR categories G3b-G5), as information
may be misleading or unhelpful. (2B)

Treatment of CKD-MBD

RATIONALE

While there is an appreciation that BMD is measured inmany elderly, this statement is intended to highlight for the84

A major component of fracture risk is related to fall risk, thus
reduction in fall risk may be achieved through establishment of falls prevention programs. Such programs include
medication review; prevention of postural hypotension;
cardiac pacing, where appropriate; home hazard assessmentand modifications; muscle strengthening and retraining; andtreatment of vitamin D deficiency.
Areas of Controversy, Confusion, or Non-consensus

The combination of measurements of bone thickness, BMD
of femoral neck, and a history of fracture may be useful toidentify CKD patients who might benefit from fracture
prevention strategies. Prospective studies are needed to assessthe utility of these parameters for fracture prediction in the
CKD population.

Disturbances of calcium, phosphate, vitamin D, and PTH
develop early during the course of CKD and are associatedwith adverse outcomes. Studies of these and other markers ofbone mineral metabolism have improved our understandingof disease mechanisms governing adverse outcomes of CKDMBD but clinical studies have yet to indicate whether or not
manipulation of these markers improves patient-level
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chapter 3

outcomes. In making recommendations for therapeutictargets for mineral metabolism abnormalities, we have been
careful not to reach beyond the evidence.
3.3.3: In people with GFR o45 ml/min/1.73m2 (GFR
categories G3b-G5), we suggest maintaining serum
phosphate concentrations in the normal range
according to local laboratory reference values. (2C)
3.3.4: In people with GFR o45 ml/min/1.73m2 (GFR
categories G3b-G5) the optimal PTH level is notknown. We suggest that people with levels of intact
PTH above the upper normal limit of the assay
are first evaluated for hyperphosphatemia, hypocalcemia, and vitamin D deficiency. (2C)RATIONALE

Higher serum phosphate concentrations are associated withmortality and experimental data suggests that serum
phosphate concentration is directly related to bone disease,vascular calcification and CVD. Serum phosphate, calcium,and PTH concentrations are all inter-related in patients with
CKD. Randomized studies linking manipulation of theseparameters to clinical outcomes are lacking but systematic
review indicates that earlier phosphate control may help
reduce the early clinical consequences of CKD-MBD. Similarly there is insufficient evidence that any specific phosphatebinder significantly impacts patient-level outcomes.
Evidence Base

Systematic review of serum concentrations of calcium,
phosphate, and PTH and the risk of death and CVD in
people with CKD showed that the risk of death increased
18% for every 1 mg/dl (0.33 mmol/l) increase in serum
phosphate concentration (RR 1.18; 95% CI 1.12-1.25).387
There was no association seen with either PTH or serum
calcium and all-cause mortality (Figure 19). Of the 327,644
subjects included in the review only 16,247 were not receiving
dialysis and of these only 8990 were people with GFR
o60 ml/min/1.73 m2 not receiving RRT. In these subjects therisk of all-cause mortality for each 1 mg/dl (0.33 mmol/l)increase in serum phosphate concentration was very similar(RR 1.29; 95% CI 1.12-1.48). As with all subjects included
there was no evidence of an association between serum
calcium concentration and all-cause mortality in people withCKD not receiving RRT (RR 1.02; 95% CI 0.81-1.29). Data
for associations of calcium, phosphate, and PTH withcardiovascular death were only available in one of the studies
included.
In the Multi-Ethnic Study of Atherosclerosis (MESA)
study, the associations of serum phosphate concentrations
with vascular and valvular calcification were examined in 439
people with GFR o60 ml/min/1.73 m2. Each 1 mg/dl(0.33 mmol/l) increase in serum phosphate concentration
was associated with a 21% (P ¼ 0.002), 33% (P ¼ 0.001), 25%(P ¼ 0.16), and 62% (P ¼ 0.007) greater prevalence ofcoronary artery, thoracic, aortic valve, and mitral valve
Kidney International Supplements (2013) 3, 73–90

calcification, respectively.388 The strength of the associations
did not differ by age, race, or diabetes. Adjustment for serum
concentrations of PTH and 1,25(OH)2D did not alter thestrength of the associations.
Factors affecting gastrointestinal phosphate absorption
include 1,25(OH)2D, food content, phosphate bioavailability
and phosphate binders (natural and prescribed). Sources of
dietary phosphate are protein-rich foods, including dairy
products, meat, and fish as well as legumes, nuts, chocolates
and inorganic phosphate additives such as those found in
carbonated drinks. In a non-vegetarian Western diet, overhalf the dietary intake of phosphate comes from animal
protein. Although the phosphate content of plant-derived
phosphate is higher than animal derived, its bioavailability interms of gastrointestinal absorption is lower.389 Inorganic
phosphate additives have the highest bioavailability. A
number of clinical studies detail benefit from dietaryphosphate and protein control in terms of secondary
hyperparathyroidism and progression of CKD in people
with moderate CKD.390 Few studies have evaluated theimpact of dietary phosphate restriction on bone disease or
vascular calcification and only one has addressed survival. In
people on hemodialysis, a post hoc analysis suggested that
more restrictive prescribed dietary phosphate was associatedwith poorer indices of nutritional status and a greater needfor nutritional supplementation.391 There was a stepwise
trend toward greater survival with more liberal phosphateprescription, which reached statistical significance among
subjects prescribed 1001 to 2000 mg/d and those with nospecified phosphate restriction, raising concerns aboutprotein energy malnutrition with dietary phosphate restriction. The means used to achieve phosphate restriction may
therefore be important.
Table 29 details the relative cost comparisons of phosphatebinders currently in clinical use for which there is observational or study trial data demonstrating their efficacy. Data
concerning comparative patient-level outcomes such asmortality are not available.
There are a number of agents available for phosphatebinding which are listed in the table ranked in order ofrelative cost, appreciating that both availability and specificcosts are country- and era-specific.
A Cochrane meta-analysis considered 60 RCTs or quasiRCTs (7631 participants) that assessed the effects of various
phosphate binders in adults with CKD.392 The authors
concluded that all available phosphate-binders reduced
serum phosphate concentrations in comparison to placebo
but that data to date do not support superiority of novel
non-calcium binding agents for patient-level outcomes suchas all-cause mortality and cardiovascular end points in CKD.
International Relevance

Availability of different phosphate binders differs around theglobe. Thus, recommendations as to specific agents are notpossible within the context of these statements. Similarly,
dietary phosphate intake may be different around the world,85

chapter 3

Phosphorus
All-cause mortality
Adequate adjustment
Partial adjustment
All studies combined
Cardiovascular mortality
Adequate adjustment
Partial adjustment
All studies combined

No. ofCohorts

No. ofParticipants

Relative Risk
(95% CI) Per
Unit Increase

3
10
13

4651
87 69492 3451.35 (1.16-1.57)
1.16 (1.09-1.23)
1.18 (1.12-1.25)

12
3

17 3265881
23 207Not estimable
1.14 (1.05-1.24)
1.10 (1.06-1.13)

Increased Serum
Phosphorus Better

0.5

Decreased Serum
Phosphorus Better

1.0

2.0

Relative Risk (95% CI)

Parathyroid hormone
All-cause mortality
Adequate adjustment
Partial adjustment
All studies combined
Cardiovascular mortality
Adequate adjustment
Partial adjustment
All studies combined

No. ofCohorts

No. ofParticipants

Relative Risk
(95% CI)1
3
4

17 326
83 732101 058

Not estimable
1.01 (0.99-1.03)
1.01 (1.00-1.02)

1
1
2

17 3265041
22 367Not estimableNot estimable
1.05 (0.99-1.11)

Increased
Serum Parathyroid
Hormone Better

0.5

Decreased
Serum Parathyroid
Hormone Better

1.0

2.0

Relative Risk (95% CI)

Calcium
All-cause mortality
Adequate adjustment
Partial adjustment
All studies combined
Cardiovascular mortality
Adequate adjustment
Partial adjustment
All studies combined

No. ofCohorts

No. ofParticipants

Relative Risk
(95% CI)2
6
8

22 367
83 789106 156

1.07 (0.91-1.24)
1.09 (0.99-1.20)
1.08 (1.00-1.16)

1
1
2

17 3265041
22 367Not estimableNot estimable
1.15 (1.08-1.23)

Increased Serum
Calcium Better

0.5

Decreased Serum
Calcium Better

1.0

2.0

Relative Risk (95% CI)

Risks of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events are shown per 1-mg/dL
increase in serum levels of phosphorus, 100-pg/mL increase in serum parathyroid hormone, and 1-mg/dL increase in serum calcium. Summary estimates are not reported when only a single cohort contributed data. CI
indicates confidence interval.

Figure 19 | Summary estimates for risks of all-cause mortality and cardiovascular mortality associated with levels of serum
phosphorus, PTH, and calcium. PTH, parathyroid hormone. Reprinted with permission from Palmer SC, Hayen A, Macaskill P, et al. Serumlevels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidneydisease: a systematic review and meta-analysis. JAMA 2011; 305(11): 1119-1127.387 Copyright & (2011) American Medical Association. All
rights reserved. Accessed http://jama.jamanetwork.com/data/Journals/JAMA/18301/jrv15003_1119_1127.pdf

rendering this problem of greater or lesser significance indifferent jurisdictions. Measurement of specific hormones(PTH, vitamin D) is expensive and may not inform caresufficiently to warrant the expense at this time.

health-care administrators are advised to appreciate thisproblem in developing targets for care or thresholds fortreatment.
Areas of Controversy, Confusion, or Non-consensus

Implications for Clinical Practice and Public Policy

Existing data support prevention of hyperphosphatemia
and associated secondary hyperparathyroidism in CKD. In
the absence of hypercalcemia, there is no indication toprescribe phosphate-binders that are less cost-effective thancalcium-based agents. Current data are insufficient to makerecommendations about target levels of serum calcium or
PTH concentrations that should be achieved in order toreduce mortality or cardiovascular morbidity in people withCKD not requiring dialysis. Assay variability of PTH
and vitamin D remains problematic and this issue isbeyond the scope of this document. The practitioner and86

As per comments above, the data to support levels oflaboratory values for interventions, types of interventions,and target values remain problematic. Thus recommendations for therapy remain similarly problematic and practicevaries depending on location and resource availability. Likely
correlation of symptoms with blood values and addressing
laboratory abnormalities within that context is a pragmatic
approach at the current time. The non-specialist is asked toseek advice from local experts for best advice for specificindividuals.
The KDIGO guidelines on this subject have not been
updated at the time of the writing of this CKD guideline.
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chapter 3

Table 29 | Phosphate binding agents in routine clinical practice and their ranked cost
Ranked
cost*

Agent

Dose/day

Clinical experience and evidence baseAluminium hydroxide

1.425-2.85 g

Calcium citrate

1.5-3 gMagnesium carbonate

Extensive clinical experience in CKD and ESRD, no RCT comparison versus placebo.
Aluminium accumulates in bone and neural tissue with long-term use, avoids
calcium
Limited trial evidence in ESRD. Reduction in phosphate and elevation in calcium
dose-dependent
Short-term RCT evidence in ESRD, less hypercalcemia

0.7-1.4 g (plus calcium
carbonate 0.33-0.66 g)
Calcium acetate 435 mg Short-term RCT evidence in ESRD, less hypercalcemia
plus
Magnesium carbonate
235 mg, 3-10 tablets daily
3-6 gExtensive clinical experience in CKD and ESRD, limited RCT evidence versus placebo.
Reduction in phosphate and elevation in calcium both dose-dependent
3-6 g
Extensive clinical experience in ESRD; RCT evidence comparing to other binders.
Reduction in phosphate and elevation in calcium dose-dependent but less than withcalcium carbonate
3g
Extensive prospective cohort evidence, RCT evidence compared to other phosphatebinders. Potential for accumulation in bone and other tissues, avoids calcium
4.8-9.6 g
Extensive prospective cohort evidence in ESRD; RCT evidence compared to otherphosphate binders; surrogate and patient-centered outcomes, avoids calcium
4.8-9.6 g
RCT evidence compared to other phosphate binders; equivalency studies compared
to sevelamer-HCl, avoids calcium

Calcium acetate andMagnesium carbonate
combination
Calcium carbonate
Calcium acetate

Lanthanum carbonate
Sevelamer-HCl
Sevelamer carbonate

1

2
3
3

4
4

5
6
6

Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; RCT, randomized controlled trial.
*The average annual cost of aluminium hydroxide in the UK, for example, is d51/year equivalent to US$84/year. The cost of lanthanum and sevelamer in the UK is 38-42 times
higher and the cost of calcium and magnesium-based binders 5-7 times higher than aluminium hydroxide (All drug costs derived from 2011 British National Formulary list
prices).

We have attempted to balance current knowledge withpublished guidance statements in non-CKD populations.
Clarification of Issues and Key points

Clinical trials comparing strategies such as vitamin D
replacement, dietary phosphate restriction, phosphate binders, and calcimimetics with placebo are needed to addresspatient-level outcomes such as mortality and cardiovascularmorbidity in people with CKD.
Measurement of vitamin D levels is problematic andexpensive and is not advocated here.
Vitamin D supplementation and bisphosphonates in people
with CKD

3.3.5: We suggest not to routinely prescribe vitamin D
supplements or vitamin D analogs, in the absence ofsuspected or documented deficiency, to suppress
elevated PTH concentrations in people with CKD
not on dialysis. (2B)
RATIONALE

This statement is intended to highlight the lack of robust data
to support either the measurement or the treatment ofvitamin D deficiency in non-dialysis CKD populations. The
statement asks the clinician to more fully evaluate theindividual situation. The internationally accepted definitionof vitamin D deficiency is a blood concentration o20 ng/ml(o50 nmol/l). Low 25(OH)D levels are common in patients
Kidney International Supplements (2013) 3, 73–90

with non-dialysis dependent CKD; concentrations ofo15 ng/ml (o37 nmol/l) occur in at least 12-15% of patientswith CKD and are more prevalent at lower GFR levels, ininstitutionalized subjects, at extremes of age, and in certain
racial groups. Deficiency of 25(OH)D increases fracturerisk and is associated with increased mortality. As CKD
progresses, levels of 1,25(OH)2D progressively fall and areclosely associated with increasing PTH concentrations. In
vitamin D-deficient subjects supplementation with vitamin D
increases BMD and muscle strength, reduces risk for fracturesand falls, and reduces PTH. In the absence of deficiency,
treatment with vitamin D and related compounds has notbeen shown to improve either mortality or cardiovascularoutcomes.
Evidence Base

There is a substantial amount of data to support 25(OH)D
deficiency in general and CKD populations367,393 which islikely multifactorial. In addition to 25(OH)D deficiency,
note has been made that there is a progressive increasein prevalence of 1,25(OH)2D deficiency with lower GFR
category, which occurs earlier than 25(OH)D deficiency(Figure 20).
No relationship between 25(OH)D levels and 1,25(OH)2D
levels was apparent but there was a strong association
between 1,25(OH)2D deficiency and PTH concentration. Of
particular note, a higher urinary ACR was associated withlower levels of 1,25(OH)2D at GFR values of o60 ml/min/
1.73 m2.
87

chapter 3

Prevalence of 1,25(OH)2D3 and 25(OH)D3 deficiency
and intact PTH by GFR
100
25(OH)D3 <15 ng /ml (<37 nmol /l)
1,25(OH)2D3 < 22 pg /ml (<57 pmol /l)Intact PTH > 65 pg/ml (>6.9 pmol /l)Patients (%)

80

that is indicated until new evidence becomes available. Except
for education or research purposes, there is no need tomeasure vitamin D levels in general practice.
Areas of Controversy, Confusion, or Non-consensus

The appropriate dose and formulation of vitamin D, target
range for treatment, frequency, route of administration, andsafety at different severities of CKD remain to be determined.

60

40

20
0
80

79− 7069− 6059 − 50

49 − 40

39 − 30

29 − 20< 20

3.3.6: We suggest not to prescribe bisphosphonate treatment in people with GFR o30 ml/min/1.73 m2(GFR categories G4-G5) without a strong clinicalrationale. (2B)(n=61) (n=117) (n=230) (n=396) (n=355) (n=358) (n=204) (n=93)

GFR level (ml/min)Figure 20 | Prevalence of deficiency of 1,25(OH)2D3, 25(OH)D3,
and secondary hyperparathyroidism by GFR intervals. GFR,
glomerular filtration rate; PTH, parathyroid hormone. Adapted bypermission from Macmillan Publishers Ltd: Kidney International.
Levin A, Bakris GL, Molitch M, et al.367 Prevalence of abnormal
serum vitamin D, PTH, calcium, and phosphorus in patients withchronic kidney disease: results of the study to evaluate earlykidney disease. Kidney Int 2007; 71: 31-38; accessed http://
www.nature.com/ki/journal/v71/n1/pdf/5002009a.pdf

The potential importance of these deficiencies has been
illustrated in a number of studies examining the relationshipbetween low levels of 25(OH)D and 1,25(OH)2D and all-cause
and cardiovascular mortality in a different cohorts.393,394
Despite the associations with mortality, systematic review ofpublished data to date on vitamin D supplementation inpatients with CKD not on dialysis has only shown an
improvement in biochemical end points. A series of publications395,396 have attempted to summarize the efficacy ofvitamin D therapy on biochemical, bone, cardiovascular, andmortality outcomes in people with CKD and not requiring
dialysis. No formulation, route, or schedule of vitamin D
compound was found to alter the mortality risk or need for
dialysis although vitamin D compounds significantly lowered
serum PTH concentrations. None of the studies assessedreported outcomes related to CVD, bone disease, or mortality.
International Relevance

The importance of vitamin D deficiency has been addressed inboth general and CKD populations. Specific populations havebeen identified as more likely to be vitamin D deficientdepending on cultural and environmental factors; estimates ofworldwide prevalence of vitamin D deficiency range from
25-60%. CKD populations within high-risk areas may be particularly vulnerable. The interplay between loss of kidney function and exacerbation of vitamin D deficiency is not known.
Implications for Clinical Practice and Public Policy

Vitamin D supplementation improves biochemical end
points similar to active vitamin D analogs with a lower
burden of costs and side effects. Measurement of serum
25(OH)D is expensive and in the CKD population withvitamin D deficiency, simple vitamin D replenishment is all
88

RATIONALE

The risk-benefit ratio of bisphosphonates has not been wellstudied in CKD populations. Indications for bisphosphonate
therapy include osteoporosis, corticosteroid therapy, malignant disease and Paget’s disease. In people with CKD and
GFR categories 460 ml/min/1.73 m2 with osteoporosis and/or at high risk of fractures, and in people with GFRs between
30-60 ml/min/1.73 m2 with normal PTH, osteoporosis
and/or at high risk of fracture, treatment should be the same
as for the general population (although dose modification
may be necessary, see Table 30).
In people with CKD at lower categories of GFR(o30-35 ml/min/1.73 m2), the correct diagnosis of osteoporosis becomes increasingly complex and other forms ofrenal osteodystrophy requiring alternative management
strategies to osteoporosis require exclusion before treatment
with bisphosphonates is considered. In people with adynamic
renal bone disease, more likely at lower GFR categories, there
is a lack of evidence of either harm or benefit of bisphosphonates on bone strength or vascular calcification.
Evidence Base

Bisphosphonates increase BMD, reduce bone turnover, andreduce the risk of fragility fractures. The bioavailability of
intravenous bisphosphonate formulations is 100% but thebioavailability of oral formulations is only 1-5%. Approximately 50-80% of available bisphosphonate is taken up bybone and the remaining 20-50% is excreted in urine without
being metabolized. Although oral bisphosphonates have notbeen shown to adversely affect kidney function in people
with GFRs as low as 15 ml/min/1.73 m2, in post hoc analysisof clinical trial data their safety and efficacy below
GFRs of 30 ml/min/1.73 m2 have not been well-validated
and intravenous bisphosphonates have been implicatedin nephrotoxicity, especially when rapidly infused(Table 30).9,397,398 Thus, from a patient’s safety perspective,
the statement serves to limit exposure of those with abnormal
kidney function to these agents.
International Relevance

Given cost and clinical practice variation, the use ofbisphosphonates varies around the world. Thus, this statement may be less applicable in different jurisdictions.
Kidney International Supplements (2013) 3, 73–90

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Table 30 | Summary data for bisphosphonates and CKD
AgentIndications

Dose, frequency and route ofadministration

Special considerations for CKD and clinical trial
notes

Alendronate

Postmenopausal osteoporosis
Corticosteroid use
Malignancy-related bone disease

10 mg daily, oral
70 mg weekly, oral
1.6-3.2 g daily, oral

Postmenopausal osteoporosis
Corticosteroid use
Paget’s disease
Malignancy-related bone disease
Postmenopausal osteoporosis
Malignancy-related bone disease
Paget’s disease
Postmenopausal osteoporosis
Corticosteroid use
Paget’s disease
Paget’s disease

400 mg daily for 14 days, oral
5-10 mg/kg daily for up to 6 months

GFR o35 ml/min/1.73 m2: not recommended
No reported adverse events specific to CKD
GFR o10 ml/min/1.73 m2: contraindicated
GFR 10–30 ml/min/1.73 m2: reduce dose by 50%
Mild renal impairment: reduce doseModerate or severe renal impairment: avoid
No data in CKD
GFR o30 ml/min/1.73 m2: not recommended
No reported adverse events specific to CKD
GFR o30 ml/min/1.73 m2: avoid
AKI reported
GFR o30 ml/min/1.73 m2: contraindicatedNo reported adverse events specific to CKD

Clodronate
Etidronate

Ibandronate
Pamidronate
Risedronate

Tiludronate
Zoledronate

Malignancy-related bone disease
Postmenopausal osteoporosis
Paget’s disease

150 mg monthly, oral
3 mg every 3-months intravenous
15-60 mg single dose, intravenous
30 mg weekly for 6 weeks, intravenous
5 mg daily, oral
35 mg weekly, oral
400 mg daily for 3 months
4-5 mg single dose, intravenous

CrCl o30 ml/min: contraindicated
No data in CKD
GFR o30 ml/min/1.73 m2: avoid
GFR o60 ml/min/1.73 m2:
graded dose reduction
No data in CKD, AKI reported in non-CKD

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; CrCl, creatinine clearance; GFR, glomerular filtration rate.

Implications for Clinical Practice and Public Policy

Given the widespread use of bisphosphonates in developed
countries, especially in older women who are also likely tohave some degree of kidney dysfunction, the cessation ofbisphosphonates in that group may be problematic. There isa need to monitor clinical practice and understand theimplications of this recommendation for large populations,
who may or may not be deriving benefit from these agents.
Areas of Controversy, Confusion, or Non-consensus

Despite these concerns, primary care data from the USA suggestthat prescription of bisphosphonates is common in people with
CKD. Even in the subset with GFR o30 ml/min/1.73 m2,
bisphosphonate use was no less prevalent than in the non-CKD
population.399 People with CKD in this study were nearly seventimes more likely to receive a bisphosphonate than active
vitamin D. Similar uncertainty about the efficacy and safety ofsuch treatment for people with CKD was demonstrated in astudy of people under the care of a UK renal unit.400 Half ofall people prescribed bisphosphonates had a GFR o30 ml/min/
1.73 m2 and yet 50% of people with higher GFRs anddocumented osteoporosis were not prescribed bisphosphonates.
Clarification of Issues and Key Points

Further study is required to elucidate whether or notbisphosphonates, through reduction of bone turnover inpeople with pre-existing low bone turnover states, would be
beneficial or harmful both for bone and vascular calcification.
3.4 ACIDOSIS

The prevalence and severity of metabolic acidosis in people
with CKD progressively rises as GFR falls (Table 27).
Kidney International Supplements (2013) 3, 73–90

Adaptations in acid excretion by the kidneys initially preventa fall in serum bicarbonate concentration but as GFR
continues to decline below 40 ml/min/1.73 m2, metabolic
acidosis commonly develops.
3.4.1: We suggest that in people with CKD and serum
bicarbonate concentrations o22 mmol/l treatment
with oral bicarbonate supplementation be given to
maintain serum bicarbonate within the normal
range, unless contraindicated. (2B)
RATIONALE

Serum bicarbonate concentrations less than 22 mmol/l areassociated with increased risk of CKD progression andincreased risk of death. Conversely, high serum bicarbonate
concentrations greater than 32 mmol/l are associated withincreased risk of death irrespective of the level of kidney
function. Small studies of alkali supplementation have shown
reduction in progression of CKD and improved nutritional
status in people with CKD. This statement is therefore
worded to reflect the potential benefits of oral bicarbonate
supplementation to maintain serum bicarbonate concentrations within the normal range, but the word ‘suggest’ in thestatement reflects the lack of robust evidence base on which
to support this statement.
Evidence Base

Chronic metabolic acidosis is associated with increased
protein catabolism, uremic bone disease, muscle wasting,chronic inflammation, impaired glucose homeostasis, impaired cardiac function, progression of CKD, and increased
mortality.401–410 The suggestion that treatment of acidosis
may be beneficial was first made by Richard Bright,411 later89

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taken up enthusiastically by Arthur Osman412 and further
explored by Lyon et al. who conducted a form of crossoverstudy of supplementation with bicarbonate in 17 people withmoderate kidney failure and suggested that treatment withalkali might preserve kidney function.413 Rustom et al.
described a reduction in proximal renal tubular catabolism
and markers of tubular injury after oral NaHCO3 in 11
people with mild/moderate renal impairment (mean51
Cr-EDTA GFR 46.2 ± 6.0 ml/min/1.73 m2) and proteinuria(3.2 ± 0.8 g/24 hours).414 They suggested that oral sodium
bicarbonate may protect the proximal renal tubule and help
delay kidney disease progression. Mathur et al. randomized
40 subjects with mild to moderate CKD to oral bicarbonate(1.2 mEq/kg of body weight) or placebo for 3 months andsuggested that correction of metabolic acidosis significantly
attenuates the rise in blood urea.415 A larger study randomly
assigned 134 adults with moderate to severe CKD (CrCl 15 to
30 ml/min/1.73 m2) and serum bicarbonate 16 to 20 mmol/lto either supplementation with oral sodium bicarbonate(1.82 ± 0.80 g/day) or standard care for 2 years.416 Primary
end points were rate of kidney function decline, theproportion of subjects with rapid decline of kidney function(43 ml/min/1.73 m2/yr), and ESRD (CrCl o10 ml/min[o0.17 ml/s]). Secondary end points were DPI, normalized
protein nitrogen appearance, serum albumin, and mid-arm
muscle circumference. Serum bicarbonate increased significantly in the bicarbonate group but despite the associatedsodium load there was no difference in BP control,prescription of antihypertensives and loop diuretics, or
hospitalization for heart failure compared with the control
group. The decline in CrCl was significantly slowed in thebicarbonate group compared with controls (5.93 versus
1.88 ml/min/1.73 m2, Po0.0001), rapid progression was lessprevalent (9 versus 45%, RR 0.15; 95% CI 0.06-0.40;
Po0.0001), and fewer subjects developed ESRD (6.5 versus
33%, RR 0.13; 95% CI 0.04-0.40; Po0.001). Nutritionalparameters also improved significantly with bicarbonate
supplementation. In a non-randomized study the effects ofsupplementation of 1 mmol of bicarbonate equivalent per kg
body weight per day for 2 years using oral sodium citrate in
30 subjects with hypertensive nephropathy was comparedwith 29 control subjects.417 There were no statisticallysignificant differences in baseline demographic data, systolicBP, venous bicarbonate levels, or parameters of kidney
function between the two groups. All subjects were receiving
angiotensin-converting enzyme inhibition throughout the
study and BP was controlled to similar levels in both groups
in a 6-month run-in period prior start of study. In thosetreated with oral sodium citrate, urine endothelin-1 excretion
and N-acetyl-b-D glucosaminidase were each significantly

90

lower while the rate of GFR decline was significantly slower
after 24 months of treatment compared to the control group.
International Relevance

Alkali supplementation appears to be a promising low-cost,high-benefit adjunct treatment for patients with CKD andmay be accessible to all populations. It is not known how
prevalent acidosis is among different communities orcountries around the world.
Implications for Clinical Practice and Public Policy

The use of sodium bicarbonate or calcium carbonate as asource of alkali should not present financial hardships inmost practices or jurisdictions.
Areas of Controversy, Confusion, or Non-consensus

A potential concern regarding treatment of patients with
CKD with sodium bicarbonate or sodium citrate is thepossible associated sodium loading. A crossover study of
200 mmol/day (17 g/day) of sodium bicarbonate versus
200 mmol/day (12 g/day) of sodium chloride in 10 subjects
with severe CKD (CrCl 2.5-16.8 ml/min [0.04-0.28 ml/s]) on
an extremely low-sodium diet showed that sodium chloride
but not sodium bicarbonate produced an increase in weightand BP.418 A subsequent follow-up study suggested that if
dietary sodium chloride intakes are near maximum tolerance,then sodium bicarbonate supplementation should be accompanied by reductions in sodium chloride intake to maintainsodium balance.419 Given the lack of large and long-term
trials, many are still not convinced that this is a reasonable
recommendation, and is thus controversial. We would like toensure that individual clinicians are aware of the controversy
rather than making no statement at all.
DISCLAIMER

While every effort is made by the publishers, editorial board,
and ISN to see that no inaccurate or misleading data, opinion
or statement appears in this Journal, they wish to make it clearthat the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contributor,
copyright holder, or advertiser concerned. Accordingly, thepublishers and the ISN, the editorial board and their respective
employers, office and agents accept no liability whatsoever
for the consequences of any such inaccurate or misleading
data, opinion or statement. While every effort is made toensure that drug doses and other quantities are presented
accurately, readers are advised that new methods andtechniques involving drug usage, and described within this
Journal, should only be followed in conjunction with the drug
manufacturer’s own published literature.

