OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF NEPHROLOGYKDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, andTreatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
VOLUME 76 | SUPPLEMENT 113 | AUGUST 2009

Supplement to Kidney International

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contents

http://www.kidney-international.org& 2009 KDIGO

VOL 76 | SUPPLEMENT 113 | AUGUST 2009

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention,
and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder(CKD–MBD)
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Tables and figures
Disclaimer
Work Group membership
KDIGO Board Members
Abbreviations and acronyms
Reference Keys
Abstract

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Foreword

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Chapter 1:

Introduction and definition of CKD–MBD and the development of
the guideline statements
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Chapter 2: Methodological approach
S22 Chapter 3.1: Diagnosis of CKD–MBD: biochemical abnormalities
S32 Chapter 3.2: Diagnosis of CKD–MBD: bone
S44 Chapter 3.3: Diagnosis of CKD–MBD: vascular calcification
S50 Chapter 4.1: Treatment of CKD–MBD targeted at lowering high serum phosphorus
and maintaining serum calcium
S70 Chapter 4.2: Treatment of abnormal PTH levels in CKD–MBD
S90 Chapter 4.3: Treatment of bone with bisphosphonates, other osteoporosis
medications, and growth hormone
S100 Chapter 5: Evaluation and treatment of kidney transplant bone disease
S111 Chapter 6: Summary and research recommendations
S115 Biographic and disclosure information
S120 Acknowledgments
S121 Referenceshttp://www.kidney-international.org

contents& 2009 KDIGOTABLES
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Table 1. KDIGO classification of CKD–MBD and renal osteodystrophy
Table 2. Grading of recommendations
Table 3. Screening criteria for systematic review topics
Table 4. Questions for topics not related to treatments
Table 5. Literature search yield of primary articles for systematic review topics
Table 6. Grading of study quality for an outcome
Table 7. GRADE system for grading quality of evidence for an outcome
Table 8. Final grade for overall quality of evidence
Table 9. Balance of benefits and harm
Table 10. Implications of the strength of a recommendation
Table 11. Determinants of the strength of a recommendation
Table 12. Suggested frequencies of serum calcium, phosphorus, and PTH measurements according to CKD stage
Table 13. Sources and magnitude of the variation in the measurement of serum calcium, phosphorus, PTH, and vitamin D
sterols
Table 14. Vitamin D2 and D3 and their derivatives
Table 15. Changes in bone histomorphometric measurements from patients in placebo groups of clinical trials or
longitudinal studies
Table 16. Relationship between fractures and PTH in patients with CKD–MBD
Table 17. Positive predictive value for iPTH and b-ALP to predict bone turnover in patients with CKD stage 5
Table 18. Correlation between PTH or other serum markers and BMD
Table 19. Phosphate-binding compounds
Table 20. RCTs of phosphate binders in children with CKD
Table 21. Summary table of RCTs examining the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing
phosphate binders in CKD stages 3–5—description of population at baseline
Table 22. Summary table of RCTs examining the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing
phosphate binders in CKD stages 3–5—intervention and results
Table 23. Evidence matrix for sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D
Table 24. Evidence profile for the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing phosphate binders in
CKD stage 5D
Table 25. Evidence matrix for lanthanum carbonate vs other phosphate binders in CKD stage 5D
Table 26. Evidence profile of lanthanum carbonate vs other phosphate binders in CKD stages 5D
Table 27. Summary table of RCT examining alternate HD regimens in CKD stage 5D—description of population at baseline
Table 28. Summary table of RCT examining alternate HD regimens in CKD stage 5D—intervention and results
Table 29. Adverse events of alternate HD regimens in CKD stage 5D
Table 30. RCTs of calcitriol or other vitamin D analogs in children with CKD
Table 31. Evidence matrix of calcitriol or vitamin D analogs vs placebo in CKD stages 3–5
Table 32. Evidence profile of treatment of CKD–MBD with calcitriol or vitamin D analogs vs placebo in CKD stages 3–5
Table 33. Evidence matrix for calcitriol vs vitamin D analogs in CKD stage 5D
Table 34. Evidence profile for calcitriol vs vitamin D analogs in CKD stage 5D
Table 35. Evidence matrix for calcimimetics in CKD stage 5D
Table 36. Evidence profile for calcimimetics in CKD stage 5D
Table 37. Evidence matrix of bisphosphonates vs placebo/control in CKD stages 3–5
Table 38. Evidence profile of bisphosphonates vs placebo/control in CKD stages 3–5
Table 39. RCTs of treatments for CKD–MBD in children with CKD stages 1–5T
Table 40. Evidence matrix of calcitriol or vitamin D analogs vs placebo or calcium alone in CKD stages 1–5T
Table 41. Evidence profile of calcitriol or vitamin D analogs vs placebo or calcium alone in CKD stages 1–5T
Table 42. Evidence matrix of bisphosphonates vs control in CKD stages 1–5T
Table 43. Evidence profile for the treatment of CKD–MBD with bisphosphonates vs control in CKD stages 1–5T
Table 44. Summary of cumulative evidence matrix with patient-centered outcomes, other surrogate outcomes, andbiochemical outcomes

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contents

S112 Table 45. Cumulative evidence matrix for all treatment studies by outcome
S113 Table 46. Grading of recommendations

FIGURES
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Figure 1. Interpreting a surrogate outcome trial
Figure 2. Evidence model
Figure 3. Parameters of bone turnover, mineralization, and volume
Figure 4. Prevalence of abnormal mineral metabolism in CKD
Figure 5. Changes in serum calcium, phosphorus, and iPTH with time in hemodialysis patients of DOPPS countries
Figure 6. PTH assays
Figure 7. Prevalence of types of bone disease as determined by bone biopsy in patients with CKD–MBD
Figure 8. Prevalence of histologic types of renal osteodystrophy in children with CKD stages 5–5DFigure 9. Types of renal osteodystrophy before and after 1995
Figure 10. Prevalence of bone histology types by symptoms in patients with CKD stage 5D receiving HD treatment
Figure 11. Distribution of osteoporosis, osteopenia, and normal bone density by creatinine clearance in general
US population
Figure 12. Overlap between osteoporosis and CKD stages 3–4
Figure 13. Bone mineral density in patients with CKD stage 5D
Figure 14. Correlation coefficients between bone formation rate as seen on bone biopsies and serum markers of PTH,
bone-specific ALP (BAP), osteocalcin (OC), and collagen cross-linking molecules (x-link)in patients with CKD stages 5–5DFigure 15. Comparison of PTH levels to underlying bone histology in chronic hemodialysis patients
Figure 16. Risk of all-cause mortality associated with combinations of baseline serum phosphorus and calcium categories by
PTH level

Additional information in the form of supplementary tables can be found online at http://www.nature.com/ki

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Disclaimer
SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINEThis Clinical Practice Guideline document is based on the best information available as of March
2009, with a final updated literature search of December 2008. It is designed to provide
information and assist decision-making. It is not intended to define a standard of care, andshould not be construed as one, nor should it be interpreted as prescribing an exclusive course ofmanagement.
Variations in practice will inevitably and appropriately occur when clinicians take into
account the needs of individual patients, available resources, and limitations unique to an
institution or type of practice. Every health-care professional making use of theserecommendations is responsible for evaluating the appropriateness of applying them in thesetting of any particular clinical situation. The recommendations for research contained within
this document 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 the Work Group are required to complete, sign, and submit a disclosure andattestation form showing all such relationships that might be perceived or actual conflicts ofinterest. 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’ Biographical and Disclosure Information section, and is kept on file at the KDIGO
administration office.

KDIGO gratefully acknowledges the following consortium of sponsors that make ourinitiatives possible: Abbott, Amgen, Belo Foundation, Coca-Cola Company, Dole Food
Company, Genzyme, JC Penney, NATCO—The Organization for Transplant Professionals, National Kidney Foundation—Board of Directors, Novartis, Robert and Jane
Cizik Foundation, Roche, Shire, Transwestern Commercial Services, and Wyeth.

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http://www.kidney-international.org& 2009 KDIGOWork Group membership
WORK GROUP CO-CHAIRS

Sharon M Moe, MD, FASN, FAHA, FACP,
Indiana University School of Medicine,
Roudebush VA Medical Center,
Indianapolis, IN, USA

Tilman B Drüeke, MD, FRCP,
Hôpital Necker,
Université Paris 5,
Paris, France

WORK GROUP

Geoffrey A Block, MD,
Denver Nephrologists, PC,
Denver, CO, USA

Alison M MacLeod, MBChB, MD, FRCP,
University of Aberdeen,
Aberdeen, Scotland, UK

Jorge B Cannata-Andı́a, MD, PhD,
Hospital Universitario Central de Asturias,
Universidad de Oviedo,
Oviedo, Spain

Linda McCann, RD, CSR, LD,
Satellite Healthcare,
Mountain View, CA, USA

Grahame J Elder, MB, BS, PhD, FRACP,
Westmead Hospital,
Sydney, Australia

Peter A McCullough, MD, MPH, FACC,
FACP, FCCP, FAHA,
William Beaumont Hospital,
Royal Oak, MI, USA

Masafumi Fukagawa, MD, PhD, FASN
Kobe University School of Medicine,
Kobe, Japan

Susan M Ott, MD,
University of Washington Medical Center,Seattle, WA, USA

Vanda Jorgetti, MD, PhD,
University of São Paulo School of Medicine,São Paulo, Brazil

Angela Yee-Moon Wang, MD, PhD, FRCP,
Queen Mary Hospital,
University of Hong Kong,
Hong Kong

Markus Ketteler, MD,
Nephrologische Klink,
Coburg, GermanyJosé R Weisinger, MD, FACP,
Universidad Central de Venezuela,
Caracas, Venezuela &Baptist Health South Florida,
Miami, Florida, USA

Craig B Langman, MD,
Northwestern University,
Feinberg School of Medicine,Children’s Memorial Hospital,
Chicago, IL, USA
Adeera Levin, MD, FRCPC,St Paul Hospital,
University of British Columbia,
Vancouver, British Columbia, Canada

David C Wheeler, MD, FRCP,
University College London Medical School,
London, UK

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
Ranjani Moorthi, MD, MPH, MS, Assistant Project Director
Amy Earley, BS, Project Coordinator
Rebecca Persson, BA, Research AssistantIn addition, support and supervision were provided by:
Ethan Balk, MD, MPH, Director, Evidence Based Medicine
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Joseph Lau, MD, Methods Consultant
Kidney International (2009) 76 (Suppl 113), Sviii–Six

KDIGO BOARD MEMBERS

Garabed Eknoyan, MD
Norbert Lameire, MD
Founding KDIGO Co-Chairs
Kai-Uwe Eckardt, MD
KDIGO Co-Chair

Bertram L Kasiske, MD
KDIGO Co-Chair

Omar I Abboud, MD, FRCP
Sharon Adler, MD, FASN
Sharon P Andreoli, MD
Robert Atkins, MD
Mohamed Benghanem Gharbi, MD, PhD
Gavin J Becker, MD, FRACPFred Brown, MBA, FACHE
Jerilynn D Burrowes, PhD, RD
Evelyn Butera, MS, RN, CNN
Daniel Cattran, MD, FRCPC
Allan J Collins, MD FACP
Ricardo Correa-Rotter, MD
William G Couser, MD
Olivier CoustereAdrian Covic, MD, PhD
Jonathan Craig, MD
Angel de Francisco, MD
Paul de Jong, MD
Tilman B Drüeke, MD
Denis P Fouque, MD, PhD
Gordon Guyatt, MD, MSc, BSc, FRCPC
Philip Halloran, MD, PhD
David Harris, MD

Michel Jadoul, MD
Vivekanand Jha, MD
Martin K Kuhlmann, MD
Suhnggwon Kim, MD, PhD
Adeera Levin, MD, FRCPCNathan W Levin, MD, FACP
Philip KT Li, MD, FRCP, FACP
Zhi-Hong Liu, MD
Francesco Locatelli, MD
Alison MacLeod, MD, FRCP
Pablo Massari, MD
Peter A McCullough, MD, MPH, FACC, FACP
Rafique Moosa, MD
Miguel C Riella, MD
Bernardo Rodriquez-Iturbe, MD
Robert Schrier, MD
Trent Tipple, MD
Yusuke Tsukamoto, MD
Raymond Vanholder, MD
Giancarlo Viberti, MD, FRCPTheodor Vogels, MSW
David Wheeler, MD, FRCP
Carmine Zoccali, MD

KDIGO GUIDELINE DEVELOPMENT STAFF

Kerry Willis, PhD, Senior Vice-President for Scientific Activities
Donna Fingerhut, Managing Director of Scientific Activities
Michael Cheung, Guideline Development Director
Thomas Manley, KDIGO Project Director
Dekeya Slaughter-Larkem, Guideline Development Project Manager
Sean Slifer, Scientific Activities Manager

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Abbreviations and acronyms
1,25(OH)2D 1,25-Dihydroxyvitamin D
25(OH)D
25-Hydroxyvitamin D
ACC/AHA
American College of Cardiology/American
Heart Association
AE
Adverse event
ALP
Alkaline phosphatases
b-ALP
Bone-specific alkaline phosphatase
BMD
Bone mineral density
BRIC
Bone Relationship with Inflammation andCoronary Calcification
BV
Bone volume
CAC
Coronary artery calcification
CaR
Calcium-sensing receptor
Ca  P
Calcium–phosphorus productCI
Confidence interval
CKD
Chronic kidney disease
CKD–MBD Chronic kidney disease–mineral and bone disorder
CrCl
Creatinine clearanceCT
Computed tomography
CTX
Carboxyterminal cross-linking telopeptide ofbone collagen
CVD
Cardiovascular disease
DCOR
Dialysis in Clinical Outcomes Revisited
DOPPS
Dialysis Outcomes and Practice Pattern Study
DPD
Deoxypyridinoline
DXA
Dual energy X-ray absorptiometry
EBCT
Electron beam computed tomography
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
ERT
Evidence review team
FDA
Food and Drug Administration
FGF
Fibroblast growth factor
GFR
Glomerular filtration rateHD
Hemodialysis
HDL-C
High-density lipoprotein cholesterol
HPLC
High-performance liquid chromatography
HPT
Hyperparathyroidism
HR
Hazard ratio
IMT
Intimal-medial thickness
IP
Intraperitoneal
iPTH
Intact parathyroid hormone
IRMA
Immunoradiometric assay
IU
International UnitIV
Intravenous
KDIGO
Kidney Disease: Improving Global Outcomes

Sx

KDOQI
KDQOL
LDL-C
MGP
MDRD
MLT
MSCT
N
NAPRTCSNHANES
NKF
NTX
OC
OPG
OR
PD
PICP
PINP
PTH
PWV
qCT
QOL
qUS
RANK-L
RCT
rhGH
RIA
RIND
RR
s.d.
SDS
SEEK
SERM
SF-36
t-ALP
TMV
TRAP
TV
US
VDR
WHO

Kidney Disease Outcomes Quality Initiative
Kidney Disease Quality of Life Instrument
Low-density lipoprotein cholesterol
Matrix Gla protein
Modification of Diet in Renal Disease
Mineralization lag timeMultislice computed tomography
Number of subjects
North American Renal Trials and Cooperative
StudiesNational Health and Nutrition Examination
SurveyNational Kidney Foundation
Aminoterminal cross-linking telopeptide ofbone collagen
Osteocalcin
Osteoprotegerin
Odds ratio
Peritoneal dialysis
Procollagen type I C propeptide
Procollagen type I N propeptide
Parathyroid hormone
Pulse wave velocity
Quantitative computed tomography
Quality of life
Quantitative ultrasonography
Receptor Activator for Nuclear Factor kB
LigandRandomized controlled trial
Recombinant human growth hormone
Radioimmunoassay
Renagel in New Dialysis
Relative risk
Standard deviation
Standard deviation score
Study to Evaluate Early Kidney Disease
Selective estrogen receptor modulator
Medical Outcomes Study Short Form 36
Total alkaline phosphatases
Turnover, mineralization, volume
Tartrate-resistant acid phosphatase
Tissue volume
Ultrasonography
Vitamin D receptor
World Health Organization

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Reference Keys
Stages of chronic kidney diseaseStage

Description

GFR (ml/min per 1.73 m2)

Treatment

1
2
3
4
5

Kidney damage with normal or m GFR
Kidney damage with mild k GFRModerate k GFRSevere k GFRKidney failure

X90
60–89
30–59
15–29
o15 (or dialysis)

1–5T if kidney transplant recipient
5D if dialysis (HD or PD)

CKD, chronic kidney disease; GFR, glomerular filtration rate; m, increased; k, decreased.