Kidney International Supplements (2013) 3, 73–90

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http://www.kidney-international.org& 2013 KDIGO

Chapter 4: Other complications of CKD: CVD,
medication dosage, patient safety, infections,
hospitalizations, and caveats for investigatingcomplications of CKD
Kidney International Supplements (2013) 3, 91–111; doi:10.1038/kisup.2012.67

This section addresses a series of important topics which
impact the outcomes of people with CKD. Specifically CVD,
interpretation of tests for CVD, infections, vaccinations andhospitalizations, medications, and patient safety are addressed. This section is designed to help the practitioner
appreciate the specific nuances related to testing and drug
administration in people with CKD and to alert all cliniciansto the fact that many common tests may not be as useful inpeople with CKD to diagnose or evaluate therapies. It was
beyond the scope of the guideline and evidence review tothoroughly evaluate all tests with respect to sensitivity andspecificity in different groups of people with CKD but future
research may consider this as a useful direction.
4.1 CKD and CVD

Population-based studies have demonstrated an increased riskof death and cardiovascular mortality as GFR falls below 60
ml/min/1.73 m2 or when albumin is detected on urinalysis.
This is not explained by an increase in traditional risk factors.
There are CKD-specific risk factors associated with moreadvanced CKD which drive the high rates of mortality andmorbidity even at young ages. People with CKD are more
likely to experience a cardiovascular event than to progress to
ESRD, have a worse prognosis with higher mortality after acute
myocardial infarction (MI), and have a higher risk of recurrent
MI, heart failure and sudden cardiac death. Management ofmodifiable cardiovascular risk factors, such as improved BP
and diabetes control, also reduces CKD progression.
4.1.1: We recommend that all people with CKD beconsidered at increased risk for cardiovasculardisease. (1A)
RATIONALE

This statement is worded in this way to reflect the strong andindependent associations between GFR and albuminuria
categories and risk of CVD in people with CKD and applies
to both adult and pediatric populations.
Evidence Base

Large cohort studies have demonstrated the strong and independent associations between CVD (acute coronary syndrome
Kidney International Supplements (2013) 3, 91–111[ACS], stroke, heart failure and sudden cardiac death) andCKD by category of eGFR, after adjusting for known CVD risk
factors, history of CVD events, and proteinuria. In those withan eGFR of 45-59 ml/min/1.73 m2, risk is increased by 43%
and in those with eGFR below 15 ml/min/1.73 m2, risk isincreased by 343%.58 Although people with GFR category G5(GFRo15 ml/min/1.73 m2) are at the highest risk of a CVD
event, there will be more events in people with GFR categories
G3a-G3b (GFR 30–59 ml/min/1.73 m2) because of the muchhigher prevalence at these categories.420 These events occur at a
younger age in people with CKD suggesting that CKD
promotes CVD at an accelerated rate.421 The prognosis afteran acute event is related to level of GFR with a significant risein mortality when eGFR falls below 45 ml/min/1.73 m2.422–424
Albuminuria is associated with duration and severity ofhypertension; an adverse lipid profile with higher levels of
total cholesterol, triglycerides and lipoprotein(a) and low
HDL-C levels;425 and abnormalities of coagulation. The
presence of higher levels of proteinuria increases the risk ofmortality and MI independently of level of eGFR.426 Many
studies have demonstrated low levels of urinary albumin to
be associated with the increased risk of CVD in people withdiabetes independent of renal function; however population
studies of non-diabetic individuals have confirmed that evensmall amounts of albuminuria are associated with increased
CVD risk. In the Third Copenhagen study, in people withmicroalbuminuria, risk of coronary heart disease wasincreased independently of age, sex, renal function, diabetes,
hypertension, and plasma lipids.427 The Chronic Kidney
Disease Prognosis Consortium demonstrated that in generalpractice cohorts there was an increase in cardiovascularmortality when ACR is higher than 30 mg/g (3 mg/mmol).4
Analysis of data from the Heart Outcomes Prevention
Evaluation (HOPE) study demonstrated that any degree ofalbuminuria is a risk factor for cardiovascular events inindividuals with or without diabetes.428 The lack of athreshold of albuminuria for cardiac risk was also confirmedin the HUNT 2 Study429 and the Losartan Intervention For
Endpoint Reduction in Hypertension (LIFE) study inpatients with LVH.430 Albuminuria and low eGFR weresynergistic cardiovascular mortality risk factors in the
HUNT 2 study and using both ACR and eGFR improved91chapter 4

cardiovascular risk stratification at all age levels, butparticularly in persons 70 years and over.429
In the MDRD Study cohort of patients with GFR
categories G3a-G4 (GFR 15–59 ml/min/1.73 m2), cystatin C
level was strongly associated with all-cause and cardiovascular mortality particularly in the elderly.431 Analysis of datafrom MESA and the Cardiovascular Health Study (CHS)
demonstrated that the worst prognosis of CVD, heart failure,
and progressive CKD was found in those subjects with CKD
diagnosed using the cystatin C-based equation.432
LVH is common with CKD, is known to reflect target
organ damage, and is associated with increased cardiovascular mortality in CKD.360 It is also important to consider
the role of CKD-specific risk factors particularly in patientswith more severe CKD (GFR o30 ml/min/1.73 m2) andcorrect them where possible. Anemia has been thought tohave a particular role in the early development of CVD in
people with CKD. Although treatment of anemia isassociated with improved well-being and greater exercise
capacity, the results of several RCTs of anemia correction
have suggested that complete correction of anemia is notadvisable in people with lower GFR (o60 ml/min/1.73 m2).
A meta-analysis of 9 RCTs comparing different target Hblevels suggests an increase in mortality and worse BP control
with the higher treatment targets, independent of the GFR
category.433,434 Those patients with LVH at baseline, a sign oftarget organ damage and which was present in 47% of the
Cardiovascular Risk Reduction by Early Anemia Treatment
with Epoetin Beta Trial (CREATE) cohort, had significantly
worse cardiovascular outcomes when treated to the higher
targets.435
Abnormalities of mineral metabolism with low 1,25dihydroxyvitamin D and PTH were found to occur early in
CKD in the Study for the Evaluation of Early Kidney disease[SEEK] study, however serum calcium and phosphate wereusually normal until eGFR fell below 40 ml/min/1.73 m2.367
An association between elevated serum phosphate andcardiovascular mortality was demonstrated in a prospective
study of people with CKD and this was also thought to be
associated with low vitamin D levels.436

proven mild to moderate CKD. In this cross-sectional
analysis of 250 children who had data on all variables ofinterest, median GFR of 45.2 ml/min/1.73 m2 (IQR 34.658.2), the prevalence of hypertension was 46%, dyslipidemia
was 44%, abnormal glucose metabolism was present in 21%,and obesity in 15%. Hypertriglyceridemia was common, seenin 33%. In aggregate, only 26% of the cohort had no risk
factors present, 39% had at least one and 22% had two, 11%
had three and 2% had all four risk factors present. The
prevalence of all these factors remained elevated even when
the population was restricted to those defined as lean, BMI
o85th. In this group, the presence of 2 or 3 cardiovascularrisk factors was still seen in 20% and 2%, respectively. Within
the lean group 12% demonstrated abnormal glucose
metabolism. Finally, multivariate regression analysis of theirdata demonstrated that glomerular disease as a cause of CKD
and the presence of nephrotic range proteinuria wereassociated with much higher odds of having cardiovascularrisk factors, 1.96 (95% CI 1.04-3.72) and 2.04 (95% CI 0.944.43), respectively.
It is also well-recognized that carotid intimal media
thickness and pulse wave velocity changes, as potential
surrogate measures for vascular damage in children, can beincreased in in children with CKD.443,444
For further detailed discussions of the pathophysiology
and complexity of CVD in the pediatric CKD population,
two recent review papers from Mitsnefes445 andShroff et al.446 are suggested. Both papers identify anddiscuss the pathophysiology of both traditional and CKDspecific cardiovascular risk factors as seen in this population.
4.1.2: We recommend that the level of care for ischemic
heart disease offered to people with CKD should
not be prejudiced by their CKD. (1A)
4.1.3: We suggest that adults with CKD at risk foratherosclerotic events be offered treatment with
antiplatelet agents unless there is an increased
bleeding risk that needs to be balanced against thepossible cardiovascular benefits. (2B)
RATIONALE

Pediatric Considerations

While the majority of data for, and evidence of, the high riskof cardiovascular morbidity and mortality in the pediatricrenal population stems from the ESRD (dialysis andtransplant) populations,437–440 there is recognition that many
if not all of the factors responsible for such outcomes willdevelop much earlier in this course of CKD. In fact, thecurrent American Heart Association’s guidelines for reduction of cardiovascular risk in pediatrics stratified the childwith CKD to the highest risk category.441
Based on data from the CKiD trial, Wilson et al.442
demonstrated extremely high prevalence rates for four
traditional cardiovascular risk factors (hypertension, dyslipidemia, abnormal glucose metabolism, and obesity) in a
subgroup of this cohort of 586 children with iohexol GFR
92

These statements are worded in this way to reflect thegrowing body of evidence that suggests that treatment oftraditional risk factors in CKD patients is of benefit, and that
attempts to modify or preclude usual investigations andtherapies are not necessary in CKD patients. Inasmuch as
CKD populations have been understudied, but likely
inadvertently included in larger population studies,
the rationale for risk factor modification is similar to thatin the general population. Modification of risk factors
includes:1. Smoking cessation
2. Exercise
3. Weight reduction to optimal targets
4. Lipid modification recognizing that the risk reduction
associated with statin therapy in adults with CKD is
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relatively constant across a broad range of baseline lowdensity lipoprotein cholesterol (LDL-C) levels
5. Optimal diabetes control HbA1C o7% (53 mmol/mol)
6. Optimal BP control to o140/90 mm Hg or o130/80
mm Hg in those with CKD and depending on the degreeof proteinuria (see Recommendations 3.1.4 and 3.1.5)
7. Aspirin is indicated for secondary prevention but notprimary prevention
8. Correction of anemia to individualized targets (seeKDIGO Clinical Practice Guideline for Anemia in CKD11)
Evidence Base

The maintenance of cardiovascular health ultimately
impacts ‘kidney health’ given the links between cardiac
function, renal perfusion, atherosclerosis, and glomerulosclerois. The details of this complex biology are beyond
the scope of these guidelines, but can be found in key
references below.
There is evidence in the general population that smoking
cessation is associated with a reduction in cardiovascular risk.
In CKD there is evidence that smoking is associated with
progression of renal disease, though no specific data exist that
support cessation of smoking and delay of progression.447
People with CKD have reduced levels of muscle strengthand aerobic activity. In those not on dialysis, exercise training
is shown to improve functional capacity and BP.448
Weight loss in obese CKD patients can reduce rate of
decline, proteinuria, and BP.354
The Study of Heart and Renal Protection (SHARP)449 is
the largest RCT in people with CKD to date. The results
demonstrate that a lipid-lowering strategy which included
fixed dose simvastatin and ezetimibe resulted in a 17%
reduction in atherosclerotic events, as compared to placebo.
The cohort enrolled included those with eGFR under 60 ml/
min/1.73 m2, age greater than 40 years, and was aninternational study including more than 9000 subjects fromaround the globe. The lipid-lowering strategy was effective
and safe. Lipid targets have not been established specificallyfor people with CKD. Treatment strategies should be
implemented in accordance with current recommendations
for high-risk populations.
At the time of this writing, the KDIGO Clinical Practice
Guideline for Lipid Management in Chronic Kidney Disease
was under preparation for public review. In brief, the key
aspects of the draft recommendations include treating thoseat high risk for atherosclerotic disease with lipid-lowering
therapies, regardless of LDL levels, in those 50 years of age
and above. Since this Guideline has not yet been finalized,
interested readers should refer to the final document when it
is formally released in 2013.
The benefits of aspirin in people with CKD andhypertension was demonstrated in a post hoc analysis of theHypertension Optimal Treatment (HOT) trial.450 Jardine
et al. reported that among every 1000 persons with eGFR
o45 ml/min/1.73 m2 treated for 3.8 years, 76 major
cardiovascular events and 54 all-cause deaths will be
Kidney International Supplements (2013) 3, 91–111

prevented while 27 excess major bleeds will occur. They
concluded that an increased risk of major bleeding appears to
be outweighed by the substantial benefits. Clopidogrel is used
as an alternative to aspirin but CKD has been shown to be
associated with an increase in platelet reactivity and there isresistance to clopidogrel in people with CKD, diabetes, andCVD.451 The Clopidogrel for Reduction of Events During
Observation (CREDO) trial concluded that clopidogrel inmild or moderate CKD may not have the same beneficial
effect as it does in people without CKD. Subjects with normal
renal function who received 1 year of clopidogrel had amarked reduction in death, MI, or stroke compared withthose who received placebo (10.4% versus 4.4%, P o0.001),
whereas those with mild and moderate CKD did not have asignificant difference in outcomes with clopidogrel therapy
versus placebo (mild: 12.8% versus 10.3%, P ¼ 0.30;
moderate: 13.1% versus 17.8%, P ¼ 0.24). Clopidogrel use
was associated with an increased RR of major or minor
bleeding, but this increased risk was not different based onrenal function.452
International Relevance

Although it is clear and mentioned in many guidelines thatCKD is associated with an increase in CVD risk, it is notincluded in many assessment tools and there is a deficiency inethnicity and regional specific tools.
The assessment tool from US Third Report of the National
Cholesterol Education Program (NCEP III) does not include
CKD. The Fourth Joint Task Force of the European Society ofCardiology suggest that both an eGFR of less than 60 ml/
min/1.73 m2 and albuminuria increase risk but do not
quantify the risk or include CKD in their Systematic
COronary Risk Evaluation (SCORE) assessment tool.453 In
the UK, the QRISKs2 online tool includes CKD as ‘yes’ or‘no’ and therefore does not allow for level of eGFR or
proteinuria.454 The Joint British Societies Guidelines regards
proteinuria as a sign of target organ damage, which conveys arisk of at least 20% in 10 years.455
A study of cardiovascular risk estimation in Chinese adults
in the USA–People’s Republic of China Collaborative Study ofCardiovascular and Cardiopulmonary Epidemiology (USAPRC Study) did not include CKD as a risk factor at all.456 It isalso important to remember that in this population stroke
was the predominant CVD. A review of 25 risk assessment
tools identified only 2 derived from an Asian population.457
However, links between GFR categories and CVD events areevident in the Asian population, for example in the Japanese
Gonryo study.458 A prospective study in a general Japanese
population demonstrated links between lower GFR, highcreatinine levels, and proteinuria with cardiovascular mortality particularly stroke.459 In Chinese patients who were atleast 50 years old and either had existing CVD or were at highrisk, 34% had an eGFR o60 ml/min/1.73 m2 and eGFR o45
ml/min/1.73 m2 was found to be an independent predictor of
all-cause and cardiovascular death.460 In a population-based
study of 2353 people aged over 40 years in Beijing, an eGFR
93chapter 4

o90 ml/min/1.73 m2 was associated with increased CVD
risk, and for each CKD category stroke was more prevalentthan MI.461
In India the increasing prevalence of type 2 diabetes isdriving an increase in CKD and both are associated withincreased cardiovascular risk. In CKD patients attending one
clinic in North India, 28% had diabetes, 27% were overweight,
and 92% had hypertension. Metabolic syndrome as defined by
the International Diabetes Federation (IDF) 2007 guidelines
was present in 39% and more frequent in women.462
Implications for Clinical Practice and Public Policy

A full CVD risk assessment in a person with CKD should
include an estimate of GFR and a quantitative assessment ofalbuminuria. Cystatin C may be helpful at risk stratifying
those at intermediate risk.
The key aspect of these recommendations is to ensure thatpeople with CKD are not deprived of treatment strategies
known to be effective in general populations.
Areas of Controversy, Confusion, or Non-consensus

Many of the traditional cardiovascular risk assessment tools
do not adjust for the presence of early CKD. Any tool should
also adjust for level of eGFR because of increasing risk
associated with lower levels of kidney function. The
Framingham risk equation underestimates true events in a
CKD population, but no validated different tools exist atpresent which better quantify cardiovascular or mortality risk
in CKD populations.
Proteinuria is considered to be a sign of target organ
damage and thus associated with high cardiovascular risk.
However, assessment of risk should also include the presenceof albuminuria. Few studies exist which demonstrate thattargeting lowering of proteinuria results in reduced cardiovascular risk, though a number of studies which havetargeted interruption of the RAAS (and in which loweringof urine protein has also been shown) have demonstrated abenefit.
An appropriate risk assessment tool should be available toassess risk in people with CKD. Addition of the presence of
CKD to conventional risk factors in the Reykjavik population
increased discrimination but did not increase risk to the same
degree as smoking or diabetes.463 In the Framingham Heart
Study, GFR category 3b (GFR 30–44 ml/min/1.73 m2) was
associated with CVD but not equivalent to previous CVD.464
Lifestyle modification has not been studied in large trials
in people with CKD but smoking cessation, achievement of
optimum weight, regular exercise, and salt restriction should
be seen as reasonable aims.
Pediatric Considerations

It is presently unclear whether children with CKD andelevated lipid levels will benefit from lipid-lowering strategies
with no prospective trials ongoing in this area. It is hopedthat data from both CKiD55 and the 4C trials78 may be able toaddress these shortcomings.
94

However, given that these children demonstrably haveelevated risk of cardiovascular and atherosclerotic disease (seeRecommendation 4.1.1), that there are data supporting theuse of a number of statins in the pediatric population,465 andthat the adult evidence for benefit of statins in a subset of the
SHARP trial449 with a GFR o60 ml/min/1.73 m2 exist, it
would seem reasonable to consider the use of such drugs inchildren with CKD and elevated lipids.
Recommendations from 2006441 for use of dietarymodifications, followed by statins in children older than 8
years of age with persistent elevation in LDL-C levels, havebeen endorsed by the American Academy of Pediatrics.
However, at the time of publication of these guidelines, theKDIGO Dyslipidemia Work Group has suggested that statin
therapy may not be appropriate.
Age- and renal function-adjusted doses of such drugs
should be carefully considered prior to any therapy being
initiated (see Recommendation 4.4.1).
Regarding diabetes control, treatment in keeping withnational and international diabetes recommendations isprudent. Note is made that there are specific caveats withrespect to drugs and side effects that are important (seeRecommendations 3.1.15-3.1.18).
There is no literature in the area of antiplatelet agents inatherosclerotic disease in the subset of children with CKD
and the suggestion to offer antiplatelet agents does not apply
to pediatric practice.
4.1.4: We suggest that the level of care for heart failureoffered to people with CKD should be the same as
is offered to those without CKD. (2A)
4.1.5: In people with CKD and heart failure, any
escalation in therapy and/or clinical deterioration
should prompt monitoring of eGFR and serum
potassium concentration. (Not Graded)
RATIONALE

This statement is worded this way to make clinicians awarethat people with CKD and heart failure should receive at least
equal benefit from heart failure therapy as those without
CKD, but that heart failure therapies (in particular increaseof RAAS blockade and diuretic therapy) may lead tosignificant changes in GFR and serum potassium concentrations. This does not imply that such therapy should be
avoided but only that clinicians are cognizant of thispossibility, monitor it, and understand it in the context ofindividual risks and benefits.
Heart failure is a complex clinical syndrome which can becaused by any structural or functional cardiac disorder that
impairs the pump function of the heart and has a highmortality. Within the general population, the commonest
causes of heart failure are ischemic heart disease causing left
ventricular systolic dysfunction, and hypertensive heartdisease with left ventricular hypertrophy and diastolic
dysfunction. Thus people with CKD are at increased risk ofboth. Evidence-based medication for heart failure impacts on
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GFR and prescribers need to be alert to this. Changes in GFR
are often transient and the downward trajectory GFR is notsustained if all other aspects of care and clinical status arestable. Monitoring and close follow-up are required.
Evidence BaseIn an outpatient setting, normal GFR is unusual in heart
failure. A study from the Alberta Heart Function Clinic foundthat in people with an ejection fraction of r35%, GFR
categories G3a and G3b (GFR 30–59 ml/min/1.73 m2) were
present in 40% and 16% of people were GFR categories G4 or
G5 (GFRo30 ml/min/1.73 m2).466 This study demonstrated a
1% increase in mortality associated with each 1 ml/min fall in
CrCl demonstrating the clear link between kidney function
and outcome for people with CKD and heart failure. Metaanalysis of 16 studies and over 80,000 people with heart failure
by Smith et al. showed that renal impairment was present in
63% and was associated with increased mortality across therange of kidney function, with an adjusted HR of 1.56 (95% CI
1.53-1.60).467 In the Candesartan in Heart Failure-Assessmentof Reduction in Mortality and Morbidity (CHARM) Programwith candesartan in heart failure, 36% of subjects had eGFR
o60 ml/min/1.73 m2 which was associated with increased
mortality and hospital admission regardless of ejection
fraction.468 The Digitalis Intervention Group (DIG) identified
a GFR of 50 ml/min as a risk threshold for increased mortality
risk in heart failure.469 Smith et al. demonstrated that 1-year
mortality after admission for heart failure was 29% in people
with normal kidney function but 52% in those with moderate
to severe renal impairment.470 Anand et al. also demonstrated
an independent association between the presence of positive
reagent strip proteinuria present in 8% of subjects andincreased mortality in heart failure.471
In the Alberta Provincial Project for Outcome Assessmentin Coronary Heart Disease (APPROACH) study of people
with heart failure related to coronary artery disease (CAD),
39% had CrCl o60 ml/min (o1 ml/s). This study also
demonstrated that the level of kidney function was a better
indicator of poor outcome than cardiac anatomy.472 In
people admitted to hospital with heart failure, increasing SCrconcentration is associated with a longer hospital stay andworse outcome.473
LVH is present in 40% of people with CKD,474
progressively increasing as kidney function declines.475
Ha et al. demonstrated LVH in 87% of people withpredialysis CKD.476 Parfrey et al. in a study of 432 people
who were predialysis, found that only 16% had a normal
echocardiogram while 41% had concentric LVH, 16% systolic
dysfunction, and 28% left ventricular dilatation.477 LVH isrelated to increased work load caused by arterial stiffness andhypertension, and at lower levels of GFR, volume overload.
Alterations in electrolyte balance, anemia, bone metabolism,
uremia, oxidative stress, inflammation, and other inflammatory mechanisms all play a role.478
In the majority of people with CKD, the myocardium
develops concentric hypertrophy476 with interstitial fibrosis
Kidney International Supplements (2013) 3, 91–111

and CKD-associated cardiomyopathy, leading to left ventricular stiffness.474 This results in diastolic heart failure; people
with CKD have higher mortality from diastolic heart failure
than systolic heart failure.479 Diastolic heart failure is morecommon in people with CKD who are older females withhypertension and/or diabetes.480
Left ventricular hypertrophy is particularly associated withanemia and a fall in Hb to less than 12.8 g/dl (128 g/l) is
associated with left ventricular growth in people with early
CKD.481 Lower Hb levels are associated with increased risk ofdeath and hospitalization in heart failure.482 Other cardiovascular conditions, for example MI and atrial fibrillation, aremore common in CKD and may exacerbate heart failure.
It is important to note that in a study of an older
population (age 464 years), heart failure was an independent predictor of rapid kidney function decline.483
Standard therapy for the management of systolic heart
failure includes an ACE-I or ARB and a beta-blocker licensed
for heart failure such as bisoprolol or carvedilol. Metaanalysis of 25 trials of RAAS blockade (ACE-I or ARB) in
people with CKD or proteinuria, demonstrated a reductionin the risk for heart failure and reduction in cardiovascularoutcomes.484 Subgroup analysis from the Valsartan Heart
Failure Trial (Val-HeFT) demonstrated the beneficial effect ofvalsartan in people with CKD and that valsartan reduced theeGFR by the same amount in people with and without
CKD.471 Candesartan was also clinically effective in the
CHARM study regardless of underlying kidney function468
while irbesartan was associated with a 23% reduction in
hospital admissions related to heart failure in people withnephropathy due to type 2 diabetes.485 Analysis of data on
bisoprolol from the Cardiac Insufficiency Bisoprolol Study II(CIBIS II)486 identified 32% of subjects with eGFR o60 ml/
min/1.73 m2. These subjects were more likely to die or beadmitted to hospital than those with eGFRZ60 ml/min/1.73
m2. However, they showed a similar benefit from bisoprolol
treatment. A post hoc analysis of data on carvedilol from theCarvedilol Post-Infarct Survival Control in Left Ventricular
Dysfunction (CAPRICORN) and Carvedilol Prospective
Randomized Cumulative Survival (COPERNICUS) trials
identified 60.8% of participants with eGFR o60 ml/min/
1.73 m2.487 Carvedilol was well tolerated by subjects with
CKD, and decreased all-cause, cardiovascular, and heart
failure mortality. However, doubts were raised over the
benefits when eGFR o45 ml/min/1.73 m2.
Aldosterone antagonists are included in standard heart
failure management, usually in addition to an ACE-I or ARB,
leading to concerns relating to risk of hyperkalemia,
particularly in people with lower GFRs. In a study ofspironolactone therapy in severe heart failure, Pitt et al.488
included subjects with SCr concentrations up to 2.5 mg/dl(221 mmol/l). There was a 30% reduction in mortality withspironolactone and the incidence of hyperkalemia was low.
However, a review of real-world practice demonstrated asignificant increase in hyperkalemia with the combination of
RAAS blockade and an aldosterone antagonist, highlighting95

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the need for close monitoring with the introduction of
combination therapy.489
In the APPROACH study on the specialist managementof heart failure, subjects with CAD and CKD, despite
being at high risk, were less likely to be taking ACE-Is,
beta-blockers, statin, and aspirin. This study demonstrated
that those subjects taking beta blockers had lower mortality,
however ACE-Is were only of benefit when eGFR was
460 ml/min/1.73 m2.472
International RelevanceThe treatment of heart failure is similar around the globe. The
ability to closely monitor kidney function or to offer
conventional therapies may differ, however. Irrespective, thisstatement should hold true internationally. The National Heart
Care Project of community subjects admitted to hospital withheart failure studied the differences between people of black
and white ethnic groups. People with worse renal function
were more likely to be black, older and female, and black
people had a greater prevalence of hypertension and diabetes
but less ischemic heart disease. Black people had a lower risk ofmortality at every level of creatinine, for every 0.5 mg/dl(44.2 mmol/l) increase in creatinine, 1-year death risk increased
10% in black people and 15% in white people.470
Implications for Clinical Practice and Public Policy

Cardiorenal syndrome, an impairment of kidney function in
the presence of heart disease, is a marker of worse prognosis.
In addition to GFR, the presence and severity of albuminuria
and anemia aid in prognostication and management.490
Where the link between LVH and heart failure in CKD is
so strong and the outcome poor for people with LVH, efforts
should be made to optimize care particularly BP. There is alack of robust evidence for the optimal medical managementof heart failure specifically in people with CKD; however, theprevalence of people with early CKD is so high in heart
failure trials that we can apply standard treatment to thesepeople. For those people with eGFR o45 ml/min/1.73 m2,
the situation is less clear.487
Areas of Controversy, Confusion, or Non-consensus

There are difficulties in making the diagnosis of heart failurein people with CKD, especially diastolic heart failure.
Biomarkers such as B-type natriuretic peptide (BNP) may
be abnormally elevated in CKD, but may or may not
be as responsive to treatment or diagnostically accurate inpeople with CKD (see Chapter 4.2). There is little evidence
to guide the management of left ventricular systolic
dysfunction in people with CKD and evidence for the
management of diastolic heart failure is generally lacking.
However, there is evidence that medications to improve theoutcome of people with heart failure are underused in people
with CKD.
Appropriate management of the metabolic complicationsof kidney disease which can exacerbate heart failure needs to
be clarified. Clinical studies are required on the role of96

device therapy in people with CKD (e.g., pacemakers,
defibrillators, etc.).
4.2 CAVEATS WHEN INTERPRETING TESTS FOR CVD INPEOPLE WITH CKD
BNP/N-terminal-proBNP (NT-proBNP)As GFR diminishes, the prevalence and severity of cardiovascular abnormalities increase and are accepted as major
causes of morbidity and mortality in people with CKD. The
presence of congestive heart failure (CHF) in people withCKD conveys a worse prognosis than either condition alone.
Therefore, early diagnosis and aggressive management of
CHF are both highly desirable. A number of cardiac
biomarkers (i.e., BNPs and cardiac troponins) appear tohave both increasing clinical importance and increasing
facility for detection and stratification of CHF. The stimulus
for secretion of these biomarkers is the hemodynamic load
(i.e., myocardial stretch) and their secretion is associated withthe severity of CHF and the degree of left ventricular
dysfunction. They are thus useful markers for diagnosis,
management, and prognosis in people with normal renal
function. However, when the eGFR is less than 60 ml/min/
1.73 m2, the accuracy of plasma BNP and NT-proBNP levels
for detection and stratification of CHF becomes unreliable
and the degree of responsiveness to treatment is not known.
4.2.1: In people with GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5), we recommend that serum concentrations of BNP/NT-proBNP be interpreted with caution
and in relation to GFR with respect to diagnosis ofheart failure and assessment of volume status. (1B)
RATIONALE

This statement is intended to remind clinicians that although
the prevalence of fluid overload and heart failure increases
with lower GFR categories, BNP becomes less reliable as apredictor of fluid overload and heart failure at lower GFRs.
While it is associated with worse outcomes, cutoff values
indicative of heart failure in general populations may or may
not be appropriate and changes in values with treatment may
or may not have the same meaning.
Evidence BaseNatriuretic peptides belong to a family of circulatory peptide
hormones from either myocardial cell origin (atrial natriuretic peptide [ANP] and BNP) or endothelial cell origin(C-type).491,492 They play an important role in regulating BP
and body fluid volume by their natriuretic and diuretic
actions, arterial dilatation, and inhibition of the RAAS.493
Natriuretic peptides for the diagnosis of CHF have been adiagnostic breakthrough in cardiology where determinationof their concentration in serum can help identify patientswith left ventricular systolic dysfunction.494,495
Concentrations of natriuretic peptides increase inpeople with CHF and other CVDs as a consequence ofKidney International Supplements (2013) 3, 91–111

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pressure and volume overload.496,497 Among people with
progressive LVH, concentrations of NT-proBNP are typicallyelevated in proportion to the degree of left ventricular mass
increase.
Overall, BNP levels provide a better index of left
ventricular mass and load than do ANP levels and BNP has
emerged as a superior biomarker to ANP for clinicalapplications involving CHF and left ventricular dysfunction.491,498 NT-proBNP may have analytical advantages over
BNP because of greater stability due to a longer half-life.
The cause of an elevated BNP level is multifactorial inorigin and may reflect cardiac dysfunction, and/or changes inrenal function.499 Since renal dysfunction intrinsically was
shown to affect BNP levels in some studies, the diagnostic
value of BNP levels in the presence of CKD has beenquestioned.500,501
Earlier research hypothesized that measurement of
natriuretic peptides could be of use in monitoringexcess fluid volume and dry weight in people requiring
dialysis,502,503 but this remains unproven and the significanceof plasma natriuretic peptides and their clinical role indialysis remains unclear.491
Although several studies revealed higher BNP levels as
GFR declined, outcomes of other studies suggest that therelationship between renal function and BNP levels may bemost strongly dependent on cardiac and volume-related
factors.504–506 To test this hypothesis, Tagore et al. studied
BNP levels in a cohort of 143 clinically euvolemic subjects
with CKD in whom absence of heart disease was clinicallyvalidated and found that plasma BNP levels were independent of GFR.504 Suresh and Farrington507 studied people on
dialysis and concluded that BNP levels were predictive ofpresence of left ventricular dysfunction, cardiac events, andsurvival in the presence of ESRD, suggesting that BNP levels
may be informative across the full range of renal function andeven in its absence. As previously established by several
studies, the level of NT-proBNP is a strong prognostic
marker in both the general population508 and in various
disease states, e.g., acute and CHF,509,510 coronary heartdisease,511,512 and hypertension.513
International Relevance

The issue of how to differentially interpret BNP in thepresence or absence of CHF and within the context ofdeclining renal function has received considerable
attention but remains incompletely resolved from a clinicalperspective. Changes in either renal or cardiac function could
potentially impact levels of natriuretic peptides and incomplete knowledge of an individual’s clinical status relative
to the degree of cardiac pathology or renal dysfunction
could confound interpretation of BNP levels. Given the costof biomarkers assays and the uncertainties related tointerpretation of serum levels of BNP/NT-proBNP in people
with CKD, competing priorities for health-care resource may
dictate reliance on clinical evaluation and local practicesof care in some areas of the world. Until better data are
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available, clinicians are asked to use this laboratory
measurement with caution as a diagnostic test for heart
failure in those with CKD.
Implications for Clinical Practice and Public Policy

Since people with ESRD with elevated levels of BNP have ahigher RR of death, this biomarker could be used as anindividual risk marker with the aim of identifying those athigh risk. Clinical correlation is of utmost importance toensure accurate diagnosis and appropriate therapy.
Studies to understand the variability of BNP by categories
of eGFR and urine ACR, within and between individuals overtime, and the response to therapy should be undertaken so as
to better inform clinicians.
Areas of Controversy, Confusion, or Non-consensus

The relationship between renal function and BNP, the role ofnatriuretic peptides as markers of fluid overload and as
predictors of mortality, and the utility of serial monitoring of
BNP/NT-proBNP levels in people with CKD, and responsiveness to therapy remains unknown.
Clarification of issues and key points

Natriuretic peptides may be surrogate markers for predictionof mortality in people with CKD reflecting the associationof mortality with left ventricular dysfunction and LVH.
Before routine measurements of these biomarkers arerecommended, their utility in guiding or changing clinicalpractice should be assessed.
Pediatric Considerations

There is robust literature in both children and neonates
regarding both the normative values of BNP514 and its value
in predicting outcomes of pediatric heart failure.515 To dateno studies in children specifically address the issue of reduced
GFR in this population. However, application of similar
principles would likely apply.
Troponins

In recent years newer markers of myocardial injury have been
introduced into clinical practice.516,517 Among these, cardiac
troponins have proven to be specific markers of myocardialdamage.518,519 Cardiac troponins have been considered thegold standard biochemical test for diagnosis of myocardialdamage because they have nearly absolute myocardial tissue
specificity, as well as high sensitivity, thereby reflecting evenmicroscopic zones of myocardial necrosis.517,520 Furthermore, increasing evidence indicates that abnormal troponinmeasurements identify a subgroup of patients who have an
increased risk of major cardiac events519,521–525 and thatmeasurement of cardiac troponin T (cTnT) prior tocommencing renal replacement is a significant independent
predictor of survival.526 However, these markers are renally
excreted and are often found to be elevated in people withCKD irrespective of specific symptomatology. Thus, there is
uncertainty as to the clinical importance of their different
97chapter 4

magnitudes of elevation in CKD. There are no data on‘expected’ values of these markers in the context of CKD, orat different categories of GFR and albuminuria.
4.2.2: In people with GFR o60 ml/min/1.73 m2 (GFR
categories G3a-G5), we recommend that serum
concentrations of troponin be interpreted withcaution with respect to diagnosis of acute coronary
syndrome. (1B)
RATIONALE

This statement is intended to remind clinicians that isolated
elevated serum concentrations of troponin (in the absence ofsymptoms or electrocardiographic changes) may not necessarily portend a diagnosis of ACS at lower GFR categories. While
there are data linking troponin elevations with poor outcomes,
the specific implications for an individual in clinical practice
are not clear. Hence, this statement simply cautions theclinician with respect to interpretation but does not suggestthat the laboratory values are not of significance. In a patientwith clinical symptoms suggestive for ischemic heart disease,
an elevated cardiac troponin I (cTnI) is suggestive for ACS.

assays, have been shown to be associated with cardiac
structural abnormalities including LVH (both left ventricularwall thickening and dilation) and left ventricular systolic
dysfunction,548 and to have a graded association with allcause and CVD mortality independent of traditional risk
factors, renal function, and levels of other biomarkers such as
high sensitivity CRP and NT-proBNP.
These findings suggest that chronic elevation of troponinlevels may be mediated to a greater extent by indices of heart
failure (such as higher left ventricular mass, left ventricular
dysfunction, or increased NT-proBNP levels) than indices ofatherosclerosis or ischemia.548
International RelevanceThe costs of these tests, the differing sensitivity of the assays
available, the paucity of data in people with CKD, and thepoor correlation of serum troponin levels with ACS in people
with CKD should be weighed against competing local healthcare priorities and resource before their introduction into
routine clinical practice. Emphasis should be placed on theclinical context and local standard practices of care.
Implications for Clinical Practice and Public Policy

Evidence BasecTnT and cTnI are low-molecular-weight proteins that form
part of the troponin complex and are integral components ofthe myofibrillar contractile apparatus of the heart.527 Loss of
integrity of cardiac myocyte membranes causes release of
cardiac troponins into the circulation, which can be detectedby highly sensitive assays developed for cTnT and cTnI to
diagnose ACS.521 A potent stimulus for the release or
production of natriuretic peptides is mechanical stretching,528 whereas plasma cTnT specifically and sensitively
reflects myocardial injury and is considered to be an index
of irreversible myocardial change.521 In addition, cTnT levels
can predict multi-vessel CAD in people requiring dialysis.529
However, the significance of screening people with CKD for
CAD using these cardiac biomarkers is questionable530 sinceincreases in serum cardiac troponin concentration can occur
in the absence of an ACS.531
Most studies517,532–545 have focused on people with ESRD
where increases in serum cTnT concentrations have been
observed in 20%–90% of subjects540 but generally much
lower when cTnI was measured. Information about cardiac
troponins and their relationship with comorbidity is sparsein people with CKD who are not receiving dialysis
treatment.526,527,546,547 Increased cardiac troponin concentrations may occur early in CKD, including GFR categories
30-59 ml/min/1.73 m2, and more commonly as CKD advances.
Powerful prognostic data emerging from the dialysis
population demonstrate that increased concentrations ofcardiac troponins reflect either subclinical myocardialdamage caused by silent ischemia or myocardial remodelingin the development of LVH.539,542
Increased levels of cTnT measured with the highly
sensitive assay, well below the detection range of standard
98

Troponin elevation may result from repeated episodes ofclinically silent MI,522,549 although CAD frequently underlies
troponin elevation and increased cTnT is also frequently
encountered in patients at low risk for CAD. Troponinelevations are as frequent in subjects without CAD as in thosewith known CAD517,550–552 and in people with CKD, serial
increasing cTn levels may be of greater utility for diagnosis of
ACS. In the context of symptoms and signs of ACS,
elevations of troponins should not be ignored nor incorrectly
attributed to simply ‘CKD.’ Thus the importance of ordering
the test for specific indications for those with CKD should beemphasized.
Areas of Controversy, Confusion, or Non-consensus

Information about cardiac troponins and their relationshipwith comorbidity is sparse in people with CKD who are notreceiving dialysis treatment. Although elevated values for
TnT are common in people with low GFR in the absence of
ACS or CHF, the prevelance of elevated TnI in the absence of
ACS or CHF in people with low GFR may be only 0.4-6%
depending on the cutoff value chosen.532
Clarification of Issues and Key Points

As pointed out by Roberts et al.,553 although management
strategies in people without CKD based on these biomarkers
are quite clear, in people with CKD it is not the case despite
the strong data on the prognostic implications. Thesebiochemical markers can only be useful if they are interpreted
in the context of the clinical history and examination withconsideration given as to what management is appropriate
for each individual, and if a cardiovascular therapy that is
effective in this population is identified or developed.553 The
importance of understanding and contextualizing elevations
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in troponin values in CKD populations cannot be overstated:
under-treatment in symptomatic individuals should be avoided,and better understanding of treatment strategies in those
asymptomatic individuals is the focus of ongoing study.
Pediatric Considerations

While normative values exist for troponin in children,554 its
utility as a general screening marker for myocardial ischemia
in pediatrics has recently been called into question,555 and nodata exist relating reduced renal function and troponin levels
in children.
Non-invasive testing

Most studies of cardiac evaluation in people with CKD have
involved candidates for kidney transplantation in order to
identify existing cardiac conditions amenable to risk
modification and to exclude people with short expectedsurvival due to cardiac morbidity. Among the tests for
cardiovascular assessment, coronary angiography is considered invasive, expensive, and associated with risks such as
contrast-induced nephropathy and cholesterol embolism.
When trying to detect CAD or predict future cardiovascular
events in people with CKD, nuclear imaging modalities using
thallium tracers have shown conflicting results, especially inthe context of small vessel disease. Clinicians should be awareof the limitations of radionuclear testing as a screening tool forsignificant CAD given the limitations of the test. Exercisedependent techniques are limited by poor exercise tolerance ofmany subjects and people with CKD frequently have cardiac
evaluation performed with pharmacological agents.556,557
4.2.3: We recommend that people with CKD presenting withchest pain should be investigated for underlying
cardiac disease and other disorders according to thesame local practice for people without CKD (and subsequent treatment should be initiated similarly). (1B)
4.2.4: We suggest that clinicians are familiar with thelimitations of non-invasive cardiac tests (e.g., exercise
electrocardiography [ECG], nuclear imaging, echocardiography, etc.) in adults with CKD and interpretthe results accordingly. (2B)
RATIONALE

These statements are worded in this way firstly because
although people with CKD are at increased risk fromcardiovascular events, observational study has shown thatthey are frequently discriminated against in terms ofinvestigation and management of such events. Secondly,
non-invasive cardiac tests have known additional limitations
in people with CKD and such limitations and theirconsequences need to be clearly understood by healthprofessionals caring for people with CKD.
Evidence Base

Noninvasive stress testing appears to be the most common
first approach to cardiac evaluation of asymptomatic
Kidney International Supplements (2013) 3, 91–111

patients, prompted by diabetes, age and risk-factor burden.
These tests include myocardial perfusion studies, stressechocardiography, and most recently, cardiac computed
tomographic angiography. However, people with CKD are
underrepresented in studies evaluating the diagnostic sensitivities and specificities of noninvasive tests. Exercise ECG islimited by lack of specificity of the ST-segment response andby inability of many people with CKD to exercise to adiagnostic workload.
These tests have imperfect sensitivity and specificity inpeople with CKD or, in the case of tomographic angiography,
evaluation in this population is as yet unpublished.556 CAD
has been detected in a high proportion of people
on long–term dialysis therapy. Studies describing associations of angiographic coronary stenosis with subsequentclinical events in people with ESRD, including those undergoing transplant evaluations, have reached inconsistentconclusions.558–562
Abnormalities on myocardial perfusion studies correlate
well with the presence of CAD in the general population,with mean weighted sensitivity of 88% and mean weighted
specificity of 74%.563 The performance of myocardial
perfusion studies in identifying CAD in people with CKD
is more variable, with reported sensitivities and specificities
in people with ESRD ranging from 37% to 90% and 40% to90%, respectively.564–567 Nonetheless, results from myocardial
perfusion studies have prognostic value for cardiac eventsand mortality.568,569 In a meta-analysis of 12 studies
involving thallium-201 scintigraphy and dobutamine stressechocardiography, people with ESRD with inducible ischemia
had approximately 6 times the risk of MI and 4 times the riskof cardiac death as those without inducible defects.570
Moreover, subjects with fixed defects also had nearly 5 times
the risk of cardiac death.
The prognostic value of myocardial perfusion studies has
been shown with other perfusion tracers. For example, in astudy of 126 people with ESRD who underwent technetium99m myocardial perfusion studies as part of their pretransplant assessment, the presence of a reversible defect was
associated with 3 times the risk of post-transplant cardiac
events (HR 3.1; 95% CI 1.1-18.2) and nearly twice the risk ofdeath (HR 1.92; 95% CI 1.1-4.4) compared with normal test
results.571
De Lima et al.572 prospectively studied 126 renal transplantcandidates clinically classified as moderate (age 450 years) or
high (diabetes, extra cardiac vascular disease, or known CAD)
coronary risk with myocardial perfusion studies, dobutamine
stress echocardiography, and coronary angiography. Significant
CAD, defined as greater than 70% stenosis in 1 or more major
epicardial artery on angiography was found in 42% of thesample. After a median follow-up of 46 months, clinical risk
stratification and coronary angiography predicted major
cardiac events, but myocardial perfusion studies and dobutamine stress echocardiography did not.
Newer imaging techniques are under current evaluation
but a review here is beyond the scope of this guideline; these99chapter 4

techniques include: stress myocardial perfusion single
photon emission computed tomography (SPECT);557,573–576
18
F-BMS, a novel fluorine-based myocardial perfusion tracer;557,577 and gated imaging using radio-labelledammonia (13NH3).

Clarification of Issues and Key Points

If cardiac evaluation is at present predominantly used forrisk stratification and prognosis, in the future it may guide
optimal therapy and monitor clinical progress.557
4.3 CKD AND PERIPHERAL ARTERIAL DISEASE

International Relevance

People with CKD who are being investigated prior totransplantation should be assessed according to the national
and international cardiology guidelines and taking into
account local practice and availability of resource.
Implications for Clinical Practice and Public Policy

There is still a need for a safe, noninvasive, diagnostic
modality that will allow stratification of cardiovascular risk
among people with CKD. With the development of new
imaging markers, it becomes difficult for clinicians to choose
the imaging tests that can best aid clinical decisions for agiven patient. Imaging methods should provide accuracy andprecision at acceptable cost. Until advanced imaging
techniques (e.g., cardiac MRI, positron emission tomography, cardiac computed tomography) are standardized,
clinicians should rely on the most reliable and familiar
techniques in their environment.578

There is a strong link between CKD and peripheral arterial disease(PAD). Symptoms of PAD may only be present in a minorityof people who have clinical evidence of PAD.579 It is therefore important to measure ankle-brachial index and perform
regular systematic assessment of the lower limbs of people athigh risk of PAD to identify bruits, loss of pulses, cool paleextremities, delay in venous filling, and skin ulceration.580
4.3.1: We recommend that adults with CKD be regularly
examined for signs of peripheral arterial disease andbe considered for usual approaches to therapy. (1B)
4.3.2: We suggest that adults with CKD and diabetes areoffered regular podiatric assessment. (2A)
RATIONALE

These statements are worded in this way in order to highlightthe increased risk of PAD in people with CKD, particularly
those with CKD and diabetes.

Areas of Controversy, Confusion, or Non-consensus

Clinical and cost-effectiveness could be improved; cardiac
evaluation in people with CKD should be based on data fromclinical trials.

Evidence Base

The prevalence of PAD is common in people with CKD and
it increases with lower levels of GFR (Table 31). PAD can be

Table 31 | Peripheral arterial disease and CKD
Study

Population

PAD definition

Outcome of interest

NHANES age 40+

ABI o0.9

O’Hare et al.587

HERS study, postmenopausal womenwith known CHD

O’Hare et al.586

Cardiovascular Health Study, adults
age 65+

De Vinuesa et al.582

102 adults in a CKD clinic, mean age
70 ± 11 years, GFR 15-60 ml/min/
1.73 m2
6-year follow up of 1027 subjects (ABI
index recording and GFR measured
within 90 d)
6760 subjects, aged 45–84 years in theMulti-Ethnic Study of Atherosclerosis

PAD event rates (amputation,
revascularization, or lumbar
sympathectomy)
Lower-extremity PAD procedure(bypass surgery, angioplasty, or
amputation)
ABI o0.9

24% prevalence in people with CKD and a CrCl ofo60 ml/min (o 1 ml/s) versus 3.7% in those withnormal kidney function
Incident PAD event rates were 0.55%, 0.92%,
and 2.73% per year with CrCl 60, 30-59, and
30 ml/min/1.73 m2, respectively
HR for PAD procedure 2.5 (95% CI 1.2-5.1) for
highest quintile of cystatin C (Z1.28 mg/l) versus
lowest (r0.9 mg/l)
17% signs and symptoms of PAD, which had
passed unnoticed; 32% had ABI o0.9 (mean0.64±0.25)
6-year mortality rate for CKD and PAD 45% versus
28% CKD alone, 26% PAD alone, and 18% forneither condition
Albuminuria was associated with PAD in subjects
with diabetes (odds ratio 1.90, 95% CI 1.19–3.04)
but not in those without
Overall, 16% prevalence of PAD in subjects with
GFRo60 ml/min/1.73 m2, increasing from 4% in
those with GFR460 to 22% in those with
GFRo30 ml/min/1.73 m2
1891 of subjects (0.2%) hospitalized at least once
for PVD, adjusted rates increased with lower GFRO’Hare et al.

585

Liew et al.584
Wattanakit et al.588

ABI o0.9
ABI o0.9

Lash et al.583

3612 subjects age 58.2±11.0 years
in the Chronic Renal Insufficiency
Cohort study

ABI o0.9

Bello et al.581

920,985 subjects with GFR andproteinuria assessment, medianfollow-up 35 months (IQR 22-44)

Time to first hospitalization with
PAD

Abbreviations: ABI, ankle-brachial index; CHD, coronary heart disease; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; d, day; GFR, glomerular
filtration rate; HERS, Heart and Estrogen/Progestin Replacement Study; HR, hazard ratio; IQR, interquartile range; NHANES, National Health and Nutrition Examination Survey;
PAD, peripheral arterial disease; PVD, peripheral vascular disease.

100

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attributed to the greater prevalence of traditional risk factors
such as diabetes, hypertension, dyslipidemia, advanced age,and renal-specific factors.581–588
Diabetes is the leading cause of CKD globally and the riskof diabetic foot ulceration and lower extremity amputation in
subjects with diabetes increases dramatically with lower GFR.
In a cohort of 90,617 individuals with diabetes over a medianobservation time of 2.4 years, the HR for amputation
increased from 2.08 (95% CI 1.68–2.58) for those with GFR
30-59 ml/min/1.73 m2 to 7.71 (95% CI 5.29–11.26) for thosewith GFR o30 ml/min/1.73 m2 compared to reference
subjects with GFR 460 ml/min/1.73 m2.589
Screening for PAD is recommended for adults in thegeneral population based on age and number of risk
factors.590 Although an ankle-brachial index of o0.9 isgenerally considered evidence of PAD, the utility of thismeasure is unproven in CKD because of the greater
prevalence of vessel calcification. Evidence-based medical
therapies for PAD in people with CKD are similarly lacking.
Smoking cessation is mandatory. Aspirin may be beneficial
for prevention of cardiovascular events. Clopidogrel has notbeen studied in people with CKD and PAD. No RCTs
evaluating percutaneous versus surgical revascularization
techniques have been conducted in people with CKD and
PAD but outcome studies all suggest that CKD confers anincreased risk of adverse outcome, regardless of therevascularization technique employed.591,592 These statements do not apply to pediatric practice.
International Relevance

There is no evidence to suggest that the international
approach to identification and management of PAD in
people with CKD should differ.
Implications for Clinical Practice and Public Policy

People with CKD are more at risk of PAD and need regularassessment and monitoring. The role of ankle-brachial index
versus other diagnostic techniques may have implications for
future practice. Prospective data on non-surgical therapies anddata regarding percutaneous versus surgical revascularization
are required to inform policy and recommended procedure.
Areas of Controversy, Confusion, or Non-consensus

There remains ongoing debate as to the timing and use of
specific diagnostic criteria for identification of PAD in people
with CKD and no studies have examined the utility of
conventional methods in early detection of PAD in CKD. The
use of specific medical and surgical management strategies inpeople with CKD and PAD has not been evaluated. There is no
reason to believe that treatment strategies should differ, thoughrisks of diagnostic testing (such as angiography) remain real.
4.4 MEDICATION MANAGEMENT AND PATIENT SAFETY IN CKD

Many drugs and investigative pharmaceuticals are renally
excreted and their dosage may need to be reduced in patients
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with CKD in order to avoid toxicity. As many people withCKD are elderly, there should also be consideration ofchronological age.
It is beyond the scope of this guideline to list all theagents that may need dose adjustment in CKD or whichshould be avoided due to potential nephrotoxicity. This
information is widely available in documents which may exist
at local, regional, or national bodies (e.g., British National
Formulary: www.bnf.org), and other textbooks of pharmacology.593,594 However key classes of commonly prescribeddrugs in people with CKD will be mentioned together withsuggestions for dose adjustment. Much of this guidance isbased upon our understanding of pharmacology andpharmacokinetics rather than randomized control trial
evidence.
The statements presented here are intended to informclinicians caring for those with CKD or at risk for CKD withrespect to common clinical situations or exposures which
may put people at risk for AKI or progression of CKD.
4.4.1: We recommend that prescribers should take GFR
into account when drug dosing. (1A)
4.4.2: Where precision is required for dosing (due tonarrow therapeutic or toxic range) and/or estimates
may be unreliable (e.g., due to low muscle mass),
we recommend methods based upon cystatin C or
direct measurement of GFR. (1C)
4.4.3: We recommend temporary discontinuation ofpotentially nephrotoxic and renally excreted drugs
in people with a GFR o60 ml/min/1.73 m2 (GFR
categories G3a-G5) who have serious intercurrent
illness that increases the risk of AKI. These agentsinclude, but are not limited to: RAAS blockers(including ACE-Is, ARBs, aldosterone inhibitors,
direct renin inhibitors), diuretics, NSAIDs, metformin, lithium, and digoxin. (1C)
4.4.4: We recommend that adults with CKD seek medicalor pharmacist advice before using over-the-counter
medicines or nutritional protein supplements. (1B)
4.4.5: We recommend not using herbal remedies inpeople with CKD. (1B)
4.4.6: We recommend that metformin be continued inpeople with GFRZ45 ml/min/1.73 m2 (GFR categories G1-G3a); its use should be reviewed in thosewith GFR 30–44 ml/min/1.73 m2 (GFR category G3b);
and it should be discontinued in people with GFRo30 ml/min/1.73 m2 (GFR categories G4-G5). (1C)
4.4.7: We recommend that all people taking potentiallynephrotoxic agents such as lithium and calcineurin
inhibitors should have their GFR, electrolytes anddrug levels regularly monitored. (1A)
4.4.8: People with CKD should not be denied therapies
for other conditions such as cancer but there
should be appropriate dose adjustment of cytotoxic
drugs according to knowledge of GFR. (Not
Graded)101

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RATIONALE

These statements are worded in this way in order to inform
appropriate prescribing and management of medical conditions in people with CKD. Recommendation 4.4.1 isspecifically worded to ensure that clinicians remember thatin those circumstances where accurate GFR is required(narrow therapeutic or toxic window), a direct measurement,
not an estimate of GFR should be undertaken.
Evidence Base

Potential problems associated with use of medication inpeople with CKD include:a) Reduced ability to excrete drugs and/or their metabolitesb) Increased sensitivity to medications (e.g., those bound toalbumin in hypoalbuminemic states such as nephrotic
syndrome)c) Diminished tolerance of side effects, particularly in theelderlyd) Loss of efficacy13
Wherever possible, people with CKD should receive thesame treatment as those with normal renal function. However,the dosages may need adjustment according to GFR.
There are medicines whose toxicity is worsened in acuteillness particularly in a setting of dehydration such as
diarrhea and vomiting. General advice about appropriate
dosing and when to restart these agents should be given to
people taking these drugs during intercurrent illness, together
with a recommendation for consultation with a health-care
professional as soon as possible.
Use of herbal and over-the-counter medicines is very
common worldwide and some (such as those containing
aristolochic acid)595,596 are known to be nephrotoxic. There isno good quality safety or efficacy data for many of thesecompounds.
Table 32 details specific advice for various classes of drugs
where CKD may be an issue. These include RAAS blocking
agents,262 beta-blockers, analgesics, antibiotics, lithium,597
hypoglycemic agents,598–600 lipid-lowering agents,449,601–604
certain chemotherapeutic agents, and anticoagulants.605
International RelevanceThis guidance is based upon knowledge of pharmacology thathas universal relevance. The main international implication iscentered on costs of some newer therapies compared to theolder ones. Somewhat paradoxically, as the weight ofevidence resides mainly with agents that have been available
for longer, they have the advantage of being less costly, andhave the side effects that are well documented; thus many ofthese older agents are preferred.
Pediatric Considerations

No specific recommendation for or against the use of a BSA
adjusted eGFR in relation to drug dosing can be made inchildren with CKD as the majority of drug studies have been102

performed in adult males and extrapolated to children
without consideration for BSA and/or pediatric renal
function or clearance.
The exception to this rule would be that for any drug
where pediatric pharmacokinetic or pharmacodynamic
studies exist, the method used in calculating the effect ofrenal function should be used when estimating the need for
dose adjustments or modifications for the individual patient.
Numerous resources for dose adjustments for pediatricCKD and ESRD patients exist, including those found innumerous textbooks606,607 and online resources.608
An additional value of dedicated pediatric renal multidisciplinary teams, in terms of caring for children with CKD
and ESRD, is their ability to provide anticipatory guidance
for the patients and families. All such teams should at theleast provide written or online information to their patientsand families directing them to seek advice in situations where
they may be prescribed medications from other providers or
may be seeking over-the-counter drugs or supplements. The
presence of trained pediatric pharmacists as part of suchteams can be invaluable in achieving such support andeducation for both families as well as the CKD health-careproviders and community resources such as local
pharmacists.
LIMITATIONS