Conversion factors of metric units to SI units

Albumin
Bicarbonate
Calcitonin
Calcium, total
Calcium, ionized
Ca  P
Cholesterol, total
Creatinine
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Parathyroid hormone
Phosphorus (as inorganic phosphate)
Protein, total
Triglycerides
Urea nitrogen
Vitamin D, 1,25-dihydroxyvitamin D
Vitamin D, 25-hydroxyvitamin D

Metric Unit

Conversion Factor

SI Units

g/dl
mEq/l
pg/ml
mg/dl
mg/dl
mg2/dl2
mg/dl
mg/dl
mg/dl
mg/dl
pg/ml
mg/dl
g/dl
mg/dl
mg/dl
pg/ml
ng/ml

10
1
1
0.24950.25
0.08070.02586
88.4
0.02586
0.02586
0.106
0.3229100.01129
0.357
2.6
2.496

g/l
mmol/lng/lmmol/lmmol/lmmol2/l2mmol/lmmol/lmmol/lmmol/lpmol/lmmol/lg/l
mmol/lmmol/lpmol/lnmol/lNote: Metric units  conversion factor=SI units.

NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINERECOMMENDATIONSEach chapter contains recommendations that are graded as level 1 or level 2, and by the quality of the supporting evidence A, B, C, or
D as shown. In addition, the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

Implications
Grade

Patients

Clinicians

PolicyLevel 1
‘We recommend’

Most people in your situation
would want the recommended
course of action and only asmall proportion would not

Most patients should receive
the recommended courseof action

The recommendation can be
adopted as a policy in mostsituations

Level 2‘We suggest’

The majority of people in yoursituation would want therecommended course ofaction, but many would not

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

The recommendation is likely torequire debate and involvement of
stakeholders before policy canbe determined

Grade

Quality ofevidence

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

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Abstract
The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on
the management of chronic kidney disease–mineral and bone disorder (CKD–MBD) is intended
to assist the practitioner caring for adults and children with CKD stages 3–5, on chronic dialysis
therapy, or with a kidney transplant. The guideline contains recommendations on evaluationand treatment for abnormalities of CKD–MBD. This disease concept of CKD–MBD is based on aprior KDIGO consensus conference. Tests considered are those that relate to the detection andmonitoring of laboratory, bone, and cardiovascular abnormalities. Treatments considered areinterventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patientswith CKD stages 3–5D and 1–5T. The guideline development process followed an evidence based
approach and treatment recommendations are based on systematic reviews of relevant treatment
trials. Recommendations for testing used evidence based on diagnostic accuracy or risk
prediction and linked it indirectly with how this would be expected to achieve better outcomesfor patients through better detection, evaluation or treatment of disease. Critical appraisal of thequality of the evidence and the strength of recommendations followed the GRADE approach. An
ungraded statement was provided when a question did not lend itself to systematic literature
review. Limitations of the evidence, especially the lack of definitive clinical outcome trials, arediscussed and suggestions are provided for future research.
Keywords: Guideline; KDIGO; chronic kidney disease; dialysis; kidney transplantation; mineraland bone disorder; hyperphosphatemia; hyperparathyroidism

CITATION

In citing this document, the following format should be used: Kidney Disease: Improving Global
Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the
diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bonedisorder (CKD–MBD). Kidney International 2009; 76 (Suppl 113): S1–S130.

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foreword& 2009 KDIGO

Foreword
Kidney International (2009) 76 (Suppl 113), S1–S2; doi:10.1038/ki.2009.188

Clinical practice guidelines serve many purposes. First andforemost, guidelines help clinicians and other caregivers deal
with the exponential growth in medical literature. It is
impossible for most busy practitioners to read, understand,and apply a rapidly changing knowledge base to daily clinicalpractice. Guidelines can help fill this important need.
Guidelines can also help to expose gaps in our knowledge,
and thereby suggest areas where additional research isneeded. Only when evidence is sufficiently strong to conclude
that additional research is not needed should guidelines beused to mandate specific medical practices with, for example,
clinical performance measures.
Methods for developing and implementing clinicalpractice guidelines are still relatively new and many questions
remain unanswered. How should it be determined when aclinical practice guideline is needed? Who should make that
determination? Who should develop guidelines? Should
specialists develop guidelines for their practice, or should
unbiased, independent clinicians and scientists develop
guidelines for them? Is it possible to avoid conflicts ofinterest when most experts in a field conduct research thathas been funded by industry (often because no other funding
is available)? Should guidelines offer guidance when strong
evidence is lacking, should they point out what decisions
must be made in the absence of evidence or guidance, or
should they just ignore these questions altogether, that is,make no statements or recommendations?
Professional societies throughout the world have decided
that there is a need for developing clinical practice guidelines
for patients with chronic kidney disease (CKD). Along withthis perceived need has come the realization that developing
high-quality guidelines requires substantial resources andexpertise. An uncoordinated and parallel or repetitive
development of guidelines on the same topics reflects awaste of resources. In addition, there is a growing awarenessthat CKD is an international problem. Therefore, Kidney
Disease: Improving Global Outcomes (KDIGO) was established in 2003 as an independent, nonprofit foundation,
governed by an international board of directors, with its
stated mission to ‘improve the care and outcomes of kidneydisease patients worldwide through promoting coordination,
collaboration, and integration of initiatives to develop andimplement clinical practice guidelines.’
To date, KDIGO guideline initiatives have originated in
discussions among the KDIGO Executive Committee members and the KDIGO Board of Directors. In some instances,
topic areas have been vetted at KDIGO ‘Controversies
Conferences.’ If there is then a consensus that guideline
development should go forward, two Work Group chairs are
Kidney International (2009) 76 (Suppl 113), S1–S2

appointed, and with the help of these chairs, other WorkGroup members are selected. Efforts are made to include a
broad and diverse expertise in the Work Group, and to haveinternational representation. Work Groups then meet andwork with a trained, professional evidence review team todevelop evidence-based guidelines. These guidelines arereviewed by the KDIGO Board of Directors, and a revision
is then sent out for public comment. Only then is a final,
revised version developed and published.
The mineral and bone disorder of CKD (CKD–MBD) has
been an area of intense interest and controversy. In 2005,
KDIGO sponsored a controversies conference ‘Definition,
Evaluation and Classification of Renal Osteodystrophy.’ The
results of this conference were summarized in a position
statement that was published in 2006. The consensus
of the attendees at this conference was that a new setof international guideline on CKD–MBD was indeed
warranted.
Therefore, KDIGO invited Sharon Moe, MD, and TilmanDrüeke, MD, to co-chair a Work Group to develop a
CKD–MBD guideline. The Work Group was supported by the
Evidence Review Team at the Tufts Center for Kidney Disease
Guideline Development and Implementation at Tufts Medical Center, Boston, MA, with Katrin Uhlig, MD, MS, as the
Evidence Review Team’s Project Director. The Work Groupmet on five separate occasions over a period of 2 years,
reviewing evidence and drafting guideline recommendations.
The KDIGO Board reviewed a preliminary draft, andultimately the final document. Importantly, the guideline
was also subjected to public review and comment.
During the development of the CKD–MBD guideline,
KDIGO continued to develop a system for rating the strengthof recommendations and the overall quality of evidence
supporting those recommendations. A task force had been
formed that ultimately made recommendations to the
KDIGO Board. After extensive discussion and debate, theKDIGO Board of Directors in 2008 unanimously approved amodification of the Grading of Recommendations Assessment, Development, and Evaluation system. The system that
was adopted allows provision of guidance even if the evidencebase is weak, but makes the quality of the available evidencetransparent and explicit. It is described in detail in thepresent CKD–MBD guideline (Chapter 2).
The strength of each recommendation is rated 1 or 2, with
1 being a ‘We recommend y’ statement implying that mostpatients should receive the course of action, and 2 being a‘We suggest y’ statement implying that different choices will
be appropriate for different patients with the suggested
course of action being a reasonable choice. In addition, eachS1forewordstatement is assigned an overall grade for the quality ofevidence, A (high), B (moderate), C (low), or D (very low).
The grade of each recommendation depends on the quality ofthe evidence, and also on additional considerations.
A key issue is whether to include guideline statements on
topics that cannot be subjected to a systematic evidence
review. KDIGO has decided to meet this need by including
some statements that are not graded. Typically, ungradedstatements provide guidance that is based on common
sense, for example, reminders of the obvious and/or
recommendations that are not sufficiently specific enoughto allow the application of evidence. Examples include thefrequency of laboratory testing and the provision of routine
medical care.
The CKD–MBD guideline encompasses many aspects ofcare for which there is little or no evidence to inform
recommendations. Indeed, there are only three recommendations in the CKD–MBD guideline for which the overall
quality of evidence was graded ‘A,’ whereas 12 were graded‘B,’ 23 were graded ‘C,’ and 11 were graded ‘D.’ Although
there are reasons other than quality of evidence to make agrade 1 or 2 recommendation, in general, there is acorrelation between the quality of overall evidence and thestrength of the recommendation. Thus, there are 10
recommendations graded ‘1’ and 39 graded ‘2.’ There were
two recommendations graded ‘1A,’ five were ‘1B,’ three were
‘1C,’ and none were ‘1D.’ There was one graded ‘2A,’ seven
were ‘2B,’ 20 were ‘2C,’ and 11 were ‘2D.’ There were 12
statements that were not graded.
The grades should be taken seriously. The lack ofrecommendations that are graded ‘1A’ suggests that there
are few opportunities for developing clinical performanceS2