People with CKD are often excluded or not identified fromtrials of medications for non-renal disease. Recommendations are partly based upon knowledge of pharmacology
rather than controlled trials in carefully defined populations.
RESEARCH RECOMMENDATIONSNational and international research groups, and thosewith CKD-focus organizations (International Society ofNephrology, International Federation of Kidney Foundations,and other national bodies) should ensure adequate representation of people with CKD in clinical trials, leading to
an improved understanding of pharmacodynamics of thosewith CKD.
4.5: IMAGING STUDIES
4.5.1: Balance the risk of acute impairment in kidney
function due to contrast agent use against thediagnostic value and therapeutic implications of
the investigation. (Not Graded)
RATIONALE

Use of iodinated radiocontrast media has been associatedwith AKI with reported rates of 0-11% depending on the
population under study, the type of agent that is used, andthe definition of nephrotoxicity.609 The following recommendations are concordant with those from the American
College of Radiology (ACR),610 the European Society of
Urogenital Radiology (ESUR)611 and the KDIGO Clinical
Practice Guideine for Acute Kidney Injury.7
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Table 32 | Cautionary notes for prescribing in people with CKDAgentsCautionary notes

1. Antihypertensives/cardiac medications
K Avoid in people with suspected functional renal artery stenosis
RAAS antagonists (ACE-Is,
2
K Start at lower dose in people with GFR o45 ml/min/1.73 m
ARBs, aldosterone antagonists,
K Assess GFR and measure serum potassium within 1 week of starting or following any dose escalation
direct renin inhibitors)
K Temporarily suspend during intercurrent illness, planned IV radiocontrast administration,
bowel preparation prior to colonoscopy, or prior to major surgery
2
K Do not routinely discontinue in people with GFR o30 ml/min/1.73 m as they remain nephroprotective
2
K Reduce dose by 50% in people with GFR o30 ml/min/1.73 m
Beta-blockers
Digoxin
K Reduce dose based on plasma concentrations
2. Analgesics
NSAIDSK
K
K
K

Opioids

KK

3. Antimicrobials
Penicillin

K
K

Aminoglycosides

K
K
K

Macrolides
Fluoroquinolones
Tetracyclines
Antifungals

K
K
K
K
K
K

4. Hypoglycemics
Sulfonylureas

K
K

Insulin
Metformin

K
K
K
K
K

5. Lipid-lowering
Statins

K
K

Fenofibrate
6. Chemotherapeutic
Cisplatin

K

K
K

Melphalan
Methotrexate

KK
K

7. Anticoagulants
Low-molecular-weight heparins

K
K

Warfarin

KK

8. Miscellaneous
Lithium

K
K
K
K
K

Avoid in people with GFR o30 ml/min/1.73 m2
Prolonged therapy is not recommended in people with GFR o60 ml/min/1.73 m2
Should not be used in people taking lithium
Avoid in people taking RAAS blocking agents
Reduce dose when GFR o60 ml/min/1.73 m2
Use with caution in people with GFR o15 ml/min/1.73 m2
Risk of crystalluria when GFR o15 ml/min/1.73 m2 with high doses
Neurotoxicity with benzylpenicillin when GFR o15 ml/min/1.73 m2 with high doses (maximum 6 g/day)
Reduce dose and/or increase dosage interval when GFR o60 ml/min/1.73 m2
Monitor serum levels (trough and peak)
Avoid concomitant ototoxic agents such as furosemide
Reduce dose by 50% when GFR o30 ml/min/1.73 m2
Reduce dose by 50% when GFR o15 ml/min/1.73 m2
Reduce dose when GFR o45 ml/min/1.73 m2; can exacerbate uremia
Avoid amphotericin unless no alternative when GFR o60 ml/min/1.73 m2
Reduce maintenance dose of fluconazole by 50% when GFR o45 ml/min/1.73 m2
Reduce dose of flucytosine when GFR o60 ml/min/1.73 m2
Avoid agents that are mainly renally excreted (e.g., glyburide/ glibenclamide)
Other agents that are mainly metabolized in the liver may need reduced dose when
GFR o30 ml/min/1.73 m2 (e.g., gliclazide, gliquidone)
Partly renally excreted and may need reduced dose when GFR o30 ml/min/1.73 m2
Suggest avoid when GFR o30 ml/min/1.73 m2, but consider risk-benefit if GFR is stable
Review use when GFR o45 ml/min/1.73 m2
Probably safe when GFR X45 ml/min/1.73 m2
Suspend in people who become acutely unwell
No increase in toxicity for simvastatin dosed at 20 mg per day or simvastatin 20 mg /ezetimide
10 mg combinations per day in people with GFR o30 ml/min/1.73 m2 or on dialysis449
Other trials of statins in people with GFR o15 ml/min/1.73 m2 or on dialysis also showed no excess toxicity
Increases SCr by approximately 0.13 mg/dl (12 mmol/l)
Reduce dose when GFR o60 ml/min/1.73 m2
Avoid when GFR o30 ml/min/1.73 m2
Reduce dose when GFR o60 ml/min/1.73 m2
Reduce dose when GFR o60 ml/min/1.73 m2
Avoid if possible when GFR o15 ml/min/1.73 m2
Halve the dose when GFR o30 ml/min/1.73 m2
Consider switch to conventional heparin or alternatively monitor plasma anti-factor Xa in those at high risk
for bleeding
Increased risk of bleeding when GFR o30 ml/min/1.73 m2
Use lower doses and monitor closely when GFR o30 ml/min/1.73 m2
Nephrotoxic and may cause renal tubular dysfunction with prolonged use even at therapeutic levels
Monitor GFR, electrolytes, and lithium levels 6 monthly or more frequently if the dose changes
or the patient is acutely unwell
Avoid using concomitant NSAIDs
Maintain hydration during intercurrent illness
Risk-benefit of drug in specific situation must be weighed

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CKD, chronic kidney disease; GFR, glomerular filtration rate; NSAIDs, nonsteroidal anti-inflammatory drugs; RAAS, renin-angiotensin-aldosterone system; SCr, serum creatinine.

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103chapter 4

These statements have been worded in order to inform safe
radiological investigation of people with CKD and to avoid
potential nephrotoxcity that can be associated with radiological imaging.

c) Although risk for AKI increases with GFR o60 ml/min/
1.73 m2, the rates are particularly high (7.8% in one
study) when GFR is o30 ml/min/1.73 m2. Implementing
preventative strategies for all with a GFR o60 ml/min/
1.73 m2 may not be practical but a graded risk assessment taking into account all factors may be more
realistic. Some guidelines such as American College
Radiology610 and ESUR611 provide a checklist as ameans of identifying patients at risk of AKI before
investigation.
d) Extracellular volume expansion is widely recommended
although there are few good quality trials on which tobase an ideal protocol.609 0.9% saline given by continuous infusion appears superior to 0.45% saline or bolus
injection and there is no demonstration of consistentsuperiority of sodium bicarbonate over saline. Current
guidance suggests either infusion of 1 ml/kg body weight/
hour for 3-12 hours before and after the procedure or
100 ml/hr, beginning 6 to 12 hours before and continuing
4 to 12 hours after intravascular iodinated contrast
medium administration.609,610e) Use of N-acetylcysteine or ascorbic acid as preventative
measures has not been shown to be a consistent benefit.

Evidence Base

International RelevanceRadiocontrast media associated AKI is a largely preventablecause of morbidity and mortality. There is no internationallyagreed definition but most studies use an increase in SCr of
40.5 mg/dl (44 mmol/l) and/or a 25% increase from baseline
SCr within 3 days of the procedure.7,609–611 Epidemiologicalstudies and case series have identified the following risk
factors for AKI:

This guidance has universal relevance although there are cost
implications as the iso-osmolar contrast media are more
expensive.

Radiocontrast

4.5.2: We recommend that all people with GFR o60 ml/
min/1.73m2 (GFR categories G3a-G5) undergoing
elective investigation involving the intravascularadministration of iodinated radiocontrast media
should be managed according to the KDIGOClinical Practice Guideline for AKI including:
K Avoidance of high osmolar agents (1B);
K Use of lowest possible radiocontrast dose (Not
Graded);K Withdrawal of potentially nephrotoxic agents
before and after the procedure (1C);K Adequate hydration with saline before, during,
and after the procedure (1A);
K Measurementof GFR 48–96 hours after theprocedure (1C).
RATIONALE

a)
b)
c)
d)
e)
f)
g)
h)
i)
j)

GFR o60 ml/min/1.73 m2 (particularly if o30 ml/min/
1.73 m2)
Diabetes
Concurrent dehydration
CHF
470 years of age
Concurrent use of known nephrotoxic agents such as
NSAIDsUse of high osmolality agents (especially in those withGFR o60 ml/min/1.73 m2)
Use of large doses of radiocontrast media
Intra-arterial injection
Gout (hyperuricemia)

Numerous studies of preventative strategies have been
performed with the following conclusions:a) High osmolar agents pose a greater risk of AKI in people
with CKD.609
b) Iso-osmolar agents compared to low-osmolar agents areassociated with lower rates of AKI in some but not all
studies. Wherever possible iso-osmolar agents should be
used in people with CKD at high risk for AKI (althoughthese tend to be more expensive).612
104

LIMITATIONS

Some of the guidance is based upon limited evidence andthere is a need for more research into simple preventative
measure such as pre-investigation rehydration (see below).
There has not previously been a universal definition for AKI
following administration of contrast media. However,recommendations from the KDIGO AKI Guideline suggestthat the same general AKI definition and staging be used forchanges in kidney function, irrespective of etiology.
RESEARCH RECOMMENDATIONSProspective studies using direct measures of GFR before andafter administration of radiological contrast media are
required to help define the incidence of AKI. Such studies
would also be able to validate creatinine or other estimates of
GFR in people undergoing radiological investigation.
Prospective controlled trials of rehydration using different
fluids (saline, bicarbonate, Hartmann’s) and validated
estimates of GFR are urgently required.
Definitive studies of N-acetylcysteine and other antioxidants would help determine their usefulness or otherwise.
Gadolinium-containing contrast media

Gadolinium is a rare earth element that is naturally highly
toxic. When bound to proprietary chelating agents, it isessentially biologically inert in people with normal renal
function and provides excellent contrast during MRI. These
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chapter 4chelates are excreted unchanged by the kidneys by glomerular
filtration and have much lower direct nephrotoxicity thanconventional radioiodine contrast media.613 However over
200 cases of a scleroderma-like condition now termed
nephrogenic systemic fibrosis (NSF) following gadolinium
use in patients with CKD have been reported.613, 614
4.5.3: We recommend not using gadolinium-containing
contrast media in people with GFR o15 ml/min/
1.73 m2 (GFR category G5) unless there is noalternative appropriate test. (1B)
4.5.4: We suggest that people with a GFR o30 ml/min/
1.73 m2 (GFR categories G4-G5) who require
gadolinium-containing contrast media are preferentially offered a macrocyclic chelate preparation. (2B)
RATIONALE

These statements have been worded in order to enable safe
administration of gadolinium to people with CKD. As withall tests requested in the CKD population, clinicians should
be aware of the risk-benefit ratio of the use of gadolinium inpeople with GFR 15-29 ml/min/1.73 m2.
Evidence Base

NSF is an untreatable and sometimes fatal condition thatcomplicates the use of gadolinium-containing contrast media
in people with CKD. Prevention is therefore the best
approach with avoidance of gadolinium exposure unlessclinically indicated and to use the lowest risk agent at thelowest dose.613,615
Although the risk of AKI with iodinated contrast media ismuch greater than that for NSF with gadolinium, the former
is treatable with dialysis whereas the latter is not. Thus,
consideration of more conventional imaging techniquesshould be undertaken in all with a GFR o30 ml/min/
1.73 m2.610,613–615
A recent meta-analysis and review have highlighted thosepatients most at risk and quantified an OR for NSF of
between 20-50 for those with a GFR o15 ml/min/1.73 m2.614
While there is general agreement that patients with a GFR
415 ml/min/1.73 m2 are at increased risk, it is not possible
to derive a precise estimate. No patients with a GFR 430 ml/
min/1.73 m2 have developed NSF without concomitantliver failure.614
There is some suggestion that the type of gadolinium
preparation plays a role:614,615 Linear chelated preparations
such as gadodiamide may be more likely to cause NSF andshould be avoided when GFR is o30 ml/min/1.73 m2.
Gadoteridol, gadobutrol, or gadoterate should be considered
if MRI with contrast is clinically essential.610,613,615 Moreover,as gadolinium is freely dialysed,616 most guidelines recommend dialysis in patients with a GFR o15 ml/min/1.73 m2
or for those already on dialysis immediately after (andperhaps repeated 24 hours later) completion of theprocedure.610,615 The role of dialysis in people with GFR
above 15 ml/min/1.73 m2 is uncertain.
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International RelevanceThis guidance has universal relevance although there are cost
implications as the non-linear chelated preparations are more
expensive.
Pediatric Considerations

Regarding both Recommendations 4.5.3 and 4.5.4, a numberof considerations specific to the use of gadolinium preparations
in young children and neonates must also be considered inaddition to the general admonishments against their use insituations of GFR o30 ml/min/1.73 m2. In particular, the FDA
currently does not license any gadolinium-based contrast agent(GBCA) product for use in children less than 2 years of age; andlikewise the European Medicines Agency cautions against theuse of any GBCA in a child less than 1 year of age.
In addition, the ability to accurately estimate the relativevalue of a neonate or young infant’s GFR leads to great
difficulty in terms of assigning risk of GBCA exposure if one
bases this on renal clearance. In a recent paper by Meng andcolleagues,617 they surveyed a worldwide group of bothcardiologists and radiologists with respect to their use ofgadolinium in their pediatric MRI practice. While 93% of the
respondents did evaluate renal function in some or all of
their patients, only a slight majority (54%) used an
estimating formula, most often the Schwartz equation, withthe remainder relying on SCr alone (31%) or urine output(6%). Perhaps of most concern was that renal function wasassessed in only 33% and 31%, respectively, of patientsclassified as ‘all neonates’ or ‘all patients o1 week of age.’
Equally concerning was the fact that 13% of the respondents
would give gadolinium to some of these children in the faceof a GFR o30 ml/min/1.73 m2.
In recognition of our inability to accurately measure GFR
in the neonate and, by extension, the clearance of compounds
such as gadolinium, all nephrologists and radiologists must
exercise caution in terms of use of GBCA in this potentiallyhigh-risk population, and all other imaging modalities
should be considered prior to choosing one requiring
gadolinium exposure.
LIMITATIONSThe evidence is largely based upon case series rather thanprospective studies or RCTs.
RESEARCH RECOMMENDATIONS

As for iodinated contrast media, a prospective study of people
with CKD undergoing nuclear MRI with gadolinium contrast
would help define change in GFR and validate estimators.
Because NSF is such a serious condition, an RCT of dialysis inpeople with GFR o30 ml/min/1.73 m2 would help todetermine risk-benefit in these patients, though recruitment
may be difficult due to potential ethical concerns.
Bowel preparation

The increasing use of colonoscopy as a screening tool forbowel cancer has resulted in many people undergoing bowel
105

chapter 4

preparation with oral sodium phosphate-containing preparations. Case reports of acute and late irreversible renal failure
with biopsy-proven phosphate deposition have led to a new
disease entity termed acute phosphate nephropathy.618,619
Less than 40 definite cases have been reported and these havebeen extensively reviewed.

This statement has been worded in order to enable safe bowel
preparation in people with CKD who need to undergo
investigation of bowel disease.

There is some debate as to whether the cause of the kidney
injury is entirely due to dehydration rather than phosphate
use per se.623 However, it is hard to understand why calcium
phosphate deposits occur and cause late renal impairment if
dehydration was the only factor.
There is a single RCT of phosphate versus non-phosphate
preparations but assessment of renal function was limited tochange in SCr and GFR at baseline is not reported.624
Notwithstanding these limitations, there were greater changes
in serum potassium, calcium, and phosphate in those given
sodium phosphate-containing preparations.
As there are non-phosphate-containing bowel preparations available, these should be used in all the above groups(and arguably in all people given the biochemical abnormalities observed in normal volunteers). As for radiocontrast
media, rehydration with saline may be required in the frail
and ill irrespective of the bowel preparation that is used.

Evidence Base

International RelevanceElectrolyte disturbances that are sometimes severe andinclude hyperphosphatemia, hypocalcemia, hypo- andhypernatremia, and hypokalemia have been reported innormal volunteers undergoing oral phosphate bowel preparation.620 Renal injury has been reported in a small numberof people although the condition is likely to be underrecorded. A recent study from Iceland estimated theincidence to be around 1 per thousand doses621 but others
would suggest incidence rates of between 1% and 4%.618,619
Two broad patterns of renal injury have been described. An early symptomatic response associated with severe
hyperphosphatemia and hypocalcemia and a later (days tomonths) irreversible kidney injury associated with a specifictubulointerstitial calcium phosphate deposition.618,619
The following people are said to be at particular risk
although the link to kidney injury is associative in many cases
and firm evidence is lacking:This guidance has universal relevance but non-phosphatecontaining bowel preparations are more expensive, so the useof these agents may differ around the world.

4.5.5: We recommend not to use oral phosphate-containing bowel preparations in people with a GFR o60
ml/min/1.73 m2 (GFR categories G3a-G5) or inthose known to be at risk of phosphate nephropathy.
(1A)
RATIONALE

a)
b)
c)
d)
e)
f)
g)
h)
i)
j)
k)

GFR o60 ml/min/1.73 m2
460 years of age
FemaleHypertension
Diabetes
CHF
Dehydration
Active colitis
Concurrent use of RAAS blocking agents, diuretics,
lithium, NSAIDs
Large and/or repeat dosing of oral phosphate preparations
Hypoparathyroidism

Although the FDA has banned oral phosphate solutions,
there is no qualitative difference with tablet preparations.
Both should be avoided in people at risk and this is thecurrent recommendation of the American Society for
Gastrointestinal Endoscopy.622
106

LIMITATIONS

The data are based upon case series with a limited number ofaffected individuals and retrospective population studies.
RESEARCH RECOMMENDATIONSProspective study in people with normal renal function andthose with different severities of CKD are urgently requiredin order to define the acute biochemical and metabolic effectsof phosphate-containing bowel preparations. There is also aneed for a study of all people undergoing bowel preparation
with whatever preparation in order to explore the effects on
GFR on the incidence of this complication. More definitive
exploration of rehydration therapy (type and volume) inpeople with CKD undergoing bowel preparation is urgently
needed.
4.6 CKD AND RISKS FOR INFECTIONS, AKI,HOSPITALIZATIONS, AND MORTALITY

The following section gives guidance for the care of people
with CKD given that they are at increased risk for a numberof events such as infections, AKI, CVD, hospitalizations, andmortality. Appreciating that increased risk and implementing
some of the recommendations below may result in improved
outcomes for people. It will be important to develop policies
and robust research agendas to address areas which do nothave a substantial evidentiary base.
CKD and risk of infections

CKD is associated with significant major infectious complications, which occur at rates 3 to 4 times the general
population. Infection is an important cause of morbidity andmortality among patients with kidney failure and is the
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second leading cause of death following CVD. CKD may be arisk-multiplier for acute infectious disease-associated mortality, as it is for CVD. Despite a less effective response tovaccination, there are data suggesting benefit from immunization among people with CKD as in the general population.
4.6.1: We recommend that all adults with CKD areoffered annual vaccination with influenza vaccine,unless contraindicated. (1B)
4.6.2: We recommend that all adults with eGFR o30 ml/
min/1.73 m2 (GFR categories G4-G5) and those athigh risk of pneumococcal infection (e.g., nephrotic
syndrome, diabetes, or those receiving immunosuppression) receive vaccination with polyvalentpneumococcal vaccine unless contraindicated. (1B)
4.6.3: We recommend that all adults with CKD who havereceived pneumococcal vaccination are offeredrevaccination within 5 years. (1B)
4.6.4: We recommend that all adults who are at high riskof progression of CKD and have GFR o30 ml/min/
1.73 m2 (GFR categories G4-G5) be immunizedagainst hepatitis B and the response confirmed byappropriate serological testing. (1B)
4.6.5: Consideration of live vaccine should include anappreciation of the patient’s immune status andshould be in line with recommendations fromofficial or governmental bodies. (Not Graded)
4.6.6: Pediatric immunization schedules should be followed
according to official international and regional
recommedations for children with CKD. (Not Graded)
RATIONALECKD is associated with alterations in primary host defense
mechanisms and increases the risk of bacterial infections(Table 33). Epidemiological study suggests that the 3 mostcommonly seen infectious complications in the CKD
population are: urinary tract infection, pneumonia, andsepsis. In the general population, there is strong evidence thatpreventive measures are effective in adults and there are datasuggesting benefit from immunization in people with CKD.
Evidence Base

Previous investigations have firmly established ESRD as astrong risk factor for infectious complications.625–628 However, few epidemiologic reports have addressed the risk ofinfections in people with CKD not treated with dialysis.629,630
Data from the US Renal Data System (USRDS) suggest thathigher rates of hospital admission because of septicemia are
noted in people with CKD compared with those without
CKD.631 Comprehensive studies of the absolute rates, risk
factors, clinical course, and outcomes of different types ofclinically relevant infections across the spectrum of CKD are
not available.
Among people with CKD, very few studies have examined
the incidence or prevalence of infections and no publisheddata describe GFR category–specific infection rates. Among
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Table 33 | Risk factors for infection in people with CKDAdvanced age
High burden of coexisting illnesses such as diabetes
Hypoalbuminemia625
Immunosuppressive therapy628
Nephrotic syndrome634
UremiaAnemia and malnutrition635
High prevalence of functional disabilities
Abbreviation: CKD, chronic kidney disese

Medicare beneficiaries aged more than 66 yr, people withdiagnosed CKD seem to have substantially higher rates of
hospitalization for diagnoses of pneumonia and sepsis
compared with people without diagnosed CKD.628 In
addition to an increased incidence of being hospitalizedwith infections, people with CKD have longer lengths of
hospital stay during infection-related admissions comparedwith people without CKD.632
Among USRDS data admission rates for all causes, CVD
and infection, are 38–46% higher for those with CKD thanfor those without.633 Rates for pneumonia in CKD were
nearly three times higher than those for non-CKD.
Hospitalizations for bacteremia/septicemia, were nearly fourtimes higher for people with CKD compared to those
without. Hospitalization rates for urinary tract infections
were three-fold higher for people with CKD.
In people with ESRD, the function of polymorphonuclear
white blood cells, lymphocytes, and monocytes is altered,resulting in an impaired host response to infection.636–638
However, these issues have not been adequately investigatedin people with CKD.
There is a growing body of evidence in the general
population for reduction in infections, hospitalizations, andmortality as a result of immunizations. Current data suggestthat vaccination is an underused prevention strategy in the
CKD and ESRD populations.639 Potential barriers toimmunization that are specific to the CKD populations havenot been systematically examined. Although lower vaccine
responsiveness has been widely recognized in the ESRD
population, to what extent moderate to advanced CKD
modifies vaccine responsiveness remains unclear.640–642
Studies that have examined vaccination in the setting of
CKD or ESRD have been limited by small study size, variable
follow-up, and ascertainment of surrogates for vaccine
effectiveness such as antibody response and rate of antibody
decline after vaccination as opposed to vaccine efficacy forpreventing infection.643
Influenza A and B vaccine. Despite potentially impaired
antibody responses, a 2-year analysis of US Medicare claims
data found that people vaccinated against influenza A and B
on dialysis had a substantially lower chance of any-cause
hospital admission and any-cause death than those patientsnot vaccinated on dialysis.644 This finding might indicate
clinical effectiveness of vaccinating this population but its
observational design might also reflect differences in theunderlying clinical status among people vaccinated and not107chapter 4

vaccinated. No unique adverse events related to influenza
vaccine have been identified in people on dialysis.
Pneumococcal vaccine. People with kidney diseasevaccinated with the pneumococcal vaccine seem todevelop different serotype-specific titers, develop lower levelsof antibody titers, and have a more rapid loss of antibody
titers as compared with healthy control subjects.639,645,646
Practitioners should be aware of the impact ofspecific vaccines on responsiveness and duration of responsiveness. Revaccination practices will be dictated by thatknowledge.
Hepatitis B vaccine. Widespread hepatitis B virus (HBV)
vaccination at the onset of dialysis has led to a marked
reduction of HBV infections in people with ESRD,
although improved screening of blood products anddissemination of recommendations for reducing the spreadof HBV infections in dialysis units have also likely
contributed.647 Among people with moderate to advanced
CKD, hepatitis B vaccination responsiveness has been shown
to range from approximately 60 to 80% depending on the
dosage, number of administered vaccines, and study
population. Although findings have been inconsistent as towhether the level of GFR affects vaccine responsiveness inpeople with CKD640,642 those with higher GFR are more
likely to respond with seroconversion, independent of otherfactors.640
S. aureus vaccine. StaphVAX has not been shown to beefficacious in reducing the risk for Staphylococcus aureus
bacteremia in people on hemodialysis.648,649 No data are
published in people with CKD.
Live vaccines. Due to the fact that people with CKD areoften immunocompromised, live vaccines should only be
used with caution on an individual basis.
In summary, although some vaccines (like influenza) inusual doses provide protection, other vaccines (HBV andpneumococcal) require more frequent dosing or larger doses
to achieve and maintain protective antibody titers. Frequency
and type of vaccination will vary according to local
circumstances and prevalence of disease.
International Relevance

The availability of different vaccinations may vary worldwide,
as does the prevalence of specific bacterial, viral, and otherinfections. It is reasonable to offer individuals appropriate
immunization according to local practices.
Implications for Clinical Practice and Public Policy

Vaccines for influenza, hepatitis B, and pneumococcus are
currently recommended for people with CKD by the local,
regional, or national advisory committees on immunization
practices from most countries.
Current recommendations are to:
K Provide influenza vaccination annually to people with
CKD.
K Provide pneumococcal vaccine with a single booster dose
5 years after the initial dose.
108

K

Provide HBV vaccine to people with CKD who are likely
to require RRT. Although the recommendation is to givethe HBV vaccine during more severe CKD (GFR o15 ml/
min/1.73 m2), it may be preferable to give this earlier tomaximize the chances of achieving immunity; there aredata to support this practice.640 This would also ensurethat all patients are immunized against HBV before
receiving a transplant. As protective antibody levels may
fall, this should be checked (possibly annually) withbooster doses given if appropriate.

Areas of Controversy, Confusion, or Non-consensus

Much remains to be understood concerning impaired host
response to infection in patients with CKD.
K Studies should be undertaken to determine the absolute
rates, risk factors, and clinical course of different types ofclinically relevant infections across the spectrum of CKD,
by GFR and albuminuria category, and by cause.
K The outcomes across the range of acute infections in
CKD population need to be ascertained.
K Studies should be undertaken to assess the rate of declineof antibody titers post-vaccination and the efficacy of
immunization in people with CKD.
Pediatric Considerations

Current immunization schedules for children are regularly
updated by both the US Centers for Disease Control andPrevention650 and American Academy of Pediatrics.651
Current and comprehensive immunization recommendations
for children with CKD have been published by Neu in 2012.652
The paper addresses key issues regarding the use of vaccines
in CKD pediatric populations who are receiving concomitant
immunosuppression and in those awaiting transplantation.
The need for, and interpretation of, protective antibody levels
for those vaccines where this is indicated is described.
An oversimplified summary of the recommendations
would be to provide all recommended childhood vaccines
to every child with CKD with the exception of any live viral
vaccine in a child receiving immunosuppressive medications.
Likewise children on dialysis should not receive the live
attenuated influenza vaccine although the inactivated version
can and should be given to all children with CKD on anannual basis otherwise. Pneumococcal vaccination is particularly important in children with nephrotic syndrome andthose with CKD, and current vaccination schedules andproducts should be carefully reviewed to ensure proper
serotype coverage is being provided. Hepatitis B status andvaccination are of extreme importance in all children who
may go onto dialysis – and specific recommendations forongoing monitoring and interpretation of antibody levels
should be carefully reviewed.
CKD and risk of AKI

Due to the epidemiological association between CKD and
AKI and the number of observational studies reporting an
association between pre-existing CKD and AKI, CKD is
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chapter 4

considered the most consistent pre-existing condition
associated with a high risk of AKI. However the potential
linkage between patients with AKI, CKD, and ESRD has been
inadequately studied to date and remains ill defined. Thissection describes AKI as a complication which needs to be
managed in those with CKD. Given its association with
progression, it is also described in that section.
4.6.7: We recommend that all people with CKD are
considered to be at increased risk of AKI. (1A)
4.6.7.1: In people with CKD, the recommendations
detailed in the KDIGO AKI Guideline should
be followed for management of those at riskof AKI during intercurrent illness, or when
undergoing investigation and procedures thatare likely to increase the risk of AKI. (Not
Graded)CKD, the progression of CKD to ESRD may sometimes bedifficult to separate from acute-on-chronic renal failure. A
cohort study by Lafrance et al. followed a referred CKD
population in British Columbia for a median of 19.4 months
after achieving a GFR of r30 ml/min/1.73 m2. Forty-five
percent had at least one episode of AKI.276 In another cohort
study of 920,985 adults in Alberta, Canada with at least one
outpatient measurement of SCr and proteinuria and not
requiring chronic dialysis, risk of admission with AKI
increased with heavier proteinuria and reduced GFR.16
International Relevance

These guidelines about AKI have relevance around the world.
While the causes of AKI may differ by region, country, socioeconomic status, and age, the consequences remain thesimilar. Where there are no facilitities to support AKI or
CKD, people will die.

RATIONALE

Areas of Controversy, Confusion, or Non-consensus

Observational data suggest a strong association between preexisting CKD and AKI. The appreciation that CKD patients
may be more susceptible to AKI is the purpose of the above setof statements. However, methodological issues such as how
CKD and AKI are defined in clinical studies and the statisticaladjustments for non-uniformity of comorbidities among
various studies may affect the validity of observed associations.

Interpretation of published data examining the influence ofpre-existing CKD on the increased likelihood of AKI ispotentially confounded by a number of issues. These include
the comorbidities associated with CKD, influenced byrepeated exposure to various nephrotoxic insults or inhospital errors,57,277 or primarily due to the alteredphysiology in CKD. There are also methodological issues
such as how CKD and AKI are defined in clinical studies andthe varying statistical adjustments for comorbidities which
may affect the validity of observed associations.
A further important issue to clarify is whether pre-existing
CKD influences the outcome of AKI. Currently, there is no
single biomarker that can differentiate ‘acute’ from ‘chronic’
kidney disease and help to address this issue. Several large
observational and database studies report, surprisingly, lower
in-hospital mortality in patients with AKI superimposed on
CKD compared with controls.278-283 Data from PICARD
reveal lower in-patient mortality and median length of stay in
ICU subjects with acute-on-chronic renal injury comparedwith non-CKD subjects with AKI, though the post-discharge
dialysis rates were higher in subjects with pre-existing CKD.284

Evidence BaseCKD is designated as a risk factor for AKI because of
the epidemiological association between the two.263,264 A
number of studies in a variety of settings report an association between pre-existing CKD and AKI. 265-271 CKD is apotent predictor of acute decline in kidney function
following exposure to radiocontrast,272 major surgery,273
and other medical conditions.274
Hsu et al.14 compared the pre-hospitalization MDRD GFR
of 1764 adult members of the Kaiser Permanente Northern
California health-care system who developed dialysis-requiring AKI during hospitalization with 600,820 individuals who
did not. Compared with a reference baseline GFR of Z60 ml/
min/1.73 m2, a baseline GFR of 45–59 ml/min/1.73 m2 wasassociated with an adjusted OR of in-hospital AKI of 1.66
(95% CI 1.40–1.97). For GFR values of 15–29 ml/min/1.73 m2,
the adjusted OR for in-hospital AKI was 20.42 (95% CI
17.40–23.96). The presence of diabetes, hypertension, andproteinuria increased the likelihood of developing in-hospital
AKI, with adjusted ORs of 1.99 (95% CI 1.78–2.23), 1.55
(95% CI 1.37–1.76) and 2.84 (95% CI 2.52–3.19), respectively.
The authors concluded that CKD is the main risk factor for
AKI during hospitalization. A contrasting approach by Singhet al. defined AKI as dialysis-requiring acute renal failure.275
Because the clinical decision to dialyze a patient is frequently
influenced by a higher overall SCr, presence of hemodialysis
access, or consideration of inevitable progression to ESRD,
this definition of AKI could bias toward capturing more AKI
cases in CKD patients. Moreover, in patients with advanced
Kidney International Supplements (2013) 3, 91–111

Pediatric Considerations

The relative paucity of pediatric specific guidelines (due tolack of high-quality studies) in the KDIGO AKI guideline
would suggest that the use of pediatric data and review
papers as well as relevant pediatric nephrology texts would beof benefit to the practitioner interested in reviewing this topic
in greater detail and applying pediatric data to theirpractice.653–658
RESEARCH RECOMMENDATIONSProspectively designed clinical studies with a clear anduniform definition of CKD and AKI and adjusted forcomorbidities are needed to determine:
K the frequency of AKI events in a CKD population
K the outcome of AKI in patients with CKD condition
109chapter 4

K

the importance of proteinuria in addition to low GFR in
the risk of AKI

CKD and risk of hospitalization and mortality

Regardless of the method used to estimate GFR, hospitalization and mortality rates are higher in people with CKD. Exactrates vary with comorbidity and severity of CKD, and are notwell-defined. Selection of interventions that could reduce
hospitalizations, morbidity, mortality, and costs in people
with CKD is not well-studied.
4.6.8: CKD disease management programs should be
developed in order to optimize the community
management of people with CKD and reduce therisk of hospital admission. (Not Graded)
4.6.9: Interventions to reduce hospitalization and mortality for people with CKD should pay close attention to the management of associated comorbid
conditions and cardiovascular disease in particular.
(Not Graded)
RATIONALE

There are observational and database studies reporting an
association between pre-existing CKD and hospitalizations
and mortality. A better understanding of the rates, causes,
and risk factors for hospitalization among people with CKD
would allow estimates of the economic burden of CKD and
identification of those at risk for increased resource
utilization. People with CKD are an ideal target forinterventions aimed at reduction of morbidity, hospitalization, mortality, and costs. These statements suggest that acoordinated approach to the identification and management
would result in better outcomes and are intended as ‘bestpractices’ statements, recognizing the difficulty in developing
an evidence base while addressing issues related to resource
allocations (Table 34).
Evidence Base

Mortality rates remain high (16-22%) with the use of
dialysis, with more than half of all deaths related to
CVD. Less is known about mortality and CVD rates, andresource use among persons with a reduced GFR who are
not yet receiving maintenance dialysis. Few studies have

Table 34 | Components of community CKD management
programs
Disease monitoring
Integration with other chronic disease management programs including
diabetes, hypertension and heart failure
Medication management and dietary advice
Anemia management programs
Vaccination programs
Information and psychosocial support
Renal replacement therapy (dialysis and transplant) education
Advanced care planning and end-of-life care (where appropriate)
Abbreviation: CKD, chronic kidney disease.

110

investigated the association between CKD and the risk of
hospitalization.
Data from the USRDS reveal that hospitalization rates
vary with comorbidity and interact with degrees of CKD.
Adjusted rates are 38% higher in people with CKD and 19%
greater in people with CKD and GFR under 60 ml/min/
1.73 m2 than in those with GFR 460 ml/min/1.73 m2, whoin turn are 20% higher than in people without CKDillustrating the graded impact of advancing kidney disease.
Not surprisingly, rates of cardiovascular hospitalization are
greater for people with CKD, particularly those withincreasing severity of CKD.659 In both the CKD and nonCKD populations, adjusted rates of hospitalization increase
with greater comorbidity. In 2008, for example, the rate forpeople with CKD with both diabetes and CHF was 726 per1000 person-years at risk — 85% greater than the rate of 393
among people with neither diagnosis. Rates of admission for
CVD increase even more in the higher categories of GFR.
Among Medicare subjects, the rate of 141 admissions per 1000
person-years for those with GFR o60 ml/min/1.73 m2 is 26%
higher than the rate of 112 reported for those with CKD and
GFR Z60 ml/min/1.73 m2. The admission rates of 101 and 90
reported for MarketScan and Ingenix i3 subjects with GFR
o60 ml/min/1.73 m2 are 48 and 16% greater, respectively,
than those occurring in people with higher GFRs.633 Adjusted
rates of mortality in USRDS 2008 increased with age, andwere highest in people with advanced categories of GFR:
31–72% higher, for example, in people with GFR o60 ml/
min/1.73 m2 compared to those with no CKD. By gender,rates in men with CKD were 91.8 per 1000 person-years at
risk compared to 85.6 in women. Rates for people with CKD
overall were similar in whites and African Americans, but inpeople with GFR o60 ml/min/1.73 m2, rates for African
Americans were 18% higher than those for whites, at 95.0 and80.5 per 1000 person-years, respectively.633
Khan et al.660 confirmed that hospital utilization amongpeople with CKD is high. During a median follow-up of 11.4
months, 47% of subjects had at least one hospitalization andthere were on average 0.96 hospitalizations, 6.6 hospital days,
and 4.0 outpatient nephrology visits per person-year at risk.
Cardiac disease/hypertension was the most common primary
diagnosis of hospitalizations and progression of CKD/acutekidney failure was the most common secondary cause of
hospitalization. The authors had previously shown that thedialysis population at their institution had 2.2 hospitalizations and 14.8 hospital days per person-year at risk,659 which
was similar to that among US hemodialysis patients between
1996 and 1998, who had 1.9 hospitalizations and 14 hospitaldays per person-year at risk.661 In the general population,
there were 0.31 hospitalizations and 1.9 hospital days perperson in 1998.662
Go et al.58 reported an independent, graded association
between GFR and the risk of death, cardiovascular events,and hospitalization in 1,120,295 adults within a large,
integrated system of health-care delivery in whom SCr had
been measured between 1996 and 2000 and who had not
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chapter 4

undergone dialysis or kidney transplantation. These risks
were evident at GFR o60 ml/min/1.73 m2 and substantially
increased at GFR o45 ml/min/1.73 m2.
The higher hospital utilization among people with CKD
compared to the general population, and the similarity in the
comorbid conditions and the causes of hospitalization
between people with CKD and ESRD, confirm the hypothesisthat the complications and comorbidity observed in ESRD
are manifest earlier in the disease process. Previous studies
have demonstrated an association between age, gender, race,
cardiac disease, peripheral vascular disease, serum albumin
and hematocrit levels, and resource utilization among people
on dialysis.659,663,664 Holland et al.665 identified baseline
predictors of first non-elective hospitalization among a
retrospective cohort of 362 predialysis subjects. Multivariate
analysis, adjusted for baseline creatinine concentration,
selected advanced age (RR 1.02; 95% CI 1.01–1.03), angina(RR 1.9; CI 1.37–2.61), peripheral vascular disease (RR 1.55,
CI 1.05–2.27), and Hb concentration (RR 0.99, CI 0.94–0.98)
as independent predictors of hospitalization. These
comorbid conditions progressively worsen with advancing
kidney disease and result in a substantial proportion ofpeople having severe complications by the time they cometo RRT.
Interventions to reduce hospitalizations and mortality forpeople with CKD should pay close attention to the management of associated comorbid conditions and CVD.666 Closer
attention to the management of heart disease in thispopulation could substantially improve outcomes.667
The influence of correction of anemia on hospitalization iscontroversial. Drüeke et al.668 randomly assigned 603 subjects
with GFR 15-35 ml/min/1.73 m2 and mild-to-moderate
anemia (Hb level: 11.0-12.5 g/dl [110-125 g/l]) to a target Hbvalue in the normal range (13.0-15.0 g/dl [130-150 g/l]) or
the subnormal range (10.5-11.5 g/dl [105-115 g/l]). There
were no significant differences between the two groups in theincidence of hospital admission (61% and 59%, respectively)or mean duration of hospitalization for cardiovascularreasons (33.0 and 28.2 days, respectively). Singh et al.669
studied 1432 people with CKD, 715 of whom were randomly
assigned to receive a dose of epoetin alfa targeted to achievea Hb level of 13.5 g/dl (135 g/l) and 717 of whomwere assigned to receive a dose targeted to achieve a levelof 11.3 g/dl (113 g/l). The median study duration was

Kidney International Supplements (2013) 3, 91–111

16 months. The primary end point was a composite of death,MI, hospitalization for CHF (without RRT), and stroke. Theyobserved an increased risk of the primary composite end
point in the high Hb group as compared with the low Hbgroup. Death and hospitalization for CHF accounted for
74.8% of the composite events. The Trial to Reduce
Cardiovascular Events with Aranesp Therapy (TREAT)375
study involved 4038 people with diabetes, CKD, and anemia.
Subjects were randomly assigned to treatment with darbepoetin alfa to achieve a Hb level of approximately 13 g/dl
(130 g/l) or to placebo, with rescue darbepoetin alfa when the
Hb level was less than 9.0 g/dl (90 g/l). The primary end
points were the composite outcomes of death or a
cardiovascular event (nonfatal MI, CHF, stroke, or hospitalization for myocardial ischemia) and of death or ESRD.
Again there were no significant between-group differences in
the outcomes of interest.
International Relevance

It is of benefit for all jurisdictions to appreciate the increase
in resource utilization by CKD populations. Identificationof people at risk for increased resource utilization andeconomic burden of CKD should result in strategies toattenuate that risk or address the resource implications.
Selection of interventions that could reduce hospitalizations,morbidity, mortality, and costs in these populations shouldbe evaluated.
DISCLAIMER

While every effort is made by the publishers, editorial board,
and ISN to see that no inaccurate or misleading data, opinion
or statement appears in this Journal, they wish to make it clearthat the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contributor,
copyright holder, or advertiser concerned. Accordingly, thepublishers and the ISN, the editorial board and their respective
employers, office and agents accept no liability whatsoever forthe consequences of any such inaccurate or misleading data,
opinion or statement. While every effort is made to ensure that
drug doses and other quantities are presented accurately,
readers are advised that new methods and techniques
involving drug usage, and described within this Journal,
should only be followed in conjunction with the drug
manufacturer’s own published literature.

111

chapter 5

http://www.kidney-international.org& 2013 KDIGO

Chapter 5: Referral to specialists and models of care
Kidney International Supplements (2013) 3, 112–119; doi:10.1038/kisup.2012.68

Early identification and referral of people with CKD has thepotential to reverse, delay, or prevent progression of disease
and is a key focus of international initiatives in the area of
kidney disease. The goals of early identification and referral
are several-fold and include:
1. Provision of specific therapy based on diagnosis
2. Slowing/arresting CKD progression
3. Evaluation and management of comorbid conditions
4. Prevention and management of CVD
5. Identification, prevention, and management of CKDspecific complications (e.g., malnutrition, anemia, bonedisease, acidosis)
6. Planning and preparation for RRT (e.g., choice ofmodality, access-placement and care, preemptive transplantation)
7. Psychosocial support and provision of conservative careand palliative care options where required
5.1: REFERRAL TO SPECIALIST SERVICES

5.1.1: We recommend referral to specialist kidney careservices for people with CKD in the following
circumstances (1B):
K AKI or abrupt sustained fall in GFR;
2
K GFR o30 ml/min/1.73 m(GFR categories
G4-G5)*;
K a consistent finding of significant albuminuria(ACR Z300 mg/g [Z30 mg/mmol] or AER
Z300 mg/24 hours, approximately equivalent
to PCR Z500 mg/g [Z50 mg/mmol] or PER
Z500 mg/24 hours);
K progression of CKD (see Recommendation
2.1.3 for definition);
K urinary red cell casts, RBC 420 per highpower field sustained and not readily
explained;K CKD and hypertension refractory to treatment
with 4 or more antihypertensive agents;
K persistent abnormalities of serum potassium;
K recurrent or extensive nephrolithiasis;
K hereditary kidney disease.
5.1.2: We recommend timely referral for planning renal
replacement therapy (RRT) in people with progressive CKD in whom the risk of kidney failure
within 1 year is 10-20% or higherw, as determinedby validated risk prediction tools. (1B)112

RATIONALE

This statement reminds the practitioner that there is a needfor timely referral for RRT planning in order to ensure gooddecision making and outcomes. The use of the word ‘timely’is vague as this is not yet determined, and is based on patientand system factors. The actual amount of time required at aminimum is at least 1 year to ensure appropriate education,
understanding and referrals to other practitioners (e.g.,vascular access surgeons, transplant teams, etc). The second
part of the statement refers to the fact that those who areprogressing (versus those who are stable) are the ones whowill benefit from this referral. Hence, there is a need to apply
prediction tools to help identify the risk of progression. We
have not stated which prediction tool is preferred as thesemay differ depending on information available in any
individual or local experience. Examples of prediction tools
can be found in recent publications.257,260,261
The scope of nephrology practice includes a wide varietyof conditions including not only ESRD but also acute andchronic primary and systemic diseases involving individual
elements of the kidney, resistant hypertension, and biochemical derangements. There are thus more potential benefits ofnephrology referral than those widely recognized such as
identification of reversible causes of CKD, provision oftreatment that may slow progression of CKD, management of
the metabolic complications of advanced CKD, and preparation for dialysis and transplantation.
In certain people, such as those with diabetes, transition to asevere reduction in GFR and kidney failure may progress rapidly.
In such individuals early nephrology referral is the watchword
but when an individual’s kidney function is relatively stable (rateof decline in GFR o5 ml/min/1.73 m2/year), we suggest using
the grid as a guide (Figure 21). Where refer is marked by anasterisk, referring clinicians may wish to discuss with theirnephrology service depending on local arrangements.
Evidence Base

Although referral recommendations in the literature areinconsistent, criteria for nephrology referral include SCr or
GFR, proteinuria, hematuria, BP, and electrolyte derange-*If this is a stable isolated finding, formal referral (i.e., formal consultationand ongoing care management) may not be necessary and advice from
specialist services may be all that is required to facilitate best care for thepatients. This will be health-care system dependent.
w
The aim is to avoid late referral, defined here as referral to specialist services
less than 1 year before start of RRT.
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chapter 5

GFR categories (ml/min/ 1.73 m2)
Description and range

Persistent albuminuria categories
Description and range
A1

A2

A3

Normal to
mildlyincreased

Moderately
increased

Severelyincreased<30 mg/g<3 mg/mmol

30–300 mg/g
3–30 mg/mmol>300 mg/g>30 mg/mmol

G1

Normal or high≥90

Monitor

Refer*

G2

Mildly decreased

60–89

Monitor

Refer*

G3a

Mildly to moderately
decreased

45–59

MonitorMonitor

Refer

G3b

Moderately toseverely decreased

30–44

MonitorMonitor

Refer

G4

Severely decreased

15–29

Refer*

Refer*

Refer

G5

Kidney failure

<15

Refer

Refer

Refer

Figure 21 | Referral decision making by GFR and albuminuria. *Referring clinicians may wish to discuss with their nephrology service
depending on local arrangements regarding monitoring or referring. GFR, glomerular filtration rate. Modified with permission from
Macmillan Publishers Ltd: Kidney International. Levey AS, de Jong PE, Coresh J, et al.30 The definition, classification, and prognosis of chronic
kidney disease: a KDIGO controversies conference report. Kidney Int 2011; 80: 17-28; accessed http://www.nature.com/ki/journal/v80/n1/
full/ki2010483a.html

ment.670 Data relating to referral for those with glomerulardisease, hypertension, AKI, and diabetes may be found in therelevant guidelines.7,8,10,262
In this section we will briefly consider summaries of theevidence relating to timely referral for planning RRT in
people with progressive CKD. In this aspect the literature
concerning late referral in the last quarter of a century has
been remarkably consistent; both studies and narrative
reviews identifying a number of adverse consequences oflate referral and related benefits of early referral (Table 35).
Patients who are aged 475 years, female, non-Caucasian,uninsured, of lower socioeconomic or educational status, or
have multiple comorbidities are most at risk for non-referral
for CKD care.671,672 Patients with kidney disease have neverbeen randomized to early or late referral to nephrology
services and the definition of late referral in the publishedstudies varies; three months is probably less than the absolute
minimum amount of time required for assessment, education,
preparation for RRT and creation of access but is the mostfrequently employed definition. Overall there are more than 50
studies in the published literature and a meta-analysis of 22 ofthese studies from 10 different countries serves to underline
some of the key messages (Table 36), giving an indication of
the size of the differences in mortality and hospital length ofstay and also highlighting the significantly lower serum
albumin level in late referred patients.673
A systematic review considered twenty-seven longitudinalcohort studies providing data on 17,646 participants ofKidney International Supplements (2013) 3, 112–119

whom 11,734 were referred early and 5912 (33%) werereferred late.674 OR for mortality reductions in patientsreferred early were evident at 3 months (OR 0.51; 95% CI
0.44-0.59; Po0.0001) and remained significant at 5 years(OR 0.45; 95% CI 0.38-0.53; Po0.0001). Initial hospitalization was 8.8 days shorter with early referral (95% CI -10.7 to-7.0 days; Po0.0001). Differences in mortality and hospitalization data between the 2 groups were not explained bydifferences in prevalence of diabetes mellitus, previous CAD,
BP control, serum phosphate, and serum albumin. Earlyreferral was associated with better preparation and earlier
placement of dialysis access and better uptake of peritoneal
dialysis.
Over a decade ago McLaughlin et al. evaluated the cost
implications of early versus late referral.675 Outcomes ofinterest were total cost of patient care, patient life-years,
patient life-years free of RRT and hospital length of stay.
Mean total costs per patient over five years were US$87,711
and US$110,056 for early and late referrals, respectively. The
mean patient life-years were 3.53 and 3.36 years, respectively,
and the patient life-years free of RRT were 2.18 and 1.76
years, respectively. Those patients referred early spentsignificantly less time in hospital (length of stay 25 days
versus 41 days). Klebe et al. subsequently investigated theannualized cost of implementation of referral guidelines for
CKD.676 Although CKD guideline implementation resulted
in significant increases in nephrology referral and additional
investigation, they estimated that the associated costs could113chapter 5

Table 35 | Early versus late referral: consequences and benefits
Consequences of late referral

Benefits of early referral

Anemia and bone disease
Severe hypertension and fluid overload
Low prevalence of permanent access
Delayed referral for transplant
Higher initial hospitalization rate
Higher 1-year mortality rate
Less patient choice of RRT modality
Worse psychosocial adjustment

Delay need to initiate RRT
Increased proportion with permanent accessGreater choice of treatment options
Reduced need for urgent dialysis
Reduced hospital length of stay and costs
Improved nutritional status
Better management of CVD and comorbid conditions
Improved patient survival

Abbreviations: CVD, cardiovascular disease; RRT, renal replacement therapy.

Table 36 | Outcomes of early versus late referral
Variable

Early referral mean (SD)

Late referral mean (SD)P value

Overall mortality, %1-year mortality, %Hospital length of stay, days
Serum albumin at RRT start, g/dl [g/l]Hematocrit at RRT start, %11 (3)
13 (4)
13.5 (2.2)
3.62 (0.05) [36.2 (0.5)]
30.54 (0.18)

23 (4)
29 (5)
25.3 (3.8)
3.40 (0.03) [34.0 (0.3)]
29.71 (0.10)

o0.0001
0.028
0.00070.001
0.013

Abbreviation: RRT, renal replacement therapy.
Adapted from Am J Med, Chan MR, Dall AT, Fletcher KE, et al.673 Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. 120:
1063-1070, 2007, with permission from Elsevier; accessed http://download.journals.elsevierhealth.com/pdfs/journals/0002-9343/PIIS000293430700664X.pdf

be recouped by delaying dialysis requirement by 1 year in one
individual per 10,000 patients managed according to guidelines.
International Relevance

Local practice and resource will dictate local referral practice
but regardless of the health-care system, delay or preventionof progression of both CKD and complications associatedwith CKD will add value. Local organizations will determine
the best methods of communication and interaction between
patients, specialists, and primary care physicians.
Implications for Clinical Practice and Public Policy

Implementation of referral guidelines will inevitably lead toan increased workload for specialist nephrology services.
However, introduction of local initiatives in conjunction withprimary care providers can improve the appropriateness andquality of the referral. Local initiatives combined withnational policy and practice changes can lead to an
improvement in the outcomes of CKD patients regardlessof the level of resource available.
Pediatric Considerations

Current pediatric practice in most areas of the world would
suggest a higher level of kidney function for referral than thatfor adults, though the principles remain the same. Much of
the pediatric nephrologist’s consultation occurs from infants,
or even antenatal sources, where the identification of thechild as being ‘at-risk’ may be apparent from radiographic
studies performed in utero. The relatively non-specific signs
and symptoms of most forms of renal disease in the young
child mandates a higher level of suspicion in the referring
114

physician, and a lower threshold of acceptance of the consultin the subspecialty clinic accepting these referrals.
Attempts to develop universal guidelines for referralof children to pediatric nephrology services would be
dependent on local resources (as is the case for adults) and
it is of value to consider in broad categories the types ofconditions for which referral to a pediatric nephrologist
would be expected to provide benefit to the referring
physician and patient/family.
In a recent review Barakat677 attempts to address anumber of these issues by outlining the most common
presentations of a child with significant renal disorders.
Barakat and Chesney also suggest a number of specific areas
in terms of initial investigations, management, and follow-up
where the primary care physician can legitimately play a rolein the care of the child with renal disease and provides a listof suggested referral triggers.678
While there will be variation in referral triggers, referral
would be recommended for the following: acute or chronic
reduction in renal function, poorly treated or severe
hypertension, severe electrolyte abnormalities, the findingof significant abnormalities in urinary tract structure, or thepresence of systemic diseases likely to produce renal effects.
Similarly, the need for education in progressive conditions,performance of and interpretation of renal biopsies, andallaying parental/patient anxiety would also be acceptablereasons for referral.
There is no ‘minimum acceptable value’ of renal
dysfunction below which one can be certain to see significant
abnormalities in clearance, electrolyte, or other side effects
associated with progressive renal disease in children such as
growth failure or neurocognitive issues. However, theKidney International Supplements (2013) 3, 112–119

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KDOQI CKD Guidelines1 stated that while a child with aeGFR o30 ml/min/1.73 m2 warranted referral to a pediatricnephrologist in all cases, that in fact it was also reasonable toconsider any child with evidence of CKD– and in particular
those with eGFR o60 ml/min/1.73 m2 – for referral to apediatric nephrologist regarding evaluation and management.43
It is reasonable to presume that, as in adults, the conceptof referral ‘early’ or ‘above’ some minimum level of function
should allow for numerous benefits to the patient and family,
but again there are few data for this in children. The mostinformative information on both of these issues can bederived from two papers examining the issue of late referralsof children who eventually required ESRD care. Kennedy
et al.679 demonstrated that at the time of referral to theircenter, the children 41 year of age had a median Schwartz
eGFR of only 27 (IQR 9-52) ml/min/1.73 m2, and in fact 55%of these children over the age of 1 year were referred with an
eGFR o30 ml/min/1.73 m2, meeting one of two definitionsof a late referral. When they considered their second
definition of initiation of RRT within 90 days of referral,commonly used in the literature for this particular topic,
30% of the eligible cohort required RRT within that 90-day
window and hence were considered late referrals on thisbasis. The potential effect on the child’s health could be
ascribed to such a delay in referral: those children had
lower mean Hb (8.7 ± 0.6 g/dl [87 ± 6 g/l]) versus (12.8 ±0.6 g/dl [128 ± 6 g/l]) and higher median urea (34 (IQR
5-14) mmol/l [203 (IQR 30-84) mg/dl] versus 6 (IQR 5-14)mmol/l [36 (IQR 30-84) mg/dl], Po0.001) than those who
presented with eGFR 430 ml/min/1.73 m2. Secondary
analysis confirmed this was also true in the groups if one
looked at those above or below an eGFR of 60 ml/min/
1.73 m2. The second paper by Boehm and colleagues680 was a
retrospective single pediatric center report that demonstrated
that over B30 years of referrals (N ¼ 111), 24% of them
could be considered as late referrals, as defined by need for
RRT within 90 days of referral. In this late referral group, theeGFR (Schwartz) was significantly lower than those presenting later, (14.9 versus 34.2 ml/min/1.73 m2, Po0.001) as was
the Hb at presentation (8.0 g/dl [80 g/l] versus 10.5 ± 2.3 g/
dl [105 ± 23 g/l]; Po0.001). Importantly the Hb deficit
persisted at the time of RRT initiation, with the Hb in the latereferral group being 8.5 g/dl [85 g/l] versus 9.8 ± 1.9 g/dl [98± 19 g/l] in the earlier referred patients, Po0.01. The othermetric of interest chosen by these authors to evaluate thepossible detrimental effect of late referral was the likelihoodof a given child having a pre-emptive transplant, i.e., prior to
dialysis initiation. While this association was not confirmed
in Kennedy’s paper, Boehm and his group demonstrated thatin their patient population children who were referred late
only 11% were preemptively transplanted as compared to
40% of children who presented to care more than 90 days
prior to the need for some form of RRT. Of further interest,
although somewhat counterintuitive, the proportion ofpatients in the Boehm study who initiated hemodialysis
Kidney International Supplements (2013) 3, 112–119

was not statistically different between those in the late versus
early referral groups, 62% versus 67%, Po0.05 respectively.
The underlying concept of referral to a pediatricnephrologist in the face of rapid progression of renal failure
is of course applicable in full. However, no current validated
risk of progression tool exists in pediatric nephrology. As towhat level of functional decline might be considered‘concerning,’ the best evidence is derived from the longitudinal iohexol GFR data as accrued in the CKiD trial. Data
from that study related to the annualized rate of decline inrenal function for children with glomerular conditions is10.5% as compared to those with a non-glomerular causes
in whom the annualized rate of change is only 3.9%.71 Anychild whose rate of decline exceeded these two values would atleast warrant much closer follow-up and/or investigation formodifiable factors to slow progression. Note this is not to saythese rates of decline should be considered to be ‘normal’ foreither category. All efforts to slow decline in renal function
would still be of vital importance in every individual.
5.2: CARE OF THE PATIENT WITH PROGRESSIVE CKD
The following section describes recommended structures andkey milestones for people with progressive CKD. The
recommendations are intended to model best practices but
it is appreciated that different health-care systems, geographical issues, and economic considerations will have variableabilities to implement these recommendations.
Key aspects of caring for people with progressive CKD, asthey approach end of life or RRT options are addressed in thissection.
5.2.1: We suggest that people with progressive CKD should
be managed in a multidisciplinary care setting. (2B)
5.2.2: The multidisciplinary team should include or haveaccess to dietary counseling, education and counseling about different RRT modalities, transplant
options, vascular access surgery, and ethical, psychological, and social care. (Not Graded)
RATIONALE