measures from this guideline. The preponderance of ‘2’
recommendations suggests that patient preferences andother circumstances should be strongly considered when
implementing most recommendations. The lack of ‘A’ and ‘B’grades of overall quality of evidence is a result of the lack ofpatient-centered outcomes as end points in the majority oftrials in this field, and thus suggests strongly that additional
research is needed in CKD–MBD. Indeed, the extensive
review that led to this guideline often exposed significant
gaps in our knowledge. The Work Group made a number of
specific recommendations for future research needs. This will
hopefully be of interest to future investigators and funding
agencies.
All of us working with KDIGO hope that the guidelines
developed by KDIGO will in some small way help to fulfill its
mission to improve the care and outcomes of patients withkidney disease. We understand that these guidelines are far
from perfect, but we are confident that they are an important
step in the right direction. A tremendous amount of work hasgone into the development of the KDIGO CKD–MBD
guideline. We sincerely thank Sharon Moe, MD, and TilmanDrüeke, MD, the Work Group chairs, for the tremendous
amount of time and effort that they put into this challenging,but important, guideline project. They did an outstanding
job. We also thank the Work Group members, the Evidence
Review Team, and the KDIGO staff for their tireless efforts.
Finally, we owe a special debt of gratitude to the founding
KDIGO Co-Chairs, Norbert Lameire, MD, and especially
Garabed Eknoyan, MD, for making all of this possible.
Kai-Uwe Eckardt, MD
Co-Chair, KDIGO

Bertram L Kasiske, MD
Co-Chair, KDIGO

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http://www.kidney-international.org& 2009 KDIGO

Chapter 1: Introduction and definition of CKD–MBD
and the development of the guideline statements
Kidney International (2009) 76 (Suppl 113), S3–S8; doi:10.1038/ki.2009.189

INTRODUCTION AND DEFINITION OF CKD–MBD

Chronic kidney disease (CKD) is an international publichealth problem affecting 5–10% of the world population.1 As
kidney function declines, there is a progressive deteriorationin mineral homeostasis, with a disruption of normal serum
and tissue concentrations of phosphorus and calcium, andchanges in circulating levels of hormones. These include
parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D),
1,25-dihydroxyvitamin D (1,25(OH)2D), and other vitamin
D metabolites, fibroblast growth factor-23 (FGF-23), andgrowth hormone. Beginning in CKD stage 3, the ability of thekidneys to appropriately excrete a phosphate load isdiminished, leading to hyperphosphatemia, elevated PTH,
and decreased 1,25(OH)2D with associated elevations in thelevels of FGF-23. The conversion of 25(OH)D to 1,25(OH)2D
is impaired, reducing intestinal calcium absorption andincreasing PTH. The kidney fails to respond adequately to
PTH, which normally promotes phosphaturia and calcium
reabsorption, or to FGF-23, which also enhances phosphateexcretion. In addition, there is evidence at the tissue level of adownregulation of vitamin D receptor and of resistance tothe actions of PTH. Therapy is generally focused oncorrecting biochemical and hormonal abnormalities in aneffort to limit their consequences.
The mineral and endocrine functions disrupted in CKD
are critically important in the regulation of both initial boneformation during growth (bone modeling) and bone
structure and function during adulthood (bone remodeling).
As a result, bone abnormalities are found almost universallyin patients with CKD requiring dialysis (stage 5D), and in the
majority of patients with CKD stages 3–5. More recently,
there has been an increasing concern of extraskeletal
calcification that may result from the deranged mineral andbone metabolism of CKD and from the therapies used tocorrect these abnormalities.
Numerous cohort studies have shown associations between
disorders of mineral metabolism and fractures, cardiovasculardisease, and mortality (see Chapter 3). These observational
studies have broadened the focus of CKD-related mineral andbone disorders (MBDs) to include cardiovascular disease(which is the leading cause of death in patients at all stages of
CKD). All three of these processes (abnormal mineralmetabolism, abnormal bone, and extraskeletal calcification)
are closely interrelated and together make a major contribution
to the morbidity and mortality of patients with CKD.
The traditional definition of renal osteodystrophy did notaccurately encompass this more diverse clinical spectrum,
Kidney International (2009) 76 (Suppl 113), S3–S8

based on serum biomarkers, noninvasive imaging, and boneabnormalities. The absence of a generally accepted definitionand diagnosis of renal osteodystrophy prompted Kidney
Disease: Improving Global Outcomes (KDIGO) to sponsor acontroversies conference, entitled ‘Definition, Evaluation,
and Classification of Renal Osteodystrophy,’ held on 15–17
September 2005 in Madrid, Spain. The principal conclusion
was that the term ‘CKD–Mineral and Bone Disorder(CKD–MBD)’ should be used to describe the broader clinicalsyndrome encompassing mineral, bone, and calcific cardiovascular abnormalities that develop as a complication of
CKD (Table 1). It was also recommended that the term ‘renal
osteodystrophy’ be restricted to describing the bone pathology associated with CKD. The evaluation and definitive
diagnosis of renal osteodystrophy require a bone biopsy,
using an expanded classification system that was developed at
the consensus conference based on parameters of boneturnover, mineralization, and volume (TMV).2
The KDIGO CKD–MBD Clinical Practice Guideline Document

KDIGO was established in 2003 as an independently incorporated nonprofit foundation governed by an internationalboard of directors with the stated mission to ‘improve thecare and outcomes of kidney disease patients worldwide
through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practiceguidelines’. The 2005 consensus conference sponsored by
KDIGO was seen as an initial step in raising awareness of theimportance of this disorder. The next stage was to develop aninternational clinical practice guideline that provides guidance on the management of this disorder.
CHALLENGES IN DEVELOPING THIS GUIDELINE

The development of this guideline proved challenging for anumber of reasons. First, the definition of CKD–MBD was
new and had not been applied to characterize populations inpublished clinical studies. Thus, each of the three components of CKD–MBD had to be addressed separately. Second,the complexity of the pathogenesis of CKD–MBD make it
difficult to completely differentiate a consequence of thedisease from a consequence of its treatment. Moreover,different stages of CKD are associated with different featuresand degrees of severity of CKD–MBD. Third, differences exist
throughout the world in nutrient intake, availability of
medications, and clinical practice. Fourth, many of the local
guidelines that already exist are based largely on expert
opinion rather than on strong evidence, whereas KDIGO
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Table 1 | KDIGO classification of CKD–MBD and renal osteodystrophy
Definition of CKD–MBD
A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:
K Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism.
K Abnormalities in bone turnover, mineralization, volume, linear growth, or strength.
K Vascular or other soft-tissue calcification.
Definition of renal osteodystrophy
K Renal osteodystrophy is an alteration of bone morphology in patients with CKD.
K It is one measure of the skeletal component of the systemic disorder of CKD–MBD that is quantifiable by histomorphometry of bone biopsy.
CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; KDIGO, Kidney Disease: Improving Global Outcomes; PTH, parathyroid hormone.
Adapted with permission from Moe et al.2

aims to base its guidelines on an extensive and systematic
analysis of the available evidence. Finally, this is a disorderunique to CKD patients, meaning that there are no randomized controlled trials in the non-CKD population thatcan be generalized to CKD patients, and only a few large
studies involving CKD patients.
COMPOSITION OF THE WORK GROUP AND PROCESSESA Work Group of international experts charged with
developing the present guideline was chosen by the WorkGroup Chairs, who in turn were chosen by the KDIGOExecutive Committee. The Work Group defined the questions and developed the study inclusion criterion a priori.
When it came to evaluating the impact of therapeutic
agents, the Work Group agreed a priori to evaluate only
randomized controlled trials of a 6-month duration with asample size of at least 50 patients. An exception was made forstudies involving children or using bone biopsy criterion as
an end point, in which smaller sample sizes were accepted
because of the inherent difficulties in conducting thesestudies.
Defining end points