Optimal care is that care which leads to the best outcomes forthe individual, the population, and society. The model of carevaries according to CKD severity, which will determine thetarget population and goals. These statements are worded to
predominantly encompass those people likely to progress to
ESRD. CKD models of care follow the same principles
embodied in the chronic disease model of care (Figure 22).
The specific components for CKD models of care include:
protocols for laboratory and clinic visits; attention to
cardiovascular comorbidities and CKD-associated comorbidities such as anemia; a vaccination program (see Recommendation 4.6.1-4.6.6); an education program which includes
both general CKD and RRT education (including conservative management where appropriate); self-management;
lifestyle modification including diet, exercise, and smoking
115chapter 5

Figure 22 | The CKD chronic care model. CKD, chronic kidneydisease. Adapted by permission from BMJ Publishing Group
Limited. Improving the quality of health-care for chronic
conditions. Epping-Jordan JE, Pruitt SD, Bengoa R, et al.681
Qual Saf Health Care. 13: 299-305, 2004; accessed
http://qualitysafety.bmj.com/content/13/4/299.full.pdf+html

cessation; and counseling and support for factors such associal bereavement, depression, and anxiety.
International RelevanceStandardized and culturally appropriate protocols should beconsidered. While it is recognized that resources may vary acrossand within jurisdictions, recommendations here are based onprinciples of care, which should be relevant across the globe.
Implications for Clinical Practice and Public Policy

CKD is a complex condition and co-exists with many otherconditions. Therefore models of care should be developedthat integrate the complexity of the clinical conditions
involved, patient-centered philosophies, and the health-care
environment. The principles of care are universal but
implementation may be customized to specific circumstances.

pediatric nephrologists, nurse clinicians, transplant coordinators, dietitians, social workers, and a psychologist.
Ajarmeh et al.682 compared the two cohorts in a number ofareas during their year of follow-up whereas Menon et al.683
chose to look at each individual patient in the 12 months
immediately prior to initiating RRT. While the studies had
different variables of interest and used slightly different
approaches for comparison of results between their groups,
both demonstrated a reduction in the rate of decline inestimated renal function, improved Hb levels, and improvement in at least some aspect of bone mineral metabolism
control in their respective cohorts cared for in the multidisciplinary era. In addition, both studies also demonstrated adecrease in resource utilization by patients in the multidisciplinary clinic as measured by median length of stay682 andnumber of unplanned admissions per patient per year.683 Alsoof note, Menon et al. demonstrated that in the patients who
initiated dialysis (which was how the cohort was chosen), morepatients who started hemodialysis did so with a functioning
arteriovenous fistula or arteriovenous graft at the time ofinitiation compared to those from the general nephrology clinicera (85.7 versus 20%, P ¼ 0.02).
5.3: TIMING THE INITIATION OF RRT

5.3.1: We suggest that dialysis be initiated when one ormore of the following are present: symptoms orsigns attributable to kidney failure (serositis, acidbase or electrolyte abnormalities, pruritus); inability
to control volume status or blood pressure; aprogressive deterioration in nutritional status refractory to dietary intervention; or cognitive impairment. This often but not invariably occurs in the
GFR range between 5 and 10 ml/min/1.73 m2. (2B)
5.3.2: Living donor preemptive renal transplantation in
adults should be considered when the GFR iso20 ml/min/1.73 m2, and there is evidence ofprogressive and irreversible CKD over the preceding 6-12 months. (Not Graded)

Pediatric Considerations

RATIONALE

Papers addressing the need for and effectiveness in the utilityof multidisciplinary clinics for management of pediatric CKD
patients have been published. In 2012, Ajarmeh et al.682 described a retrospective comparison of two cohorts of children
aged 0-18 years of age and followed at a single Canadiantertiary care referral center over a 1-year time period either
before or following the full implementation of a multidisciplinary CKD clinic which included the services ofdedicated pediatric nephrologists, renal nursing, pharmacy,
dietitians, social workers, and a renal database manager. In
2009, Menon et al.683 published data from a large American
pediatric referral center and compared the outcomes ofchildren from one of two 5-year cohorts in the period
immediately preceding or following the initiation of a specific
Chronic Renal Insufficiency clinic which was staffed by

The statement is worded very precisely to highlight the needfor RRT to address symptoms and to avoid the institution of
dialysis therapy at an arbitrary number representing thedegree of residual renal function. Given the risks and benefitsof RRT, as well as the potential imprecision of measurements,
patients need to be treated according to symptoms and signs,
not simply based on a laboratory value.
Data from national registries has shown a consistent risein GFR at initiation of RRT. This rise has been driven partly
by a desire to improve nutritional status and also by earlier
observational data suggesting adverse outcomes associatedwith RRT initiation at lower GFR. These early data were
subject to much confounding. RCT data, supported by large
registry-based studies corrected for confounding, show nosurvival advantage to early start dialysis (Initiating Dialysis

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Early and Late [IDEAL] study, see Evidence Base Below).
Thus, the statement as written should help the clinician tobalance symptoms with laboratory values in decision making.
The statement regarding living donor transplantation isintended to ensure that practitioners think about this option
in the context of the totality of RRT options. It is worded tobe concordant with local living donation transplant policies.
It aims to reflect the need for risk-benefit assessment of
preemptive renal transplantation in all individuals. Note thatthe statement asks clinicians to consider this option, but does
not state at which level of GFR the preemptive transplant
would occur as this is a matter of local practice and patientspecific considerations.
Evidence Base

The perceived survival advantage of early start of dialysis wasquestioned by a study from the Netherlands Cooperative
Study on the Adequacy of Dialysis Study Group (NECOSAD).684 Of 253 patients with new ESRD, 94 (37%)
started dialysis late (GFR 4.9 ± 1.7 ml/min/1.73 m2) and 157
started in a timely fashion (GFR 7.1±2.4 ml/min/1.73 m2).
Although there was a small gain in survival time over 3 years
after start of dialysis for the timely start group (2.5 months)
there was no significant difference in survival between the
2 groups and the gain in survival time was offset by an
estimated lead-time bias of between 4.1 and 8.3 months. In a
study eliminating the effect of lead-time bias Traynor et al.
found no benefit in survival in those initiating dialysis
early.685 Subjects starting dialysis early (N ¼ 119) had a
median IQR CrCl of 10.4 (9.1-11.9) ml/min versus 6.7 (5.67.5) ml/min in 116 subjects starting dialysis late. Aftercorrection for multiple confounders, they found an 11%
greater hazard for mortality with each 1 ml/min increase in
CrCl at start of dialysis (HR 1.11; 95% CI 1.01-1.21;
P ¼ 0.024). Subsequent observational studies, including large
dialysis registry studies from around the globe, have all
suggested increased mortality when dialysis is started
early.686–696 These studies encountered multiple difficulties
in drawing conclusions from this observational approach
including lead-time bias, problems with estimating GFR from
SCr in people with low muscle mass and/or fluid overload,
the fact that people with symptoms and/or increased
comorbidity are more likely to start dialysis early, and finallysurvivor bias in studies including people only when they start
dialysis (and therefore excluding those who die prior tostarting diaysis). These confounders were largely addressed bya multicenter controlled trial in which 828 adults with
progressive CKD and CrCl 10-15 ml/min/1.73 m2 wererandomly assigned to early (CrCl 10-14 ml/min [0.170.23 ml/s]) or late (CrCl 5-7 ml/min [0.08-0.12 ml/s]) initiation of dialysis.697 The study protocol allowed an earlier start
where deemed clinically necessary by investigators andalthough the difference in GFR at dialysis initiation between
the 2 groups was significant (early start CrCl 12.0 versus latestart 9.8 ml/min, MDRD GFR 9.0 versus 7.2 ml/min/
1.73 m2), it was less than planned because 19% of early
Kidney International Supplements (2013) 3, 112–119

starters started late and 76% of late starters started early. There
was no difference in mortality between the early and late startgroups and no difference in the study’s secondary outcomes(cardiovascular events, infectious events and complications ofdialysis) between the 2 groups. Finally, a further observational
study sought to examine the effect of early initiation of dialysis
on survival in a ‘healthy’ group of 81,176 subjects with ESRD
aged 20-64 years, without diabetes, and with no comorbidity
other than hypertension.698 The unadjusted 1-year mortality
by MDRD GFR at dialysis initiation ranged from 6.8% in thereference group (GFR o5.0 ml/min/1.73 m2) to 20.1% in
the highest GFR group (Z15.0 ml/min/1.73 m2). In an even
healthier subset of 35,665 subjects with serum albumin
concentrations of 3.5 g/dl or higher prior to hemodialysis
initiation, the 1-year mortality was 4.7%. In this group theadjusted HR for mortality was 1.27 for GFR 5.0-9.9 ml/min/
1.73 m2, 1.53 for GFR 10.0-14.9 ml/min/1.73 m2, and 2.18 for
GFR Z15.0 ml/min/1.73 m2 compared with the referencegroup of GFR o5.0 ml/min/1.73 m2.
International Relevance

The availability of resources for formal multidisciplinary
teams, educational materials, and access to specialized
counseling for diet, advance directives, access planning, andpre-emptive transplantation varies around the world. Thesestatements are proposed so that ‘best practices’ can be
documented or aspired to. The need for education, planning,
and appropriate expertise for the management of this patientgroup is internationally relevant. The methods, frequency,
and tools with which this can be accomplished will be region
specific.
Implications for Clinical Practice and Public Policy

There is a need to focus on regular symptom assessment as
part of CKD review in those with lower eGFR values.
Individual assessment and availability of resources will
dictate specific timing of therapies.
Clinicians should be aware of the impact of early dialysis
start on QOL699 before recommending this strategy topatients.
Pediatric Consideration
Timing of initiation of dialysis.

As might be expected,
information as to the proper timing for initiation of dialysis
does not exist for children. Thus, it would seem reasonable tofollow the guidelines as set out for the adults. A review by
Greenbaum and Schaefer700 provides the reader withgenerally agreed upon absolute and relative indications for
initiation of dialysis in the child. The absolute indications
listed are those of neurologic consequences attributable touremia; hypertension that fails to respond to antihypertensive therapy; pulmonary edema unresponsive to diuretics;
pericarditis; bleeding tendency; and refractory nausea orvomiting. However, the authors clearly state that there is no
current consensus as to the validity of the relative indications
and specifically the level at which each engenders the need for117

chapter 5

dialysis. Relative indications to commence dialysis include
less severe uremic symptoms, hyperkalemia, hyperphosphatemia, malnutrition, and growth failure. The authors
point out as well that the answer to ‘early’ versus ‘late’dialysis initiation cannot be addressed in any meaningful
way in children as there is currently lack of data; and theunique factors to consider in a child such as growth,
psychosocial development, likely renal transplant, and needfor extended time on both dialysis and in transplant make theprobability of a clinical trial to address this issue nearly
impossible.
Timing of living donor transplant. There is no direct
evidence to guide the pediatric nephrologist as to the ‘best’timing for a living donor transplant in children. In eachindividual case the relative likelihood of improvement inpresumed uremic symptoms and burden of disease as related
to management of CKD will need to be balanced against therisks of transplant surgery itself and the attendant medication
risks with prolonged immunosuppression. While there islittle doubt as to the benefit in overall lifespan accrued by achild who is transplanted as opposed to one maintained onstandard dialysis therapies during their childhood (average
life expectancy of 63 versus 38 years respectively),701 the issue
as to what level of residual function is sufficient to justify
delay or conversely proceeding to transplant is simply notreadily available.
It should also be noted that reliance on GFR as the solemarker of disease intensity is unlikely to be sufficient formaking such a decision, and patient symptoms and/or
unique family factors may play a significant role in thedecision as to timing of a living donor transplant (e.g., ayoung grandparent available and healthy to donate at age 60
years may not be eligible at age 63 years and so an earliertransplant would be favored).
5.4: STRUCTURE AND PROCESS OF COMPREHENSIVECONSERVATIVE MANAGEMENT

5.4.1: Conservative management should be an option inpeople who choose not to pursue RRT and thisshould be supported by a comprehensive management program. (Not Graded)
5.4.2: All CKD programs and care providers should be
able to deliver advance care planning for people
with a recognized need for end-of-life care,including those people undergoing conservative
kidney care. (Not Graded)
5.4.3: Coordinated end-of-life care should be available
to people and families through either primarycare or specialist care as local circumstances
dictate. (Not Graded)
5.4.4: The comprehensive conservative management
program should include protocols for symptom
and pain management, psychological care, spiritual care, and culturally sensitive care for the
dying patient and their family (whether at home,118

in a hospice or a hospital setting), followed by theprovision of culturally appropriate bereavement
support. (Not Graded)
RATIONALE

These statements are intended to highlight the need forcomprehensive conservative care processes and resources in thecare of this complex patient group. There is increasing
recognition that provision of organized care to those who are
dying or choose to not pursue dialysis and transplant care is ofvalue to the patients and their families. Clinicians involved in
caring for these patients should be alerted to this need. Thesestatements are positioned so as to overtly state this need.
In different societies or cultural areas, the formand structure of this care may vary tremendously andfamilies or religious organizations may be able to deliver
expert and sensitive care. The details here are listed not to beprescriptive but rather to articulate the ‘best practices’ incommunities where resources may be available and to serve a
construct to review in those locations where resources are
more limited.
Evidence Base

The evidence base for these statements is limited to
documents describing the burden of illness and unmet needs
in patients with CKD as they decide either not to pursue
dialysis or to withdraw from RRT. As the readers willappreciate, there are neither RCTs nor even large cohort
studies to inform these statements within the CKD populations. Analogies with oncology have been drawn andliterature from there has been used to justify the concepts
above.
Patients with advanced CKD have extensive palliative careneeds for years before death. Throughout their illness
trajectory, symptom burden is high.702–707 The number andseverity of physical and emotional symptoms are similar to
those of cancer patients hospitalized in palliative caresettings.703,708 Advanced CKD patients managed without
dialysis are equally symptomatic.706 An increasing number of
dialysis patients die after withdrawal of dialysis (10-15% in
1990, 20% in 2004), primarily due to poor QOL, representing
the second leading cause of death after CVD.
Conservative care focuses on slowing the decline inrenal function, actively managing symptoms, advance careplanning, and the provision of appropriate palliative care.
In oncology, receiving early palliative care is associated with
better QOL, fewer emergency department visits andhospitalizations, less aggressive care at the end of life, andsurprisingly, longer survival.709 These observations
suggest that development of clinical models that integrate
appropriate palliative care, including the creation ofconservative care pathways, are likely to be hugely beneficial
and would help avoid harmful dialysis to thosepatients unlikely to realize benefit. Such conservative careprograms are slowly being developed, primarily in the UK
and Canada.
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chapter 5

The literature describing experiences of specific programs
and symptom burden in CKD, as well as advocating for better
care, has only become more prevalent since 2005.709–716
Poor quality, hospitalized deaths began to improve forpatients dying with cancer as a result of an increasingemphasis on palliative care teams providing attention tosymptom control, psychosocial needs, and options forlocation of care. The literature suggests that current modelsof palliative care for cancer patients that deinstitutionalized
health-care services have not only improved patient outcomes and quality of care717–720 but have been costneutral.721
International RelevanceAll countries have people with CKD who withdraw either
voluntarily or involuntarily from dialysis services. Best carefor those patients will obviously need to respect cultural andreligious values, but would necessarily be based on the samephilosophical grounds of maintaining dignity of the individual. Appreciating the need for and articulating conservative care pathways overtly would be internationallyapplicable.
Implications for Clinical Practice and Public Policy

There is a need to ensure appropriate access to services
and education surrounding quality care during terminal
stages of a chronic condition. There is increasing attention
to this in many societies but not in all. Appreciating thevariability in the resources required and their availability
to different groups of patients is important for implementation. Furthermore, involvement of religious and cultural
leaders in recognition of these care practices can be enhanced
if they are overtly recognized as part of the care continuum.
There is a need for robust assessment of best practices in
CKD and other chronic conditions so that we may provide

Kidney International Supplements (2013) 3, 112–119

best care throughout the continuum of life. Researchers
around the world are actively pursuing this so that we may
have better tools, programs, and ultimately, better outcomesfor our patients.
Pediatric Consideration

Despite the lack of published evidence, there is no reason
to believe that children and families faced with the needto consider conservative care or a palliative approach totheir impending ESRD would not benefit from all of theabove recommendations. It would seem reasonable forpediatric nephrology centers to liaise with their pediatriconcology or palliative care teams, ethicists, and pastoral careproviders to assist them in developing, defining, and/or
identifying locally available resources for situations where achild is not deemed a candidate for RRT prior to theiroccurrence.
DISCLAIMER

While every effort is made by the publishers, editorial board,
and ISN to see that no inaccurate or misleading data, opinion
or statement appears in this Journal, they wish to make it
clear that the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board andtheir respective employers, office and agents accept noliability whatsoever for the consequences of any suchinaccurate or misleading data, opinion or statement. While
every effort is made to ensure that drug doses and otherquantities are presented accurately, readers are advised thatnew methods and techniques involving drug usage, anddescribed within this Journal, should only be followed inconjunction with the drug manufacturer’s own publishedliterature.

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methods for guideline development

http://www.kidney-international.org& 2013 KDIGO

Methods for guideline development
Kidney International Supplements (2013) 3, 120–127; doi:10.1038/kisup.2012.69

AIM

The overall aim of this project was to develop an evidencebased clinical practice guideline for evaluation and management of CKD. The guideline consists of recommendation
statements, rationales, and a summary of systematicallygenerated evidence on relevant pre-defined clinical topics. To
a large extent the guideline builds on the output of the
KDIGO Controversies Conference in 2009,30 which generated
epidemiological data to support a revision of the classification and staging system. The vision for this KDIGO guidelineis that it would endorse the current CKD definition as animperfect convention for describing a state of function, revise
classification based on risk, revise risk states, and revise andupdate action plans in view of the revised classifications.
Additional systematic evidence review focused on specifictopics.
OVERVIEW PROCESSThe guideline development process included the following steps:
K Appointing Work Group members and the ERTK Discussing process, methods, and results
K Developing and refining topics
K Identifying populations, interventions or predictors, andoutcomes of interest
K Selecting topics for systematic evidence review
K Standardizing quality assessment methodology
K Developing and implementing literature-search strategies
K Screening abstracts and retrieving full text articles on thebasis of predefined eligibility criteria
K Creating data extraction forms
K Extracting data and performing critical appraisal of theliterature
K Grading the methodology and outcomes in individual
studies
K Tabulating data from individual studies into summary
tablesK Grading the strength of recommendations on the basis of
the quality of evidence and other considerations
K Finalizing guideline recommendations and supporting
rationales
K Sending the guideline draft for peer review to the KDIGO
Board of Directors in January 2012 and for public review
in May 2012
K Publishing the final version of the guideline

Collaboration Among Participants

The KDIGO Co-Chairs appointed the Work Group
Co-Chairs, who then assembled the Work Group of domain
120experts, including individuals with expertise in internal
medicine, adult and pediatric nephrology, diabetology/
endocrinology, clinical chemistry, and epidemiology. The
Tufts Center for Kidney Disease Guideline Development and
Implementation at Tufts Medical Center in Boston, Massachusetts, USA, was contracted to conduct systematic evidence
review and provide expertise in guideline development
methodology. The ERT consisted of physician–methodologists with expertise in nephrology, a project coordinator, aresearch assistant, and a medical writer–editor. The ERT
instructed and advised Work Group members in all steps ofliterature review, critical literature appraisal, and guideline
development. The Work Group and the ERT collaborated
closely throughout the project.
The Work Group and its Chairs, KDIGO Co-chairs, ERT,and KDIGO support staff met for three 2-day meetings fortraining in the guideline development process, topic discussion, and consensus development.
Throughout the project, the ERT offered suggestions for
guideline development and led discussions on systematic
review, literature searches, data extraction, assessment ofquality and applicability of articles, evidence synthesis,
grading of evidence and guideline recommendations, andconsensus development. The Work Group took the primaryrole of writing the recommendation statements and rationales and retained final responsibility for their content.
Defining Scope and Topics

This KDIGO CKD guideline was set out to update theKDOQI Clinical Practice Guidelines for CKD: Evaluation,
Classification, and Stratification1 in 2002, which spans many
topics related to the diagnosis, classification, stratification,and management of CKD.1
The Work Group Co-Chairs prepared the first draft of thescope of work document as a series of open-ended questions
to be considered by Work Group members. At their first 2day meeting, members added further questions until the
initial working document included all topics of interest to theWork Group. The inclusive, combined set of questions
formed the basis for the deliberation and discussion that
followed. The Work Group strove to ensure that all topics
deemed clinically relevant and worthy of review wereidentified and addressed.
Updating the topics of definitions and classification was
based on the output from the KDIGO Controversies
Conference and the CKD Prognosis Consortium.4,30
Additional topics that relate to explicit selection ofdiagnostic tests or interventions were chosen to undergosystematic review of the best available evidence. Systematic
Kidney International Supplements (2013) 3, 120–127

methods for guideline development

evidence review entails a priori question formulation,
specification of important outcomes for the review, systematic searches, data extraction, tabulation, analysis, andsynthesis of evidence and is described in detail for each of
the specific questions. The process followed for each evidence
review topic (a total of four non-treatment topics and four
treatment topics) is detailed below.
The eight topics for which the ERT conducted searches
and evidence review are shown in Table 37. For the systematic
review topics, the Work Group and ERT further developed
and refined each topic and specified screening criteria,
literature search strategies, and data extraction forms.
Many other topics were not suitable to be addressed by indepth evidence review. When the anticipated outcome of an
extensive literature search was unlikely to yield evidence that
directly informs practice choices, the approach chosen wasthat of a narrative review.
APPROACH TO EVIDENCE REVIEW TOPICS
Formulating Questions of Interest

Questions of interest were formulated according to the
PICODD (Population, Intervention or Predictor, Comparator, Outcome, study Design, and Duration of follow-up)
criteria. Details of the PICODD criteria are presented inTable 37.
Literature Searches and Article Selection for Evidence Review
TopicsSearch strategies were developed by the ERT, with input fromthe Work Group, for each topic of interest (whether
treatment or non-treatment topics). The ERT performed
literature searches and conducted abstract and article
screening. The ERT also coordinated the methodologicaland analytic processes, data extraction, and summarizing of
the evidence. Before initiating our own de novo systematic
review, we searched for existing systematic reviews that could
be used. The searches and search terms are provided in
Supplemental Table 1 and the search dates and yields for all
topics are presented in Table 38.
Selection of Outcomes of Interest

The Work Group selected outcomes of interest on the basis of
their importance for informing clinical decision making.
Importance of mortality and ESRD was considered to be
critical; the importance of progression of CKD andcategorical or continuous measures of kidney function wasconsidered to be high; and the importance of QOL, BP, gout
attacks, and proteinuria was considered to be moderate.
Data Extraction

Text articles were extracted by the ERT onto forms
customized to capture data on design, methodology, baselinecharacteristics, interventions or predictors, comparators,
outcomes, results, and limitations of individual studies.
Study methodology and risk of bias were also systematically
graded for each outcome and recorded.
Kidney International Supplements (2013) 3, 120–127

Summary Tables

Pertinent information for systematic review topics wastabulated in summary tables. Summary tables list outcomes of interest as well as relevant population characteristics, descriptions of interventions and comparators,
results, and quality grades for each outcome. Categoricaland continuous outcomes were summarized separately.
Work Group members reviewed all summary table dataand quality grades.
Evidence Profiles

Evidence profiles are usually constructed as a means to assess
the quality and record quality grades and descriptions ofeffect for each outcome across studies, as well as the quality
grades and description of net benefits or harms of theintervention or comparator across studies. These profiles aim
to make the evidence synthesis process transparent. However,since no treatment or non-treatment topic had more than
one study in a summary table for which the quality was
graded, no evidence profiles were generated, and theinformation in the summary table shows the highest levelof synthesis.
Grading of Quality of Evidence for Outcomes of Individual
Studies
Methodological quality. Methodological quality (internal

validity) refers to the design, conduct, and reporting ofoutcomes of a clinical study. A previously devised three-levelclassification system for quality assessment was used to grade
the overall study quality and quality of all relevant outcomes inthe study (Table 39). Variations of this system have been usedin most KDOQI and all KDIGO guidelines and have been
recommended for the US Agency for Healthcare Research andQuality Evidence-based Practice Center program.722
Each study was given an overall quality grade on the basisof its design, methodology (randomization, allocation,
blinding, definition of outcomes, appropriate use of statistical methods, etc.), conduct (drop-out percentage, outcome
assessment methodologies, etc.), and reporting (internalconsistency, clarity, thoroughness, and precision, etc.). Eachreported outcome was then evaluated and given an individual
grade depending on the quality of reporting and methodological issues specific to that outcome. However, the quality
grade of an individual outcome could not exceed the quality
grade for the overall study.
Grading the Quality of Evidence and the Strength of
Guideline Recommendations

A structured approach, based on the GRADE approach,723–725
was used to grade the quality of the overall evidence and thestrength of recommendations for each topic. This grading
scheme-with two levels for the strength of a recommendation
together with four levels of grading for the quality of theevidence, as well as the option of an ungraded statement
for general guidance-was adopted by the KDIGO Board in
December 2008.
121

122

How do SCr- or
SCysC-based prediction
equations perform
compared to gold
standard measurementof GFR?

Question

When should dialysis bestarted: early or late?
Should patients withCKD be on a proteinrestricted diet?

Timing of initiationof RRT in CKD
Protein restriction

Late start of dialysis
Usual protein intake

Reduced protein intake

No allopurinol

No bicarbonate or
citrateEarly start of dialysis

Allopurinol

GFR o60 ml/min/
1.73 m2 and/or kidneytransplant with orwithout hyperuricemia

GFR o30 ml/min/
1.73 m2
GFR o60 ml/min/
1.73 m2 and/or
kidney transplant

Bicarbonate or citrate

Narrative review ofcase–control
studies;
observational
cohort studies

SR of case–control
and cohort studies

ESRD, mortality,
categorical orcontinuous kidney
function

RCT

Mortality,
RCT
cardiovascular
events, ESRD, CKD
progression, gout
attacks; QOL and BP
control as adverse
events; proteinuria
Mortality, ESRD
RCT

ESRD, categorical or RCT
continuous kidney
function; QOL and
BP control asadverse events

Categorical kidney
outcomes

Nephrogenic
fibrosingdermopathy

Longtudinal cohort
study

Cross-sectional or
diagnostic test
study

Study design

SR
Equation must be
validated in an external
datasetMethodologicalapproach

N 4100N 4100N 4100N 4100None

1

1 SR + 1 RCT

2

1

2

15

No. of reports
or articles
yielded

Review of studies
1
identified by WG
Review of Cochrane SRs 3 SR+ 1 RCT
plus systematic search
for RCTs published after
search dates in mostrecent Cochrane SR

SR

Review of Cochrane SRs
plus systematic search
for RCTs published after
search dates in mostrecent Cochrane SR

Search for recent
guidelines, SRs, RCTs,
observational studies, or
narrative reviews

Equation
Studies identified bymust beWG
validated in
an external
dataset
N 4100None
Search for SRs

Overall N
4100 N450 forsubgroups

Inclusion
criteria

Abbreviations: AKI, acute kidney injury; BP, blood pressure; CKD, chronic kidney disease; cys C, cystatin C; DM, diabetes mellitus; EDTA, ethylenediamine tetraacetic acid; ESRD, end-stage renal disease; GFR, glomerular filtration rate;
HTN, hypertension; IDMS, isotope dilution mass spectrometry; KTR, kidney-transplant recipient; NA, not applicable; NFD, nephrogenic fibrosing dermopathy; QOL, quality of life; RCT, randomized controlled trial; RRT renalreplacement therapy; SCr, serum creatinine; SCysC, serum cystatin C; SR, systematic review; WG, Work Group.
w
Accuracy specifically measured as the percentage of GFR estimates within 30% (P30) of the measured GFR. Higher P30 values reflect greater accuracy; values are decreased by both greater bias and worse precision.

Does treatment withallopurinol in CKD
improve clinicaloutcomes?

Treatment withallopurinol

No gadolinium
exposure

Exposure to phosphate- No exposure tocontaining bowel
phosphate-containing
preparation
bowel preparation

Gadolinium exposure

ESRD,
mortality

NA

Candidate predictors
had to include at leastage, sex, SCr, and DM
statusOutcome (ranked
by importance)

Gold standard measure Bias precision,of GFR (e.g.,accuracy expressed
iothalamate, EDTA,
as P30 w
iohexal, inulin clearance)
Not 24-hr urine
collection

Comparator oralternative testor gold standard

GFR prediction basedon SCr or SCysC must
be directly traceable to(not just indirectly
calibrated to) IDMS
standards

GFR o60 ml/min/
1.73 m2 and/or kidneytransplant

Any GFR category;
individuals without
CKD

What is the incidenceof AKI after taking aphosphate-containing
bowel preparation?

Does treatment withbicarbonate in CKD
improve clinicaloutcomes?

GFR o60 ml/min/
1.73 m2 and/or
kidney transplantPatients in steady statewith or without CKD
and other special
populations (DM, HTN,
KTR or donors, various
age groups, races, or
ethnic groups)
GFR o60 ml/min/
1.73 m2 and/or
kidney transplant

Population

What is the incidenceof NFD after exposure
to gadolinium?

Treatment withbicarbonate

Treatment

Gadolinium
exposure andnephrogenic
fibrosingdermopathy
AKI and phosphatecontaining bowel
preparations

Prediction
What prediction
equations for risk of equations exist to
kidney failure
predict kidney failure?

Prediction
equations for
GFR

Non-Treatment

Topic

Treatment,
predictor orindex test

Table 37 | Topics of interest for the management of CKD guideline

methods for guideline development

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methods for guideline development

Table 38 | Literature yield of primary articles for all topics

Topic

Systematic
review
performed

Search dates

Search terms‘‘kidney,’’ and ‘‘prediction,’’‘‘equation,’’ ‘‘formula,’’ or‘‘regression analysis’’ndArticlesretrieved

Articleswith fulltext
screened

Articlesused intables

2921

86

15

10*

10

2

0

0

Non-treatment topics
Prediction equations for eGFRY

MEDLINE search from 2006 until
2011, with an update in June 2011

Prediction equations for risk ofkidney failure or death
Risk from gadolinium fornephrogenic fibrosing
dermopathy

N

nd

Y

MEDLINE search from 1996 until
2011 was run in March 2011

Risk for nephropathy from
phosphate-containing bowel
preparationsN

MEDLINE search for recent (20082011) narrative reviews was run inMarch 2011

Treatment with bicarbonateY

MEDLINE search from 2005 until
2011, with an update in May 2011

Treatment with allopurinol

Y

MEDLINE search from 1996 until
2011, with an update in May 2011ndw‘‘kidney,’’ and ‘‘gadolinium,’’‘‘nephrogenic fibrosing
dermopathy,’’ or ‘‘nephrogenic
systemic fibrosis,’’ and systematic
review‘‘Phosphate nephropathy’’

1

2

2

2

‘‘randomized controlled trial,’’ and‘‘kidney,’’ or ‘‘metabolic acidosis,’’and ‘‘bicarbonate’’‘‘randomized controlled trial,’’ and‘‘kidney,’’ and ‘‘allopurinol’’
nd

3981

6

1

393

4

1

z

8

1

‘‘randomized controlled trial,’’ and‘‘kidney,’’ and ‘‘diet, proteinrestricted’’

561

1

1

Treatment topics

Earlier versus later initiation of
RRT in CKDTreatment with protein
restrictionNY

Three Cochrane systematic reviews
were identified and used instead of
a de novo systematic review.
MEDLINE search from 1996-2011,
with an update in March 20118Abbreviations: CKD, chronic kidney disease; eGFR, estimated GFR; nd, not done; RRT, renal replacement therapy.
*References were provided by Work Group members.
w
Systematic review provided to Work Group members.
z
References were provided by Work Group members.

The strength of a recommendation indicates the extent towhich one can be confident that adherence to therecommendation will do more good than harm. The qualityof a body of evidence refers to the extent to which ourconfidence in an estimate of effect is sufficient to support a
particular recommendation.724 The process of transparently
grading evidence and recommendations for treatment topics
is described below in further detail. However, the approach
had to be adapted for the main topics of the KDIGO CKD
guideline because they were not treatment-related topics.

Table 39 | Classification of study quality

Grading the Quality of Evidence for Each Outcome AcrossStudies

important inconsistencies in the results across studies, if there
was uncertainty about the directness of evidence (including
limited applicability of the findings to the population ofinterest), if the data were sparse (for example if there wasonly one study or if the results include just a few events orobservations and were uninformative) or imprecise (forexample the CI spans a range greater than 1 or confidence
limits are o0.5 to 42.0). The final grade for the quality ofthe evidence for an intervention–outcome pair was thenassigned as high, moderate, low, or very low (Table 40).

Following the GRADE approach, the quality of a body ofevidence pertaining to a particular outcome of interest was
initially categorized on the basis of study design (Table 40).
For questions of interventions, the initial quality grade washigh if the body of evidence consisted of RCTs, low if itconsisted of observational studies, and very low if it consistedof studies of other designs. For questions of interventions, theWork Group decided to use only RCTs. The grade for thequality of evidence for each intervention–outcome pair wasthen lowered if there were serious limitations to themethodological quality of the aggregate of studies, if there
was thought to be a high likelihood of bias, if there were
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Good
quality
Fair
qualityPoor
quality

Low risk of bias and no obvious reporting errors, complete
reporting of data. Must be prospective. If study ofintervention, must be randomized controlled study.
Moderate risk of bias, but problems with study or paper are
unlikely to cause major bias. If study of intervention, must be
prospective.
High risk of bias or cannot exclude possible significant biases.
Poor methods, incomplete data, reporting errors. Prospective
or retrospective.

Grading the Overall Quality of Evidence

The quality of the overall body of evidence was thendetermined on the basis of the quality grades for all123methods for guideline development

Table 40 | GRADE system for grading quality of evidence
Step 1: Starting grade for
quality of evidence basedon study design
Randomized trials = High

Step 2: Reduce grade

Step 3: Raise grade

Final grade for quality of evidence and definition

Study quality-1 level if serious limitations-2 levels if very serious limitations

Strength of association+1 level is stronga, no plausible
confounders+2 levels if very strongb, no major
threats to validity
Other+1 level if evidence of adose-response gradient+1 level if all residual plausible
confounders would have
reduced the observed effectHigh = Further research is unlikely to change confidence
in the estimate of the effectConsistency-1 level if important inconsistency
Observational study = Low

Directness-1 level if some uncertainty-2 levels if major uncertainty

Any other evidence = VerylowOther:-1 level if sparse or imprecise datac-1 level if high probability ofreporting bias

Moderate = Further research is likely to have an
important impact on confidence in the estimate of effect,
and may change the estimate
Low = Further research is very likely to have an important
impact on confidence in the estimate and may change
the estimate
Very low = Any estimate of effect is very uncertain

Abbreviation: GRADE, Grading of Recommendations Assessment, Development, and Evaluation.
Strong evidence of association is defined as ‘significant relative risk of 42 (o0.5)’ based on consistent evidence from two or more observational studies, with no plausible
confounders.
bVery strong evidence of association is defined as ‘significant relative risk of 45 (o0.2)’ based on direct evidence with no major threats to validity.
cSparse if there was only one study or if the results include just a few events or observations and were uninformative. Imprecise if the confidence interval spans a range
greater than 1 or confidence limits are o0.5 to 42.0
Adapted by permission from Macmillan Publishers Ltd: Kidney International. Uhlig K, Macleod A, Craig J et al.725 Grading evidence and recommendations for clinical practiceguidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058–2065; accessed http://www.nature.com/
ki/journal/v70/n12/pdf/5001875a.pdf
aTable 41 | Final grade for overall quality of evidence

Table 42 | Balance of benefits and harm

We are confident that the true effect lies close to that of
the estimate of the effect.
The true effect is likely to be close to the estimate of theeffect, but there is a possibility that it is substantiallydifferent.
The true effect may be substantially different from theestimate of the effect.
The estimate of effect is very uncertain, and often will be
far from the truth.

When there was evidence to determine the balance of medical benefits
and harm of an intervention to a patient, conclusions were categorized asfollows:
K For statistically significant benefit/harm, report as ‘benefit [or harm]of drug X’.
K For non-statistically significant benefit/harm, report as ‘possible
benefit [or harm] of drug X’.
K In instances where studies are inconsistent, report as ‘possible
benefit [or harm] of drug X’.
K ‘No difference’ can only be reported if a study is not imprecise.
K ‘Insufficient evidence’ is reported if imprecision is a factor.

outcomes of interest, taking into account explicit judgments
about the relative importance of each outcome. The resulting
four final categories for the quality of overall evidence wereA, B, C, and D (Table 41).

not only by the quality of the evidence, but also by other,often complex judgments regarding the size of the net
medical benefit, values and preferences, and costs. Formal
decision analyses including cost analysis were not conducted.

Assessment of the Net Health Benefit Across All Important
Clinical Outcomes

Ungraded Statements

Grade

Quality ofevidence

A

High

B

Moderate

C

Low

D

Very low

Meaning

The net health benefit was determined on the basis of the
anticipated balance of benefits and harms across all clinicallyimportant outcomes (Table 42). The assessment of net
benefit also involved the judgment of the Work Group andthe ERT.
Grading the Strength of the Recommendations

The strength of a recommendation is graded as level 1 orlevel 2. Table 43 shows the KDIGO nomenclature for grading
the strength of a recommendation and the implications ofeach level for patients, clinicians, and policy makers. Recommendations can be for or against doing something. Table 44shows that the strength of a recommendation is determined
124

This category was designed to allow the Work Group to issue
general advice. Typically an ungraded statement meets thefollowing criteria: it provides guidance that is based oncommon sense, it provides reminders of the obvious, and it is
not sufficiently specific to allow for application of evidence tothe issue and therefore it is not based on systematic evidence
review. The GRADE system is best suited to evaluate evidence
on comparative effectiveness. Some of our most important
guideline topics involve diagnosis and staging within CKD,
about which the Work Group chose to provide ungradedstatements. These statements are indirectly supported byevidence on risk relationships and are the consensus of theWork Group. Thus, we believe that ungraded statements
should not be viewed as weaker than graded recommendations.
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methods for guideline development

Table 43 | KDIGO nomenclature and description for grading recommendations
Implications
Grade*

Patients

Clinicians

PolicyLevel 1
‘We recommend’

Most people in your situation would
want the recommended course of action
and only a small proportion would not.

Most patients should receive therecommended course of action.

The recommendation can be evaluated asa candidate for developing a policy or aperformance measure.

Level 2‘We suggest’

The majority of people in your situation
would want the recommended course ofaction, but many would not.

Different choices will be appropriate fordifferent patients. Each patient needs help
to arrive at a management decisionconsistent with her or his values andpreferences.

The recommendation is likely to require
substantial debate and involvement of
stakeholders before policy can be
determined.

Abbreviation: KDIGO, Kidney Disease: Improving Global Outcomes.
*The additional category ‘‘Not Graded’’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence.
The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations
are generally written as declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Table 44 | Determinants of strength of recommendation
FactorComment

Balance between desirable andundesirable effects
Quality of the evidence
Values and preferences

The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation
is warranted. The narrower the gradient, the more likely a weak recommendation is warranted.
The higher the quality of evidence, the more likely a strong recommendation is warranted.
The more variability in values and preferences, or more uncertainty in values and preferences, the more likely aweak recommendation is warranted.
The higher the costs of an intervention—that is, the more resources consumed—the less likely a strong
recommendation is warranted.

Costs (resource allocation)

Reproduced from Going from evidence to recommendations. Guyatt GH, Oxman AD, Kunz R, et al.724 BMJ 336: 1049-1051, 2008 with permission from BMJ Publishing Group
Ltd.; accessed http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376019/pdf/bmj-336-7652-analysis-01049.pdf

Table 45 | The Conference on Guideline Standardization727 checklist for reporting clinical practice guidelines
Topic

Description

Discussed in KDIGO CKD Guideline

1. Overview material

Provide a structured abstract that includes theguideline’s release date, status (original, revised,
updated), and print and electronic sources.
Describe the primary disease/condition andintervention/service/technology that theguideline addresses. Indicate any alternative
preventative, diagnostic, or therapeuticinterventions that were considered during
development.
Describe the goal that following the guideline is
expected to achieve, including the rationale fordevelopment of a guideline on this topic.

Abstract and Methods for Guideline Development.

2. Focus

3. Goal

4. User/setting

Describe the intended users of the guideline (e.g.,
provider types, patients) and the settings in which
the guideline is intended to be used.

5. Target population

Describe the patient population eligible for
guideline recommendations and list any exclusion
criteria.
Identify the organization(s) responsible for
guideline development and the names/
credentials/potential conflicts of interest of
individuals involved in the guideline’s
development.
Identify the funding source/sponsor and describe
its role in developing and/or reporting theguideline. Disclose potential conflict of interest.

6. Developer

7. Funding
source/sponsor

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Evaluation and management of adults and children with CKD.

This clinical practice guideline is intended to assist the practitioner
caring for patients with CKD and to prevent deaths, cardiovasculardisease events and progression to kidney failure while optimizing
patients’ quality of life.
Providers: Nephrologists (adult and pediatric), Dialysis providers(including nurses), Internists, and Pediatricians.
Patients: Adult and pediatric individuals at risk for or with CKD.
Policy Makers: Those in related health fields.
Individuals at risk for or with CKD.

Organization: KDIGO.
Refer to Biographic and Disclosure Information section.

KDIGO is supported by the following consortium of sponsors:
Abbott, Amgen, Bayer Schering Pharma, Belo Foundation, BristolMyers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole
Food Company, Fresenius Medical Care, Genzyme, HoffmannLaRoche, JC Penney, Kyowa Hakko Kirin, NATCO—The Organization
for Transplant Professionals, NKF-Board of Directors, Novartis,
Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik

125methods for guideline development

Table 45 | Continued
Topic

Description

8. Evidence collection

Describe the methods used to search the scientific
literature, including the range of dates anddatabases searched, and criteria applied to filter
the retrieved evidence.

9. Recommendation
grading criteria

Describe the criteria used to rate the quality ofevidence that supports the recommendations andthe system for describing the strength of therecommendations. Recommendation strengthcommunicates the importance of adherence to a
recommendation and is based on both the qualityof the evidence and the magnitude of anticipatedbenefits and harms.
Describe how evidence was used to create
recommendations, e.g., evidence tables, metaanalysis, decision analysis.

10. Method forsynthesizing
evidence
11. Prerelease review

Describe how the guideline developer reviewed
and/or tested the guidelines prior to release.

12. Update plan

State whether or not there is a plan to update theguideline and, if applicable, expiration date forthis version of the guideline.

13. Definitions

Define unfamiliar terms and those critical tocorrect application of the guideline that might besubject to misinterpretation.
State the recommended action precisely and thespecific circumstances under which to perform it.
Justify each recommendation by describing thelinkage between the recommendation and its
supporting evidence. Indicate the quality ofevidence and the recommendation strength,
based on the criteria described in Topic 9.
Describe anticipated benefits and potential risks
associated with implementation of guideline
recommendations.

14. Recommendations
and rationale

15. Potential benefits
and harm

16. Patient preferences

17. Algorithm

18. Implementationconsiderations

Describe the role of patient preferences when arecommendation involves a substantial elementof personal choice or values.
Provide (when appropriate) a graphicaldescription of the stages and decisions in clinicalcare described by the guideline.
Describe anticipated barriers to application of therecommendations. Provide reference to any
auxiliary documents for providers or patients thatare intended to facilitate implementation. Suggest
review criteria for measuring changes in carewhen the guideline is implemented.

Discussed in KDIGO CKD Guideline
Foundation, Shire, Takeda Pharmaceutical, Transwestern
Commercial Services, Vifor Pharma, and Wyeth.
No funding is accepted for the development or reporting of specificguidelines.
All stakeholders could participate in open review.
Screening criteria are outlined in the methods chapter. The search
was updated through June 2011 and supplemented by articles
identified by Work Group members through November 2012.
We also searched for pertinent existing guidelines and systematic
reviews.
Quality of individual studies was graded in a three-tiered grading
system (see Table 39). Quality of evidence (Table 40) was gradedfollowing the GRADE approach. Strength of the recommendation
was graded in a two-level grading system which was adapted fromGRADE for KDIGO with the quality of overall evidence graded on afour-tiered system (Tables 41 and 43).
The Work Group could provide general guidance in ungradedstatements.
For systematic review topics, summary tables and evidence profiles
were generated.
For recommendations on treatment interventions, the steps
outlined by GRADE were followed.
The guideline had undergone internal review by the KDIGO Board of
Directors in January 2012 and external review in May 2012. Public
review comments were compiled and fed back to the Work Group,
which considered comments in its revision of the guideline.
There is no date set for updating this entire guideline. The need for
updating of the guideline will depend on the publication of new
evidence that would change the quality of the evidence or theestimates for the benefits and harms. Results from registeredongoing studies and other publications will be reviewed periodicallyto evaluate their potential to impact on the recommendations inthis guideline. Specific sections may be updated separately from theentire guideline within the next 3–5 years depending on theevidence base.
Acronyms and Abbreviations.

Each guideline chapter contains recommendations for evaluationand management of CKD patients. Each recommendation builds on
a supporting rationale with evidence tables if available. The strengthof the recommendation and the quality of evidence are provided inparenthesis within each recommendation.

The benefits and harm for each comparison of interventions isprovided in summary tables and summarized in evidence profiles.
The estimated balance between potential benefits and harm wasconsidered when formulating the recommendations.
Many recommendations are ungraded which indicates a greaterneed to help each patient arrive at a management decisionconsistent with her or his values and preferences.
Algorithm for proteinuria/albuminuria testing in Chapter 1.

These recommendations are global and the Work Groupacknowledges the importance of local application. Review criteria
were not suggested because implementation with prioritization anddevelopment of review criteria must proceed locally. Furthermore,most recommendations are discretionary, requiring substantial
discussion among stakeholders before they can be considered for
adoptions as review criteria.
Suggestions were provided for future research.

Abbreviations: CKD, chronic kidney disease; COGS, Conference on Guideline Standardization; GRADE, Grading of Recommendations Assessment, Development, andEvaluation; KDIGO, Kidney Disease: Improving Global Outcomes; NKF, National Kidney Foundation.
Adapted with permission from Shiffman RN, Shekelle P, Overhage JM, et al.727 Standardized reporting of clinical practice guidelines: a proposal from the Conference on
Guideline Standardization. Ann Intern Med 2003; 139(6): 493-498; accessed http://annals.org/data/Journals/AIM/20049/0000605-200309160-00013.pdf

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methods for guideline development

The Work Group took on the primary role of writing therecommendations and rationale statements and retained final
responsibility for the content of the guideline statements andthe accompanying narrative. The ERT reviewed draft
recommendations and grades for consistency with theconclusions of the evidence review.

the only database searched. Hand searches of journals were
not performed, and review articles and textbook chapterswere not systematically searched. However, important studies
known to domain experts that were missed by the electronic
literature searches were added to the retrieved articles andreviewed by the Work Group.

Format for Guideline Recommendations

Summary of the Review Process

Each chapter contains one or more specific recommendations. Within each recommendation, the strength ofrecommendation is indicated as level 1 or level 2 and thequality of the supporting evidence is shown as A, B, C or D.
The recommendation statements and grades are followed by
the rationale and clarification of the wording of thestatement, a brief background with relevant definitions ofterms, and then a chain of logic which summarizes the key
points of the evidence base and the judgments supporting therecommendation. Some sections also contain research
recommendations in variable degrees of detail, suggesting
future research to resolve current uncertainties.

Several tools and checklists have been developed to assess thequality of the methodological process for systematic review andguideline development. These include the Appraisal of Guidelines
for Research and Evaluation (AGREE) criteria,726 the Conference
on Guideline Standardization (COGS) checklist,727 and theInstitute of Medicine’s recent Standards for Systematic Reviews728
and Clinical Practice Guidelines We Can Trust.729 Table 45 andAppendix 1 demonstrate the level of concurrence to the COGS
criteria and the Institute of Medicine standards, respectively.

Limitations of Approach

Although the literature searches were intended to becomprehensive, they were not exhaustive. MEDLINE was

Kidney International Supplements (2013) 3, 120–127

SUPPLEMENTARY MATERIAL

Supplemental Table 1: Search strategy.
Appendix 1: Concurrence with Institute of Medicine standards for
systematic reviews and for guidelines.
Supplementary material is linked to the online version of the paper at
http://www.kdigo.org/clinical_practice_guidelines/ckd.php

127

biographic and disclosure information

http://www.kidney-international.org& 2013 KDIGO

Biographic and Disclosure Information
Kidney International Supplements (2013) 3, 128–133; doi:10.1038/kisup.2012.70

Adeera Levin, MD, FRCPC (Work Group Co-Chair), isProfessor of Medicine, Division Head of Nephrology at the
University of British Columbia, and Consultant Nephrologist
at Providence Health Care/St Paul’s Hospital, in Vancouver
Canada.
Dr Levin is the Executive Director of the BC Renal
Agency, which oversees the care, planning, and budgets forkidney services in the province of British Columbia. In thiscapacity, she has leveraged her epidemiological training,clinical knowledge, and health outcomes research to develop
an evidence-based transparent system which enhances thecare of patients across the continuum of care (fromidentification of CKD to dialysis, transplant, and death).
She is active in international activities across the spectrumof kidney activities including her appointment as Secretary
General of the International Society of Nephrology (ISN),
founding executive committee member of KDIGO, and as coChair of the Declaration of Istanbul Custodian group(DICG). Dr Levin has a long-standing clinical and researchinterest in CKD and CVD, and is Founding Director of theKidney Function Clinic at St Paul’s Hospital.
As an active researcher and mentor, she is involved in anational curriculum development for clinician scientists
interested in kidney disease (KRESCENT), and mentors
students, residents, and nephrology fellows in Vancouver aswell. She has over 210 peer-reviewed publications, numerous
book chapters, and is co-editor of a textbook Chronic Kidney
Disease: A Practical Guide to Understanding and Management.
Her major research areas of interest include non-traditionalrisk factors for CVD in CKD patients, with particular focus
on anemia, phosphate and vitamin D, and progression of
CKD variability.
Advisor/Consultant: Merck; Otsuka
Grant/Research Support: Abbott; Amgen; Canadian
Institutes of Health Research; Genzyme, Kidney Foundationof Canada; Merck; Ortho
Paul E Stevens, MB, FRCP (Work Group Co-Chair), is
Consultant Nephrologist and Associate Medical Director,
East Kent Hospitals University NHS Foundation Trust, Kent
and Canterbury Hospital in the UK. He is a member of the
Department of Health’s Renal Advisory Group and Renal
Pathology Group and immediate past-President of the British
Renal Society. Dr Stevens established the Kent Kidney Care
Centre, one of the largest general hospital renal units in the
UK and served as a clinical advisor on NICE publications
Anaemia Management in People with Chronic Kidney Disease
128

and Chronic Kidney Disease: National Clinical Guideline for
Early Identification and Management in Adults in Primary andSecondary Care. He is also Chair of NICE Quality Standards
in Chronic Kidney Disease.
His main interests include the epidemiology of CKD and
AKI, prospective evaluation of a new method of assessing
adequacy in peritoneal dialysis, evaluation of anemia in
unreferred patients with CKD and in patients with diabetes,
collaborative research with the elderly CKD care team, andthe development of information technology-based solutionsin the referral and follow-up of patients with kidney disease.
Over the last several years, his program has also developed aclinical decision support system to aid management of
CKD in primary care and this system is currently running live
in a population of over 300,000 primary care patients.
Dr Stevens has authored over 90 publications in peerreviewed journals and textbooks, and has given over 100
presentations and 65 guest lectures in national andinternational society meetings.
Dr Stevens reported no relevant financial relationships
Rudy W Bilous, MD, is Professor of Clinical Medicine at
Newcastle University and Honorary Consultant Physician
at the James Cook University Hospital, Middlesbrough, UK.
He studied medicine at Guy’s Hospital and completed his
clinical training at various hospitals in London. He was an
National Institutes of Health (NIH) Fellow at the Unit for
Metabolic Medicine at Guy’s from 1980-1982 working forProfessor Harry Keen and with Drs John Pickup andGiancarlo Viberti examining the effects of metabolic control
on microvascular complications. From 1985-1987 he wasJuvenile Diabetes Research Foundation fellow at the University of Minnesota working for Drs Mike Steffes and Mike
Mauer. He was awarded his MD from the University of
London in 1987 and elected Fellow of the Royal College ofPhysicians of London in 1991. He served as Secretary and
Chair of the Specialty Advisory Committee for Endocrinology and Diabetes and Chairman of the Professional section of
Diabetes UK. He is currently Chairman of the workgroup
reviewing the NICE guideline for Diabetes in Pregnancy
and President of the European Diabetic Nephropathy
Study Group of the European Association for the Study ofDiabetes.
Advisor/Consultant: Abbott; Boehringer Ingelheim; Novartis;
Roche
Speaker: Boehringer Ingelheim; Novo Nordisk; Roche
Kidney International Supplements (2013) 3, 128–133

biographic and disclosure information

Josef Coresh, MD, PhD, MHS, is Professor, Department of
Epidemiology, Medicine, and Biostatistics at Johns Hopkins
Bloomberg School of Public Health and School of Medicine
where he also received his medical degree and PhD in
epidemiology, and a master’s in biostatistics. He is alsopresently the Director of the George W Comstock Center for
Public Health Research and Prevention, and the Cardiovascular Epidemiology Program and Training Grant at
Johns Hopkins Bloomberg School of Public Health.
Dr Coresh’s primary research interest has been theinvestigation of risk factors for CVD in CKD and their rolein mediating the excess risk among patients with various
degrees of CKD severity. With the use of innovative
epidemiologic methods and statistical analyses, his recent
work uncovered several novel genetic susceptibility loci forgout as well as a susceptibility locus (MYH9/APOL1) which
accounts for much of the excess risk of non-diabetic kidneydisease among African-Americans. Since 2000, he has focusedhis attention on enhancing CKD classification, management
and prognostication by improving the estimation of kidney
function. In 2002, he served as Co-Chair on the KDOQIClinical Practice Guidelines for CKD which produced the
CKD definition and classification system that have been
adopted widely today. More recently, his research led to thedevelopment of the 2009 CKD-EPI equation for estimatingkidney function which is rapidly become the new standard
for GFR estimation globally. In 2010, he became Steering
Committee Chair of Chronic Kidney Disease Prognosis
Consortium (CKD-PC) which analyzes data from two
million study participants in order to provide better
estimation on CKD prognosis. Dr Coresh has authored close
to 300 publications and has mentored over 60 students. In
recognition of his contributions, he was awarded the NKF’s
Garabed Eknoyan Award (2010), American Heart Association’s 2010 Epidemiology and Prevention Mentoring Awardand served as plenary speaker at the American Association
for Clinical Chemistry 2011 Annual Meeting.
Advisor/Consultant: Merck
Grant/Research Support: Amgen; National Institutes of
Health; National Kidney Foundation
Speaker: Abbott; Amgen
Angel LM de Francisco, MD, PhD, is Head of Dialysis Unit
and Nephrology Section, Hospital Universitario Valdecilla,
Santander (Spain), and Full Professor of Nephrology at
Faculty of Medicine in Cantabria University. He completed
his medical residency and nephrology fellowship at Hospital
Puerta de Hierro in Madrid, and received his Doctor of
Medicine degree from University of Cantabria (Spain). Profde Francisco is an active member of several professionalsocieties, an Executive member of the KDIGO Board, and
was President of the Spanish Society of Nephrology from2002 to 2008. He has been a frequently invited lecturer,
speaking extensively on advancements in treatment ofKidney International Supplements (2013) 3, 128–133