End points were categorized into three levels for evaluation:
those of direct importance to patients (for example,
mortality, cardiovascular disease events, hospitalizations
fracture, and quality of life), intermediate end points (forexample, vascular calcification, bone mineral density (BMD),
and bone biopsy), and biochemical end points (for example,
serum calcium, phosphorus, alkaline phosphatases, and
PTH). Importantly, the Work Group acknowledged thatthese intermediate and biochemical end points are notvalidated surrogate end points for hard clinical events unlesssuch a connection had been made in a prospective treatment
trial (Figure 1).
CONTENT OF THE GUIDELINE

The guideline includes detailed evidence-based recommendations for the diagnosis and evaluation of the threecomponents of CKD–MBD—abnormal biochemistries, vascular calcification, and disorders of the bone (Chapter 3)—
and recommendations for the treatment of CKD–MBD(Chapter 4). In preparing Chapter 3, studies that assessedS4

the diagnosis, prevalence, natural history, and risk relationships of CKD–MBD were evaluated. Unfortunately, there was
frequently no high-quality evidence to support recommendations for specific diagnostic tests, thresholds for defining
disease, frequency of testing, or precisely which populations
to test. Multiple studies were reviewed that allowed thegeneration of overview tables listing a selection of pertinent
studies. For the treatment questions, systematic reviews
were undertaken of randomized controlled trials and thebodies of evidence were appraised following the Grades ofRecommendation Assessment, Development, and Evaluation
approach.
Public review version

The initial version of the CKD–MBD guideline was developedby using very rigorous standards for the quality of evidence
on which clinical practice recommendations should be based.
Thus, the Work Group limited its recommendations to areasthat it felt were supported by high- or moderate-quality
evidence rather than areas in which the recommendation was
based on low- or very-low-quality evidence and predominantly expert judgment. The Work Group was most sensitive
to the potential misuse and misapplication of recommendations, especially, as pertains to targets and treatment
recommendations. The Work Group believed strongly thatpatients deserved treatment recommendations based onhigh-quality evidence and physicians should not be forced
to adhere to targets and use treatments without soundevidence showing that benefits outweigh harm. The WorkGroup recognized that there had already been guidelines
developed by different entities throughout the world that did
not apply these criteria. In the public review draft, the WorkGroup provided discussions under ‘Frequently Asked
Questions’ at the end of each chapter to provide practicalguidance in areas of indeterminate evidence or to highlightareas of controversy.
The public review overwhelmingly agreed with theguideline recommendations. Interestingly, most reviewers
requested more specific guidance for the management of
CKD–MBD, even if predominantly based on expert judgment, whereas others found the public review draft to be arefreshingly honest appraisal of our current knowledge basein this field.
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chapter 1

Surrogate outcome Observational
trial
association1(phosphate binder A)

Clinical outcome trial
in same drug class2(phosphate binder B)

Clinical outcome trial
in different drug class3(phosphate binder C)

Intervention

Intervention

Intervention

Treatment withphosphate binder A

Treatment withphosphate binder B

Treatment withphosphate binder C

SurrogateoutcomeSurrogateoutcomeSurrogateoutcomeSurrogateoutcomeSlowing of calcification

Less calcification

Slowing of calcification

Slowing of calcification

ClinicaloutcomeClinicaloutcomeClinicaloutcomeLess CVD risk

Less CVD events

Less CVD events

Figure 1 | Interpreting a surrogate outcome trial. When interpreting the validity of a surrogate outcome trial, consider the following
questions: 1. Is there a strong, independent, consistent association between the surrogate outcome and the clinical outcome? This is anecessary but not, by itself, sufficient prerequisite. 2. Is there evidence from randomized trials in the same drug class that improvements inthe surrogate outcome have consistently led to improvements in the clinical outcome? 3. Is there evidence from randomized trials in otherdrug classes that improvement in the surrogate outcome has consistently led to improvement in the clinical outcome? Both 2 and 3 should
apply. This figure illustrates principles outlined in Users’ Guide for Surrogate Endpoint Trial3 and the legend is modified after this reference.
Phosphate binders, calcification, and CVD are chosen as an example. CVD, cardiovascular disease.

Responses to review process and modifications

In response to the public review of the CKD–MBD guideline,
and in the context of a changing field of guideline
development, grading systems, and the need for guidancein complex areas of CKD management, the KDIGO Board inits Vienna session in December 2008 refined its remit to
KDIGO Work Groups. It confirmed its charge to the WorkGroups to critically appraise the evidence, but encouraged
the Work Groups to issue practical guidance in areas ofindeterminate evidence. This practical guidance rests on a
combination of the evidentiary base that exists (biological,
clinical, and other) and the judgment of the Work Group
members, which is directed to ensuring ‘best care’ in thecurrent state of knowledge for the patients.
In the session of December 2008, the KDIGO Board also
revised the grading system for the strength of recommendations
to align it more closely with Grades of Recommendation
Assessment, Development, and Evaluation (GRADE), aninternational body committed to the harmonization of guideline grading across different speciality areas. The full descriptionof this grading system is found in Chapter 2, but can besummarized as follows: there are two levels for the strength ofrecommendation (level 1 or 2) and four levels for the quality ofoverall evidence supporting each recommendation (grade A, B,
C, or D) (see Chapter 2). In addition to graded recommendations, ungraded statements in areas in which guidance wasbased on common sense and/or the question was not specificenough to undertake a systematic evidence review are alsopresented. This grading system allows the Work Group to betransparent in its appraisal of the evidence, yet provides
practical guidance. The simplicity of the grading system also
permits the clinician, patient, and policy maker to understandthe statement in the context of the evidentiary base more clearly.
Kidney International (2009) 76 (Suppl 113), S3–S8

In response to feedback by the KDIGO Board of Directors,
the CKD–MBD Work Group reconvened in January 2009,
revised some recommendations, and formulated some additional recommendations or ungraded statements, integratingsuggestions for patient care previously expressed in the
Frequently Asked Questions section. Approval of the final
recommendations and rating of their strength and theunderlying quality of evidence were established by voting,with two votes taken, one including and one excluding
those Work Group members who declared potential
conflicts of interest. (Note that the financial relationships ofthe Work Group participants are listed at the end of thisdocument.) The two votes generally yielded a 490%
agreement on all the statements. When an overwhelming
agreement could not be reached in support of a recommendation, the issue was instead discussed in the rationale.
Finally, the Work Group made numerous recommendations for further research to improve the quality of evidence
for future recommendations in the field of CKD–MBD.
Summary and future directions

The wording has been carefully selected for each statement toensure clarity and consistency, and to minimize the possibility of misinterpretation. The grading system offers anadditional level of transparency regarding the strength ofrecommendation and quality of evidence at a glance. We
strongly encourage the users of the guideline to ensure theintegrity of the process by quoting the statements verbatim,
and by including the grades assigned after the statement
when quoting/reproducing or using the statements, as well as
by explaining the meaning of the code that combines an
Arabic number (to indicate that the recommendation is‘strong’ or ‘weak’) and an uppercase letter (to indicate
S5chapter 1that the quality of the evidence is ‘high’, ‘moderate’, ‘low’, or‘very low’).
We hope that as a reader and user, you appreciate the rigor of
the approach we have taken. More importantly, we strongly
urge the nephrology community to take up the challenge of
expanding the evidence base in line with our research
recommendations. Given the current state of knowledge, clinicalequipoise, and the need for accumulating data, we strongly
encourage clinicians to enroll patients into ongoing and futurestudies, to participate in the development of registries locally,nationally, and internationally, and to encourage fundingorganizations to support these efforts, so that, over time, manyof the current uncertainties can be resolved.