chronic kidney diseases and comorbid conditions such as
metabolic bone disease, anemia, dialysis, and kidneytransplantation. Prof de Francisco has authored or coauthored over 150 publications, including original peerreviewed articles and book chapters. His primary focus has
been on improving outcomes in patients receiving hemodialysis, and on issues surrounding organ transplantation andthe impact of treatment guidelines on clinical practice.
Advisor/Consultant: Amgen
Speaker: Abbott; Fresenius
Paul E de Jong, MD, PhD, was Professor of Nephrology andHead, Division of Nephrology of the Groningen University
Medical Center in Groningen, the Netherlands from 1992
to 2011. His main research interest is prevention of CKD.
From 1980 to 2000, he focused most of his attention on themechanisms of urinary protein loss in CKD patients andoptions to lower proteinuria with ACE-I. His studies had
indeed shown that such treatment prevented ESRD progression. In 1996, he initiated the PREVEND study which
consisted of a large cohort of 8592 subjects followed for thedevelopment of kidney disease and CVD. This prospective
longitudinal study demonstrated the impact of albuminuria,
even in the ranges of microalbuminuria and below, in
predicting future cardiovascular and renal events. As former
Director of the Groningen Institute of Kidney Diseases, his
research program encompasses the studying of underlying
susceptibility to kidney damage in health subjects and theidentification of common pathophysiological pathways
between CKD and CVD. Currently, he serves on the boardof KDIGO, CKD-PC, and European Kidney Health Alliance.
In 2010, he was the recipient of International Distinguished
Medal from the US National Kidney Foundation and wasawarded the Officer in the Order of Orange-Nassau for his
lifetime achievement by Her Majesty Queen Beatrix of theNetherlands in 2011.
Dr de Jong reported no relevant financial relationships
Kathryn E Griffith, BM, BS, MSc, MRCP, MRCGP, is a
general practitioner affiliated with The University HealthCentre, York University and York Hospital Foundation Trust.
Dr Griffith has a long-standing interest in the relationshipbetween CVD and renal disease from a primary care
physician’s perspective. In this vein, she has served as a panel
member for the Royal College of Physicians (RCP)
Edinburgh Consensus Conference on CKD and was involvedin the development of the 18-week Commissioning Pathway
to CKD with the Department of Health. She is presently amember of the Renal Advisory Group at the Department of
Health and a member of both UK Renal Association andBritish Renal Society. Dr Griffith has also been involved in
the education of general practitioners and practice nurses,
and most recently she has lectured extensively on various
topics such as atrial fibrillation, heart failure, coronary heart129

biographic and disclosure informationdisease, hypertension, and stroke. For the past two years, she
has worked with Yorkshire Cardiac and Stroke Networks
on a guide to stroke prevention in atrial fibrillation, andcontributed to the RCP Edinburgh Consensus on atrial
fibrillation management and European Society of Cardiology’s clinical practice guideline on management ofdyslipidemias.
Advisor/Consultant: Boehringer Ingelheim
Honoraria: Pfizer
Travel Stipend: Merck Sharp & Dohme
Grant/Research Support: Roche
Speaker: Boehringer Ingelheim
Brenda R Hemmelgarn, MD, PhD, FRCP(C), is Associate
Professor in the Departments of Medicine and Community
Health Sciences, University of Calgary, Calgary, Alberta. She
is a clinician scientist with clinical training in nephrology
as well as a PhD in Epidemiology and Biostatistics.
Dr Hemmelgarn’s research interests are in the study ofchronic medical conditions including CKD, diabetes, hypertension and CVD, as well as health services research aimed
at improving management of these chronic conditions.
Dr Hemmelgarn holds provincial and national salary awards
and operating grants, and is the recipient of the Roy and
Vi Baay Chair in Kidney Research. She is also actively
involved in Clinical Practice Guideline development bothnationally through the Canadian Society of Nephrology
and internationally through KDIGO, and has over 180
peer-reviewed publications.
Grant/Research Support: Roche
Kunitoshi Iseki, MD, is currently affiliated with
University Hospital of the Ryukyus in Okinawa, Japan.
Dr Iseki received his medical training at Kyushu University
in Fukuoka, Japan and completed his fellowship at Universityof Southern California under Professors Shaul Massry
and Vito Campese. He was Senior Assistant Professor of
Medicine at Ryukyu University Hospital and later became
its Director of Dialysis Unit. Dr Iseki is a member ofnumerous professional organizations including the JapaneseSociety of Nephrology and Japanese Society for Dialysis
Therapy. He is also an organizing member for Asian Forumof Chronic Kidney Disease Initiatives (AFCKDI) since 2007
and an ISN-COMGAN Educational Ambassador since2009. Dr. Iseki has also participated and contributed data
to the CKD-PC whose collaborative meta-analyses wereconducted to study CKD prognosis. He has previously served
as Editorial board member for American Journal Kidney
Disease and is presently an editorial board member ofNephrology, Nephron Clinical Practice and Nephrology Dialysis
Transplantation.
Dr Iseki reported no relevant financial relationships
130

Edmund J Lamb, PhD, FRCPath, is a Consultant Clinical
Scientist and Head of Clinical Biochemistry at East Kent
Hospitals University NHS Foundation Trust, Canterbury,
Kent, UK. He has a special interest in kidney disease andundertook his PhD in the Renal Research Laboratory at
St Bartholomew’s Hospital, London. He has 30 years
experience as a clinical biochemist and his researchinterests relate to the use of biochemical markers to diagnose and monitor kidney disease, including the assessment of kidney function using eGFR, the evaluation ofrenal bone disease, the use and role of cystatin C, and thesignificance and use of cardiac biomarkers in kidneydisease. Dr Lamb has authored or co-authored more than
60 full peer-reviewed papers in this area. He is a memberof the UK Kidney Research Consortium Clinical Study
Group on CKD-MBD and he is the lead investigator on two
National Institute for Health Research-Research for Patient
Benefit funded studies investigating aspects of kidney
function testing. He has been involved in national andinternational committees and guidelines (e.g., Royal Collegeof Physicians UK CKD Guidelines Group, NICE CKDGuideline Development Group, KDIGO Chronic Kidney
Disease Guideline Work Group) and was recently involvedin the Department of Health initiative to roll-out eGFR
across England. He is Editor-in-Chief of Annals of Clinical
Biochemistry.
Grant/Research Support: Siemens
Andrew S Levey, MD, is Dr Gerald J and Dorothy
R Friedman Professor of Medicine at Tufts University Schoolof Medicine, Chief of the William B Schwartz, MD Divisionof Nephrology at Tufts Medical Center, Senior Scientist at the
US Department of Agriculture Human Nutrition ResearchCenter on Aging at Tufts University, and Professor, ClinicalResearch at the Sackler School of Graduate Biomedical
Sciences at Tufts University. His research is mainly in theareas of epidemiology of CKD and CVD in CKD, controlled
trials to slow the progression of CKD, clinical assessment ofkidney function, assessment and improvement of outcomesin dialysis and transplantation, and clinical practice guideline
development and implementation. Dr Levey is currently
Program Director for an NIDDK-funded clinical researchtraining program, ‘‘Clinical Trials, Epidemiology and Outcomes Research in Nephrology.’’ He is also the Director of theTufts Center for Guideline Development and Implementationand Editor of American Journal of Kidney Disease. Dr Levey
is past Chair of the NKF’s Task Force on Cardiovascular
Disease in Chronic Renal Disease and served on KDOQIWork Group on Chronic Kidney Disease: Evaluation,
Classification and Stratification, KDOQI Work Group on
Hypertension and Antihypertensive Agents in Chronic
Kidney Disease, and KDIGO Work Group on Acute Kidney
Injury Guideline.
Dr Levey reported no relevant financial relationships
Kidney International Supplements (2013) 3, 128–133

biographic and disclosure information

Miguel C Riella, MD, PhD, FACP, is a graduate of Federal
University of Parana in Curitiba, Brazil and has undertaken
his post-graduate training in the United States, first inInternal Medicine Residency at Mount Sinai Hospital in
New York City and then Research Renal Fellowship at the
University of Washington in Seattle, USA under the leadership of Prof Belding H Scribner, pioneer of chronic
hemodialysis. Dr Riella’s main interest has been on dialysis,
particularly peritoneal dialysis and nutrition in uremia. Morerecently his research work has concentrated on the relationship of inflammation, uremia, nutrition and cardiovascularcomplications, and interventional nephrology. As part ofhis new Renal, Diabetes and Hypertension Research Center,he has recently established the Islet Cell Laboratory at Catholic
University of Parana in Curitiba, Brazil for cell transplant indiabetic patients. Dr Riella has published several books in
Portuguese and Spanish language in the area of nephrology
and nutrition. His book Principles of Nephrology and Electrolyte
Disturbances (Guanabara Koogan Group Gen, 2010) is on its
5th Edition. He has more than 150 publications and has given
more than 600 lectures locally and internationally. He is a past
Board member and executive committee member of the ISN
and is currently the Chairman of the ISN-Interventional
Nephrology Committee. Dr Riella is a member of the editorial
board of several medical journals, including as Associate Editorof Hemodialysis International and International Editor of
Seminar in Dialysis for Interventional Nephrology. He is also
President and founder of Pro-Renal Foundation of Brazil(www.pro-renal.org.br), a non-for-profit organization dedicated to patient assistance, CKD prevention and education,and supporting research in kidney and metabolic diseases. The
Foundation provides free medical care to more than 1800 renal
patients through a multidisciplinary team of physicians, nurses,
psychologists, social workers, and dietitians. The Foundation is
maintained by donations of the community and receives no
public funds. Dr Riella is the past-President of the International Federation of Kidney Foundations (IFKF) 2009-2011.
He is also the co-chairman of World Kidney Day, a joint
project of IFKF and and ISN. He is a member of the Executive
Committee of KDIGO, National Academy of Medicine in
Brazil, and the Academy of Medicine of Parana, Brazil. He hasreceived many awards such as the International Distinguished
Medal from the US NKF and Honorary Citizenship of the cityof Curitiba and of the State of Parana in Brazil.
Advisor/Consultant: Abbott
Michael G Shlipak, MD, MPH, is Professor of Medicine,
Epidemiology, and Biostatistics at University of California,
San Francisco. Dr Shlipak obtained his MD degree from
Harvard Medical School and his MPH from Harvard Schoolof Public Health. His research program has been dedicated tounderstanding the causes and consequences of age-related
kidney disease and to utilize novel biomarkers for the early
detection of kidney damage and reduced kidney function.
Along with his colleagues from the Cardiovascular Health
Kidney International Supplements (2013) 3, 128–133

Study and Health Aging and Body Composition study,
Professor Shlipak has conducted the pioneering work todemonstrate with cystatin C the remarkable prognostic
importance of impaired kidney function in elders. He coined
the entity of ‘‘preclinical kidney disease’’ to describe the large
population of elders with elevated cystatin C levels, but
normal creatinine-based estimates of kidney function, who
are at high risk for death and CVD.
The recent work from his research group has been
dedicated to finding early markers of kidney injury in theurine that will precede any detectable loss in kidney function.
They will study these urine biomarkers in several populations, including the ambulatory elderly, HIV-infected men
and women, and in population-based studies. The groupbelieves that these injury markers hold promise both forunderstanding how various exposures impact the kidney, andalso to forecast future declines in kidney failure.
Dr Shlipak reported no relevant financial relationships
Haiyan Wang, MD, is Professor of Medicine at Peking
University First Hospital. She is the current President of
Peking University Institute of Nephrology and the Vice
Director, Academic Committee, Peking University Health
Science Center and Member, Academic Degree Committee,
Peking University Health Science Center.
Professor Wang is very active in the academic area ofnational and international nephrology and internal medicine.
She was the Vice President of Chinese Medical Association(1999-2009) and the President of Chinese Society of Internal
Medicine (2000-2008), as well as the President of Chinese
Society of Nephrology (1992-1998). She has also served
as the ISN Councilor member (2004-2008), Executive
Councilor of ISN (2006-2008) and is now Chair, East Asia
committee of ISN GO (2004-present).
Dr Wang reported no relevant financial relationships
Colin T White, MD, FRCPC, completed his medical degree atthe University of Ottawa, Canada and Pediatric Residency at
the University of Western Ontario, Canada. His pediatricnephrology training took place at the University of Western
Ontario and University of British Columbia. He is a Clinical
Associate Professor in Pediatrics/Nephrology at the Universityof British Columbia and has a clinical appointment at BC
Children’s Hospital where in addition to an interest and participation in the CKD clinic, he is the Director of the Dialysis
Program and is the Fellowship Program Director. Dr White wasa work group member for the 2006 and 2007 Updated KDOQI
Anemia Guidelines, and for the Canadian Society of Nephrology’s Clinical Practice Guidelines for Anemia Management in2007-2008; he is currently on the 2011-2012 CSN Workgrouprevisiting these guidelines. He is the site Principal Investigator
for the North American multicenter NIH-sponsored CKiDs
trial and has particular research interests in hemodialysis andperitoneal dialysis as well as CKD management. His particular131biographic and disclosure information

areas of research interest include estimation of clearance,
anemia protocol development, and translation of evidence
into functional guidelines. He is active at the undergraduate
medical school level and has coordinated the UBC Renal andGenitourinary Course for 1st year medical students for nearly adecade. He is currently the President of the Western Society ofPediatric Research and an invited member of the Renal WorkGroup for the World Health Organization’s ICD-11 Code
Revision.
Advisor/Consultant: Baxter Healthcare
Christopher G Winearls, MB, DPhil, FRCP, graduated in1973 from University of Cape Town and as a Rhodes Scholar
completed a PhD from University of Oxford in transplant
immunology. Dr Winearls later pursued training in nephrology at the Hammersmith Hospital where he was part of theteam that investigated the first clinical use of erythropoietin.
Dr Winearls was appointed consultant in Oxford in 1988 and
was Clinical Director 1995 to 2009. He has been Secretaryand later Clinical Vice President of The Renal Association
and an Editor of the Oxford Textbook of Clinical Nephrology.
His research interests include myeloma kidney and autosomal dominant polycystic kidney disease, and has recently
taken an interest in the new classification of CKD.
Dr Winearls reported no relevant financial relationships

David C Wheeler, MD, FRCP, holds an academic position in
Nephrology (Reader) at University College London, UK andis an Honorary Consultant Nephrologist at the Royal Free
Hospital. His research is focused on the cardiovascularcomplications of CKD and the role of vascular risk factors inprogression of kidney damage. Dr Wheeler is a member of
the International Steering Committee of the Study ofHeart and Renal Protection (SHARP) and was UK National
Coordinator for the trial. He is involved in several otherrandomized trials and observational studies involving
patients with CKD.
Dr Wheeler is Co-Chair of KDIGO, having served
previously on its Executive Committee and Board. He
received an International Distinguished Medal from the
US NKF in recognition of his contribution to guideline
development. In the UK, he has been elected President of
the Renal Association for the term 2012-2014.
Dr Wheeler has served on the editorial boards of American
Journal of Kidney Diseases and Journal of the American Societyof Nephrology and is presently Co-Editor for Nephrology
Dialysis Transplantation.
Advisor/Consultant: Amgen
Honoraria: Abbott; Amgen; Fresenius; Otsuka; Shire
Travel Stipend: Amgen; Merck Sharp & Dohme; Shire
Grant/Research Support: Abbott; Genzyme

KDIGO CHAIRSEVIDENCE REVIEW TEAM

Bertram L Kasiske, MD, is Professor of Medicine at the
University of Minnesota, USA. He received his medical
degree from the University of Iowa and completed his
Internal Medicine residency and fellowship training in
Nephrology at Hennepin County Medical Center where heis currently Director of Nephrology.
Dr Kasiske is former Deputy Director of the United States
Renal Data System and former Editor-in-Chief of American
Journal of Kidney Diseases. He has served as Secretary/
Treasurer and on the Board of Directors of the American
Society of Transplantation, and on the Organ Procurement
and Transplantation Network/United Network of Organ
Sharing Board of Directors, and the Scientific Advisory
Board of the US NKF. He is currently serving on the Board of
Councilors of the ISN and he is the Principal Investigator for
a National Institutes of Health-sponsored, multicenter studyof long term outcomes after kidney donation. Dr Kasiske is
the Director of the Scientific Registry of Transplant
Recipients and has over 160 scientific publications in major
peer-reviewed journals, and 230 review articles, editorials andtextbook chapters. Dr Kasiske is also a recipient of the US
NKF’s Garabed Eknoyan Award in 2003.

Katrin Uhlig, MD, MS, is the Director, Guideline Development at the Tufts Center for Kidney Disease Guideline
Development and Implementation, Boston, MA, USA,
Associate Professor of Medicine at Tufts University Schoolof Medicine, and a staff nephrologist at Tufts Medical Center.
Dr Uhlig completed her training in internal medicine,
nephrology, and rheumatology in Germany (Aachen University Hospital and Munich University Hospital) and theUSA (Georgetown University Medical Center and Tufts
Medical Center). Since 2001, she has been participating in or
directing the evidence review for KDOQI and KDIGO
guidelines. As Director of Guideline Development, Dr Uhlig
has a substantial role in coordinating the ERT. She
orchestrates and supervises the guideline development
process and didactic curriculum that provides Work Group
members with formal instruction on topics related to guideline development. As project director on individual guidelines, she directs and supervises the collection, evaluation,
grading, and synthesis of evidence and the drafting andrevisions of the final evidence report. She provides methodological guidance and training to Work Group members at
meetings regarding topic refinement, key question formulation, data extraction, study assessment, evidence grading,and recommendation formulation. She provides nephrology
expertise in the interpretation and review of guideline recommendations and evidence reports. In this capacity,

Advisor/Consultant: Litholink
Grant/Research Support: Bristol-Myers Squibb; Merck(Schering Plough)132

Kidney International Supplements (2013) 3, 128–133

biographic and disclosure information

Dr Uhlig possesses unique knowledge as a methods expert inevidence synthesis and critical literature appraisal in thedomain of nephrology.
In 2005, she co-chaired the KDIGO Evidence RatingGroup to develop a consensus on grading of KDIGO
guidelines and also co-chaired the KDIGO Consensus
Conference on Guideline Methodology in October
2007. From 2006 to 2007, she served as Co-Editor of
American Journal of Kidney Diseases. Her teaching andresearch focus includes evidence-based medicine, systematic
review, clinical practice guideline development, and critical
literature appraisal. Dr Uhlig lectures on guideline topics andis a co-instructor of an annual course on meta-analysis in the
Master of Science Program at the Sackler School of Graduate
Biomedical Sciences at Tufts University.
Dr Uhlig reported no relevant financial relationships
Dana C Miskulin, MD, MS, is Assistant Professor of
Medicine at Tufts University School of Medicine, Boston,
MA, USA. She completed a fellowship in Clinical Care
Research and participated in the conduct of systematic
reviews and critical literature appraisals for this guideline.
Her primary research interests are in comparative effectiveness research in dialysis patients, BP treatment in dialysis
patients, and autosomal dominant polycystic kidney disease.
Dr Miskulin reported no relevant financial relationships
Amy Earley, BS, is a project coordinator at the Tufts Center
for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She is key in coordinating theKidney International Supplements (2013) 3, 128–133

guideline development activities within the ERT, especially inthe development of the evidence reports for all guidelines.
Ms Earley also heads the actual evidence review, which
includes running searches, screening, data extraction,
drafting of tables and methods sections, proofing of guideline
drafts, and critical literature appraisals. She participates in
the conduct of research projects at the Center and actively
collaborates with other members of the Center on independent research topics and manuscript submissions.
Ms. Earley reported no relevant financial relationships
Shana Haynes, MS, DHSc, is a research assistant at the Tufts
Center for Kidney Disease Guideline Development and
Implementation in Boston, MA, USA. She participates inall aspects of evidence review and guideline development. She
screens abstracts and articles, extracts data, and assists in thedrafting and editing of evidence tables. Dr Haynes also assistsin the development of clinical practice guidelines andconducts systematic reviews and critical literature appraisals.
Dr Haynes reported no relevant financial relationships
Jenny Lamont, MS, is a project manager and medical writerat the Tufts Center for Kidney Disease Guideline Development and Implementation in Boston, MA, USA. She
participates in all aspects of evidence review and guideline
development, assists in the preparation of talks and manuscripts, and edits KDIGO draft guidelines currently inprogress.
Ms. Lamont reported no relevant financial relationships

133

acknowledgments

http://www.kidney-international.org& 2013 KDIGO

Acknowledgments
Kidney International Supplements (2013) 3, 134–135; doi:10.1038/kisup.2012.71

A special debt of gratitude is owed to the KDIGO Co-Chairs
Kai-Uwe Eckardt, Bertram Kasiske, David Wheeler, and the
KDIGO Board for their invaluable guidance throughout
the development of this guideline. In particular, we thank the
ERT members: Katrin Uhlig, Dana Miskulin, Amy Earley,
Shana Haynes, and Jenny Lamont for their substantial
contribution to the rigorous assessment of the available
evidence. We are also especially grateful to the WorkGroup members for their expertise throughout theentire process of literature review, data extraction, meeting
participation, the critical writing and editing of thestatements and rationale, which made the publication ofthis guideline possible. The generous gift of their time anddedication is greatly appreciated. The entire Work Group andits Co-Chairs would also like to extend a special debt ofgratitude to Michael Cheung, who has committed time andenergy above and beyond, to the formatting and proof
reading of the completed manuscript. Without his help, we
would have been hard pushed to complete this task. Finally,
and on behalf of the Work Group, we gratefully acknowledge
the careful assessment of the draft guideline by external
reviewers. The Work Group considered all of the valuablecomments made and where appropriate, suggested changes
were incorporated into the final publication. The following
individuals provided feedback during the public review of thedraft guideline:
Mario Abbud-Filho; Hugo Abensur; Patricia Abreu;
Matias Abuchanab; Nasrulla Abutaleb; Anil K Agarwal;
Ahmed Akl; Mona Al-Rukhaimi; Fernando A Almeida; Altun
Bulent; Maria Almerinda Ribeiro Alves; Pablo Amair;
Richard Amerling; Alessandro Amore; Ryoichi Ando; Rajeev
Annigeri; Ramadan Arafa; Mustafa Arici; Mariano Arriola;
Ferruh Artunc; Suheir Assady; Marcelo Rodrigues Bacci;
Ashraf AM Bakr; Breda Peèovnik Balon; Rashad S Barsoum;
Don Batisky; Dawlat Belal; Mohammed Benyahia; Murray
Berall; Anatole Besarab; Premila Bhat; Mar Biechy; Patrick
Biggar; Brenda Brewer; Inga Arune Bumblyte; Jian-Fang Cai;
Rafael Burgos Calderon; Bernard Canaud; Jorge B CannataAndı́a; Antonio Carlos Duarte Cardoso; Laurence Carroll;
Sue Cary; Luis Castillo; Arlene Chabanuk; Philippe Chauveau; Jiang-Hua Chen; Kathleen Claes; Peter Clausen; Jean
Colaneri; Mario Cozzolino; Andrew Crannage; MichaelCunningham; Jane S Davis; Kimberly Davis; Rodrigo Daza;
Julián Segura de la Morena; Luca De Nicola; Rodrigo Bueno
de Oliveira; Rogerio Baumgratz de Paula; Goffredo Del
Rosso; David DeMicco; Sheila Deziel; Bruno Didier;
Guillermo J Rosa Diez; Ian Dittmer; Walter Guillermo
Douthat; Reham Eid Elsayed; Montserrat Mercedes Dı́az
134

Encarnación; Tracy Evans-Walker; Joyce Ezaki-Yamaguchi;
Jarraya Faical; Bonita Falkner; Sandro Feriozzi; ManuelFerreira; Charles Ferro; Joseph T Flynn; Patricia Folk; Lui G
Forni; Costas Fourtounas; Roberto Jorge da Silva Franco;
Ping Fu; Naohiko Fujii; Susan L Furth; Suzanne Gagne; SishirGang; Colin C Geddes; Rozina Ghazalli; Karla Giles; Rodney
Gilkey; Cheryl Gilmartin; Matthias Girndt; Richard J
Glassock; Carlo Francisco S Gochuico; Eliezer Golan; DavidJ Goldsmith; Fatima Ramirez Gonzalez; Suzanne Gore; Sı́lvia
Gràcia-Garcia; Martin Haas; Lisa Hall; Karen Hamacher;
Kathy Schiro Harvey; Niwrutti Hase; Domingo Hernandez;
Elisabeth M Hodson; Ronald J Hogg; Hallvard Holdaas;
Michael F Holick; Noriyuki Homma; Lai Seong Hooi; MarkHouser; Christian Hugo; Salwa Ibrahim; Enyu Imai; Jula
Inrig; Sanjay Jain; Matthew James; Alan G Jardine; Andrzej
Jaroszynski; Simon Jenkins; Chandra Mauli Jha; Kazibek
Joldoshov; Graham Jones; Kamyar Kalantar-Zadeh; Nada
Kanaan; Gülc¸in Kantarci; Frederick J Kaskel; Cecelia Kasnick;Hasan Kayabasi; James S Kennedy; Johannes Kessel; Bryce A
Kiberd; Vera Koch; Daisuke Koya; Peter Krisper; Batya
Kristal; Stefan Krivoshiev; Dirk R J Kuypers; Francisco
Lacordelle; Craig B Langman; Roberta Lattes; Rakesh
Lattupalli; Keith Lau; Edgar V Lerma; Visnja Lezaic; Hao
Li; Yuan Liang; Robert Liebl; Jimmy A Light; Petrica Ligia;
Tuta Liliana; Annabelle Sy Lim; Jelka Lindic; Zhangsuo Liu;
Attilio Losito; Richard Lund; Kelvin Lynn; Linlin Ma; Janette
Mansour; Abeera Mansur; Judith Marin; Alberto MartinezCastelao; Ken Massey; Timothy Mathew; Michael Mauer;
Sandro Mazzaferro; Peter A McCullough; Amanda Medland;
Gong Mengchun; Enisa Mesic; Sergio A Mezzano; Marius
Miglinas; Tanuja Mishra; Takehiko Miyaji; Rosario
Montañés-Bermúdez; Assad Monzer; José M Morales;
Eugen Mota; Ricardo Mouzo; Cesar Loza Munarriz; Mohsen
Nafar; Judit Nagy; Ramesh Naik; Takahiro Nakayama;
Lavinia Negrea; Armando Luis Negri; Robert G Nelson;
Marcus Vinı́cius de Pádua Netto; Alicia M Neu; Eezsafryna
Azalin Nordin; Maurizio Nordio; Diego Novo; Thomas
Oates; Yun Kyu Oh; Raymond Oliva; Patricia de Sequera
Ortiz; Messaoud Ouziala; Antonino Paglialunga; Sonia
Pasquali; Ioan Mihai Patiu; Saime Paydas; Glenda Payne;
Erling Bjerregaard Pedersen; Adriana Peñalba; Graciela
Pennacchiotti; Harry Brian Peppiatt; Gerson Marques Pereira
Junior; Virginia Pernas; Todd E Pesavento; Frida Liane
Plavnik; Claudio Ponticelli; Roberto Pontremoli; Amilee
Poucher; Kearkiat Praditpornsilpa; Anastasia Ptinopoulou;
Wajeh Qunibi; Rashida Rahman; Venkataraman Ramanathan; Roberto Ramirez; Harun ur Rashid; Hugh Rayner;
Leonardo Marin Restrepo; Enrique Andrés Ribes; Peter Ricci;
Kidney International Supplements (2013) 3, 134–135

acknowledgments

Troels Ring; A Adibul Rizvi; Nicolas Roberto Robles;
Karen Rochelle; Hector J Rodriguez; Sara Rotaru; Jacques
Rottembourg; Luis M Ruilope; Domenico Russo; Karen E
Ryals; Jordi Bover Sanjuan; Francisco Santa-Cruz; Rafael
Santamaria; Bento C Santos; Sergio Santos; Kenneth R Say;
Sharon Schatz; Francesco Paolo Schena; Adalbert Schiller;
Bernhard Schmekal; Rebecca Schmidt; Ammar Serawan;
Mehmet Sever; Deepak Sharma; Robert Shay; Mitesh B
Sheth; Alexander Shutov; Aleksandar Sikole; Fernando Simal;
Dhavee Sirivongs; Itzchak Slotki; Yves Smets; Kimberly
Smith; Laura Sola; Yalcin Solak; David Spiegel; Maria
Stasios; Pavai Sthaneshwar; Gere Sunder-Plassmann; Charles
Swanepoel; Mihály Tapolyai; Natalia Tomilina; Rezan

Kidney International Supplements (2013) 3, 134–135

Topaloglu; Robert D Toto; Giorgio Triolo; Kriang Tungsanga;
Katherine R Tuttle; Anitha Vijayan; Rowan Walker; Marc R
Weber; Clare Weekes; Talia Weinstein; Matthew R Weir;
Kerstin Westman; Jack F Wetzels; Sara Wolfson; Mai-Szu Wu;
Yanhua Wu; Li Xuemei; Jerry Yee; Elena Zakharova;
Kostyantyn Zakon; Weiming Zhang; Carmine Zoccali;
Alessandro Zuccalà.
Participation in the review does not necessarily constituteendorsement of the content of this report by the above
individuals, or the organization or institution they represent.
Adeera Levin, MD, FRCPC, Work Group Co-ChairPaul E Stevens, MB, FRCP, Work Group Co-Chair

135

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http://www.kidney-international.org& 2013 KDIGO

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