3.1.5. In patients with CKD stages 3–5D, we suggest that
individual values of serum calcium and phosphorus,
evaluated together, be used to guide clinical practicerather than the mathematical construct of calcium–phosphorus product (Ca  P) (2D).
3.1.6. In reports of laboratory tests for patients with CKD
stages 3–5D, we recommend that clinical laboratories
inform clinicians of the actual assay method in use andreport any change in methods, sample source (plasma
or serum), and handling specifications to facilitate theappropriate interpretation of biochemistry data (1B).

Chapter 3.2: Diagnosis of CKD–MBD: bone
SUMMARY OF RECOMMENDATIONS
Chapter 3.1: Diagnosis of CKD–MBD: biochemical
abnormalities

3.1.1. We recommend monitoring serum levels of calcium,
phosphorus, PTH, and alkaline phosphatase activity
beginning in CKD stage 3 (1C). In children, we suggest
such monitoring beginning in CKD stage 2 (2D).
3.1.2. In patients with CKD stages 3–5D, it is reasonable tobase the frequency of monitoring serum calcium,
phosphorus, and PTH on the presence and magnitude
of abnormalities, and the rate of progression of CKD(not graded).
Reasonable monitoring intervals would be:K
in CKD stage 3: for serum calcium and phosphorus, every 6–12 months; and for PTH, basedon baseline level and CKD progression.
K
In CKD stage 4: for serum calcium and phosphorus, every 3–6 months; and for PTH, every
6–12 months.
K
In CKD stage 5, including 5D: for serum calcium
and phosphorus, every 1–3 months; and for PTH,
every 3–6 months.
K
In CKD stages 4–5D: for alkaline phosphataseactivity, every 12 months, or more frequently inthe presence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for CKD–MBD,
or in whom biochemical abnormalities are identified,
it is reasonable to increase the frequency of measurements to monitor for trends and treatment efficacy
and side-effects (not graded).
3.1.3. In patients with CKD stages 3–5D, we suggest that
25(OH)D (calcidiol) levels might be measured, andrepeated testing determined by baseline values andtherapeutic interventions (2C). We suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for thegeneral population (2C).
3.1.4. In patients with CKD stages 3–5D, we recommend thattherapeutic decisions be based on trends rather thanon a single laboratory value, taking into account allavailable CKD–MBD assessments (1C).
S6

3.2.1. In patients with CKD stages 3–5D, it is reasonable toperform a bone biopsy in various settings including,but not limited to: unexplained fractures, persistentbone pain, unexplained hypercalcemia, unexplained
hypophosphatemia, possible aluminum toxicity, andprior to therapy with bisphosphonates in patients withCKD–MBD (not graded).
3.2.2. In patients with CKD stages 3–5D with evidence ofCKD–MBD, we suggest that BMD testing not be
performed routinely, because BMD does not predict
fracture risk as it does in the general population, and
BMD does not predict the type of renal osteodystrophy (2B).
3.2.3. In patients with CKD stages 3–5D, we suggest thatmeasurements of serum PTH or bone-specific alkaline
phosphatase can be used to evaluate bone diseasebecause markedly high or low values predict underlying bone turnover (2B).
3.2.4. In patients with CKD stages 3–5D, we suggest not
to routinely measure bone-derived turnover markers
of collagen synthesis (such as procollagen type I
C-terminal propeptide) and breakdown (such as type I
collagen cross-linked telopeptide, cross-laps, pyridinoline, or deoxypyridinoline) (2C).
3.2.5. We recommend that infants with CKD stages 2–5D
should have their length measured at least quarterly,
while children with CKD stages 2–5D should beassessed for linear growth at least annually (1B).

Chapter 3.3: Diagnosis of CKD–MBD: vascular calcification

3.3.1. In patients with CKD stages 3–5D, we suggest that alateral abdominal radiograph can be used to detect thepresence or absence of vascular calcification, and an
echocardiogram can be used to detect the presence orabsence of valvular calcification, as reasonable alternatives to computed tomography-based imaging (2C).
3.3.2. We suggest that patients with CKD stages 3–5D withknown vascular/valvular calcification be considered at
highest cardiovascular risk (2A). It is reasonable to use
this information to guide the management of
CKD–MBD (not graded).
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Chapter 4.1: Treatment of CKD–MBD targeted at loweringhigh serum phosphorus and maintaining serum calcium

4.1.1. In patients with CKD stages 3–5, we suggest maintaining serum phosphorus in the normal range (2C).
In patients with CKD stage 5D, we suggest lowering
elevated phosphorus levels toward the normal range(2C).
4.1.2. In patients with CKD stages 3–5D, we suggest
maintaining serum calcium in the normal range (2D).
4.1.3. In patients with CKD stage 5D, we suggest using a
dialysate calcium concentration between 1.25 and1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).
4.1.4. In patients with CKD stages 3–5 (2D) and 5D (2B), wesuggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable that the
choice of phosphate binder takes into account CKD
stage, presence of other components of CKD–MBD,
concomitant therapies, and side-effect profile (notgraded).
4.1.5. In patients with CKD stages 3–5D and hyperphosphatemia, we recommend restricting the dose of
calcium-based phosphate binders and/or the doseof calcitriol or vitamin D analog in the presence of
persistent or recurrent hypercalcemia (1B).
In patients with CKD stages 3–5D and hyperphosphatemia, we suggest restricting the dose of calciumbased phosphate binders in the presence of arterial
calcification (2C) and/or adynamic bone disease (2C)
and/or if serum PTH levels are persistently low (2C).
4.1.6. In patients with CKD stages 3–5D, we recommend
avoiding the long-term use of aluminum-containing
phosphate binders and, in patients with CKD stage 5D,
avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C).
4.1.7. In patients with CKD stages 3–5D, we suggest limiting
dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with othertreatments (2D).
4.1.8. In patients with CKD stage 5D, we suggest increasing
dialytic phosphate removal in the treatment of
persistent hyperphosphatemia (2C).

persistently above the upper limit of normal for theassay despite correction of modifiable factors, wesuggest treatment with calcitriol or vitamin D analogs(2C).
4.2.3. In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two tonine times the upper normal limit for the assay (2C).
We suggest that marked changes in PTH levels ineither direction within this range prompt an initiationor change in therapy to avoid progression to levels
outside of this range (2C).
4.2.4. In patients with CKD stage 5D and elevated or rising
PTH, we suggest calcitriol, or vitamin D analogs, or
calcimimetics, or a combination of calcimimetics
and calcitriol or vitamin D analogs be used to lower
PTH (2B).
K
It is reasonable that the initial drug selection for
the treatment of elevated PTH be based on serum
calcium and phosphorus levels and other aspects
of CKD–MBD (not graded).
K
It is reasonable that calcium or non-calcium-based
phosphate binder dosage be adjusted so thattreatments to control PTH do not compromiselevels of phosphorus and calcium (not graded).
K
We recommend that, in patients with hypercalcemia, calcitriol or another vitamin D sterol be
reduced or stopped (1B).
K
We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol
be reduced or stopped (2D).
K
We suggest that, in patients with hypocalcemia,
calcimimetics be reduced or stopped depending
on severity, concomitant medications, and clinicalsigns and symptoms (2D).
K
We suggest that, if the intact PTH levels fall below
two times the upper limit of normal for the assay,
calcitriol, vitamin D analogs, and/or calcimimetics
be reduced or stopped (2C).
4.2.5. In patients with CKD stages 3–5D with severe
hyperparathyroidism (HPT) who fail to respond to
medical/pharmacological therapy, we suggest parathyroidectomy (2B).

Chapter 4.2: Treatment of abnormal PTH levels in CKD–MBD

4.2.1. In patients with CKD stages 3–5 not on dialysis, theoptimal PTH level is not known. However, we suggestthat patients with levels of intact PTH (iPTH) above
the upper normal limit of the assay are first evaluatedfor hyperphosphatemia, hypocalcemia, and vitamin D
deficiency (2C).
It is reasonable to correct these abnormalities with any
or all of the following: reducing dietary phosphateintake and administering phosphate binders, calcium
supplements, and/or native vitamin D (not graded).
4.2.2. In patients with CKD stages 3–5 not on dialysis, inwhom serum PTH is progressively rising and remains
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Chapter 4.3: Treatment of bone with bisphosphonates, other
osteoporosis medications, and growth hormone

4.3.1. In patients with CKD stages 1–2 with osteoporosis
and/or high risk of fracture, as identified by World
Health Organization criteria, we recommend management as for the general population (1A).
4.3.2. In patients with CKD stage 3 with PTH in the normal
range and osteoporosis and/or high risk of fracture, as
identified by World Health Organization criteria, wesuggest treatment as for the general population (2B).
4.3.3. In patients with CKD stage 3 with biochemical
abnormalities of CKD–MBD and low BMD and/or
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chapter 1

fragility fractures, we suggest that treatment
choices take into account the magnitude and reversibility of the biochemical abnormalities and theprogression of CKD, with consideration of a bonebiopsy (2D).
4.3.4. In patients with CKD stages 4–5D having biochemical
abnormalities of CKD–MBD, and low BMD and/or
fragility fractures, we suggest additional investigation
with bone biopsy prior to therapy with antiresorptive
agents (2C).
4.3.5. In children and adolescents with CKD stages 2–5D andrelated height deficits, we recommend treatment withrecombinant human growth hormone when additional
growth is desired, after first addressing malnutrition
and biochemical abnormalities of CKD–MBD (1A).

Chapter 5: Evaluation and treatment of kidney transplantbone disease

5.1. In patients in the immediate post-kidney-transplant
period, we recommend measuring serum calcium andphosphorus at least weekly, until stable (1B).
5.2. In patients after the immediate post-kidney-transplant
period, it is reasonable to base the frequency ofmonitoring serum calcium, phosphorus, and PTH on
the presence and magnitude of abnormalities, and therate of progression of CKD (not graded).
Reasonable monitoring intervals would be:K
In CKD stages 1–3T, for serum calcium andphosphorus, every 6–12 months; and for PTH,
once, with subsequent intervals depending on
baseline level and CKD progression.
K
In CKD stage 4T, for serum calcium andphosphorus, every 3–6 months; and for PTH,
every 6–12 months.
K
In CKD stage 5T, for serum calcium andphosphorus, every 1–3 months; and for PTH,
every 3–6 months.
K
In CKD stages 3–5T, measurement of alkaline
phosphatases annually, or more frequently in thepresence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for CKD–MBD, orin whom biochemical abnormalities are identified, it isS8

reasonable to increase the frequency of measurements tomonitor for efficacy and side-effects (not graded).
It is reasonable to manage these abnormalities asfor patients with CKD stages 3–5 (not graded) (seeChapters 4.1 and 4.2).
5.3. In patients with CKD stages 1–5T, we suggest that
25(OH)D (calcidiol) levels might be measured, andrepeated testing determined by baseline values andinterventions (2C).
5.4. In patients with CKD stages 1–5T, we suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for the general
population (2C).
5.5. In patients with an estimated glomerular filtration rate
greater than approximately 30 ml/min per 1.73 m2, wesuggest measuring BMD in the first 3 months after
kidney transplant if they receive corticosteroids, or
have risk factors for osteoporosis as in the general
population (2D).
5.6. In patients in the first 12 months after kidney transplantwith an estimated glomerular filtration rate greater thanapproximately 30 ml/min per 1.73 m2 and low BMD, wesuggest that treatment with vitamin D, calcitriol/
alfacalcidol, or bisphosphonates be considered (2D).
K
We suggest that treatment choices be influenced by
the presence of CKD–MBD, as indicated byabnormal levels of calcium, phosphorus, PTH,
alkaline phosphatases, and 25(OH)D (2C).
K
It is reasonable to consider a bone biopsy to guidetreatment, specifically before the use of bisphosphonates due to the high incidence of adynamic
bone disease (not graded).
There are insufficient data to guide treatment after the
first 12 months.
5.7. In patients with CKD stages 4–5T, we suggest that BMD
testing not be performed routinely, because BMD does
not predict fracture risk as it does in the general
population and BMD does not predict the type ofkidney transplant bone disease (2B).
5.8. In patients with CKD stages 4–5T with known low
BMD, we suggest management as for patients with CKD
stages 4–5 not on dialysis, as detailed in Chapters 4.1
and 4.2 (2C).

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http://www.kidney-international.org& 2009 KDIGO

Chapter 2: Methodological approach
Kidney International (2009) 76 (Suppl 113), S9–S21; doi:10.1038/ki.2009.190

This clinical practice guideline contains a set of recommendations for the diagnosis, evaluation, prevention, andtreatment of chronic kidney disease–mineral and bonedisorder (CKD–MBD). The aim of this chapter is to describe
the process and methods by which the evidence review was
conducted and the recommendations and statements weredeveloped.
The members of the Work Group and of the Evidence
Review Team (ERT) collaborated closely in an iterative
process of question development, evidence review, andevaluation, culminating in the development of recommendations that have been graded according to an approachdeveloped by the GRADE (Grading of Recommendations
Assessment, Development and Evaluation) Working Group(Table 2).14 This grading scheme with two levels for thestrength of a recommendation was adopted by the KDIGO(Kidney Disease: Improving Global Outcomes) Board in
December 2008. The Board also approved the optionof an ungraded statement instead of a graded recommendation. This alternative allows a Work Group to issue
general advice on the basis of what it considers a reasonableapproach for clinical practice. We ask the users of thisguideline to include the grades with each recommendationand consider the implications of the respective grade(see detailed description below). The importance of the
explicit details provided in this chapter lies in thetransparency required of this process, and strives to instill
confidence in the reader about the methodological rigor of
the approach.

OVERVIEW OF THE PROCESSThe development of the guideline included concurrent
steps to:K appoint the Work Group and ERT, which were responsible for different aspects of the process;K confer to discuss process, methods, and results;
K develop and refine topics;
K define specific populations, interventions or predictors,
and outcomes of interest;
K create and standardize quality assessment methods;
K create data extraction forms;
K develop literature search strategies and run searches;
K screen abstracts and retrieve full articles on the basis ofpredetermined eligibility criteria;
K extract data and perform a critical appraisal of theliterature;
K grade the quality of the outcomes of each study;
K tabulate data from articles into summary tables;
Kidney International (2009) 76 (Suppl 113), S9–S21

grade the quality of evidence for each outcome and assess
the overall quality of bodies of evidence with the aid ofevidence profiles;
K write recommendations and supporting rationale;
K gradethe strength of the recommendations on
the basis of the quality of evidence and otherconsiderations;
K write the narrative; andK respond to peer review by the KDIGO Board of Directors
in December 2007 and again in early 2009, and public
review in 2008 before publication.
K

The KDIGO Co-Chairs appointed the Co-Chairs of theWork Group, who then assembled the Work Group to be
responsible for the development of the guideline. The WorkGroup consisted of domain experts, including individuals
with expertise in adult and pediatric nephrology, bonedisease, cardiology, and nutrition. The Tufts Center for
Kidney Disease Guideline Development and Implementation
at Tufts Medical Center in Boston, MA, USA wascontracted to provide expertise in guideline development
methodology and systematic evidence review. One WorkGroup member (Alison MacLeod) also served as aninternational methodology expert. KDIGO support
staff provided administrative assistance and facilitatedcommunication.
The ERT consisted of physicians/methodologists withexpertise in nephrology and internal medicine, andresearch associates and assistants. The ERT instructed andadvised Work Group members in all steps of literature
review, in critical literature appraisal, and in guideline
development. The Work Group and the ERT collaborated
closely throughout the project. The Work Group, KDIGO
Co-Chairs, ERT, liaisons, and KDIGO support staff
met five times for 2-day meetings in Europe and in North
America. The meetings included a formal instructionin the state of the art and science of guideline development,
and training in the necessary process steps, including thegrading of evidence and the strength of recommendations, aswell as in the formulation of recommendations. Meetings
also provided a forum for general topic discussion andconsensus development with regard to both evidence
appraisal and specific wording to be used in the recommendations.
The first task was to define the overall topics and goals forthe guideline. The Work Group Chairs drafted a preliminary
list of topics. The Work Group then identified key clinicalquestions. The Work Group and ERT further developed andrefined each topic specified for a systematic review ofS9chapter 2

Table 2 | Grading of recommendations
Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

CKD

Abnormal levels and bioactivity of laboratory parameters:
Laboratory
surrogateoutcomes

Bone and CVD
surrogateoutcomes

PTH

Calcium

Phosphorus

25(OH)D

1,25(OH)2D

High
NormalLow

High
NormalLow

High
NormalLow

NormalLow

NormalLow

Bone turnover: osteocalcin,bone-specific alkaline
phosphatase,c-terminal cross links
Bone mineralization /density :DXA, qCT, qUS
Bone turnover,mineralization& structure : histology

Vessel andvalve
disease:abnormalstructure orfunction

Bonedisease:abnormalstructure orfunction

Fractures, pain,
decreases in mobility,
strength or growth

Vessel stiffness : pulse wave
velocity, pulse pressure
Vessel / valve calcification :X-ray, US, CT, EBCT,MSCT, IMT
Vessel patency:
coronary angiogram, Doppler
duplex US

Cardiovasculardisease events

Clinicaloutcomes

Disability,
decreased QOL,
hospitalizations,death

Figure 2 | Evidence model. Arrows represent relationships and correspond to a question or questions of interest. Solid arrows represent
well-established associations. Dashed arrows represent associations that need to be established with greater certainty. The relationships
between laboratory abnormalities and organ diseases other than bone and cardiovascular diseases are not depicted here. In addition to thelaboratory abnormalities shown, there are other factors that are determinants of bone and cardiovascular health, which are not depicted.
CKD, chronic kidney disease; CVD, cardiovascular disease; DXA, dual-energy X-ray absorptiometry; EBCT, electron beam computed
tomography; IMT, intimal-medial thickness; MSCT, multislice computed tomography; PTH, parathyroid hormone; (q)CT, (quantitative)
computed tomography; (q)US, (quantitative) ultrasound; QOL, quality of life.

treatment questions, and summarized the literature for
nontreatment topics.
The ERT performed literature searches, and abstract andarticle screening. The ERT also coordinated the methodological and analytical process of the report. It definedand standardized the method for performing literaturesearches and data extraction, and for summarizing evidence.
Throughout the project, ERT offered suggestions for guideline development, and led discussions on systematic review,
literature searches, data extraction, assessment of quality and
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applicability of articles, evidence synthesis, and grading ofevidence.
The ERT provided suggestions and edits on thewording of recommendations, and on the use of specificgrades for the strength of the recommendations and thequality of evidence.
The Work Group took on the primary role of writing therecommendations and rationale, and retained final responsibility for the content of the recommendations and for theaccompanying narrative.
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chapter 2

DEVELOPMENT OF AN EVIDENCE MODEL

With the initiation of the evidence review process of the
KDIGO CKD–MBD guideline, the ERT developed anevidence model and refined it with the Work Group(Figure 2). This was carried out to conceptualize what is
known about epidemiological associations, hypothesizedcausal relationships, and the clinical importance of different
outcomes. Ultimately, this model served to clarify thequestions for evidence review and to weigh the evidence fordifferent outcomes. The model depicts laboratory abnormalities as a direct consequence of CKD and bone disease, andcardiovascular disease (CVD) as a consequence of laboratory
abnormalities as well as due to direct consequences of CKD.
Bone disease and CVD are defined as abnormalities instructure and function, which can be seen on imaging tests or
tissue examination. Bone disease and CVD are then shown asfactors that—together with other direct consequences of
CKD—lead to clinical outcomes, such as fractures, pain, anddisability on the one hand, and clinical CVD events on theother. All of these contribute to morbidity and mortality. The
arrows represent relationships and correspond to a questionor questions of interest. Solid arrows represent wellestablished associations. Dashed arrows represent associations that need to be established with greater certainty.
The model suggests a hierarchy with the clinical importanceof each condition increasing from top to bottom. The modelis incomplete in that it does not show other factors or disease
processes that may contribute to, or directly result in,abnormalities at every level. For example, bone abnormalities
in a patient with CKD may also be the result of aging
and osteoporosis, and abnormalities of CVD will be a resultof other traditional and nontraditional CVD risk factors.
Thus, the model does not reflect the complexity ofthe multifactorial processes that result in clinical disease,nor the uncertainty with regard to the relative and absoluterisk attributable to each risk factor. However, it does
highlight the complexity of the issues facing the WorkGroup, which evaluated the evidence to make recommendations for the care of patients, but found that the majority ofoutcomes from clinical trials in this field studied laboratory
outcomes.

(Table 3). For these topics, the ERT created forms to extract
relevant data from articles, and extracted information forbaseline data on populations, interventions, and study
design. Work Group experts extracted the results of included
articles and provided an assessment of the quality ofevidence. The ERT reviewed and revised data extraction forresults and quality grades performed by Work Group
members. In addition, the ERT tabulated studies in summary
tables, and assigned grades for the quality of evidence in
consultation with the Work Group.
For nontreatment questions, that is, questions related toprevalence, evaluation, natural history, and risk relationships,
the ERT conducted systematic searches, screened the yield forrelevance, and provided lists of citations to the Work Group(Table 4). The Work Group took primary responsibility forreviewing and summarizing this literature in a narrative
format.
On the basis of the list of topics, the Work Group and ERT
developed a list of specific research questions for which
systematic review would be performed. For each systematic
review topic, the Work Group Co-Chairs and the ERT
formulated well-defined systematic review research questions
using a well-established system.4 For each question, clear andexplicit criteria were agreed upon for the population,intervention or predictor, comparator, and outcomes ofinterest (Table 3). Each criterion was defined as comprehensively as possible. A list of outcomes of interest was generated
and the Work Group was advised to rank patient-centeredclinical outcomes (such as death or cardiovascular events) as
being more important than intermediate outcomes (such asbone mineral density) or laboratory outcomes (such as
phosphorus level), and not to include experimental biomarkers. In addition, study eligibility criteria were decided on thebasis of study design, minimal sample size, minimal followup duration, and year of publication, as indicated (Table 3).
The specific criteria used for each topic are explained below
in the description of review topics. In general, eligibility
criteria were determined on the basis of clinical value,
relevance to the guideline and clinical practice, a determination on whether a set of studies would affect recommendations or the quality of evidence, and practical issues such asavailable time and resources.

REFINEMENT OF TOPICS, QUESTIONS, AND DEVELOPMENT
OF MATERIALSLITERATURE SEARCH

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
2-day 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.
For questions of treatments, systematic reviews of theliterature, which met prespecified criteria, were undertaken

A MEDLINE search was carried out to capture all abstracts
and articles relevant to the topic of CKD and mineralmetabolism, bone disorders, and vascular/valvular calcification. This search encompassed original articles, systematic
reviews, and meta-analyses. The entire search was updated
through 17 December 2007; the search for randomized
controlled trials (RCTs) was updated through November
2008, and articles (including RCTs in press) identified by WorkGroup members were included through December 2008. The
starting point of the literature search was the reference lists
from the KDOQI (the Kidney Disease Outcomes Quality
Initiative) Bone Guidelines for Adults and Children,5,6 which

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chapter 2

Table 3 | Screening criteria for systematic review topics
Articles in summary tables
Intervention

Treatment targets

Phosphate binders

Vitamin D

Calcimimetics

Calcium
supplementation
Bisphosphonates,
calcitonin, estrogen,progesterone, SERMs,
intermittent PTH

Diet

PTx

Pediatric

Screening criteria
Treatment to different targets of phosphorus; or treatment todifferent targets of PTH
CKD stages 3–5, 5D, or 1–5T
RCTsa
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Any P Binder vs placebo/active control (except Ca vs placebo)b
CKD stages 3–5, 5D, or 1–5T
RCTsa
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Vitamin D, calcitriol, or vitamin D analogs vs placebo/active control
CKD stages 3–5, 5D, or 1–5T
RCTsa,c
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Calcimimetics vs placebo/active control
CKD stages 3–5, 5D, or 1–5T
RCTsa
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Calcium supplementation vs active or control medical treatment
CKD stages 3–5
RCTsa,c
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Treatment vs placebo/active control
CKD stages 3–5, 5D, or 1–5T
RCTsa,c
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Dietary phosphate restriction vs standard diet(must quantify phosphate intake)
CKD stages 3–5, 5D, or 1–5T
RCTsa
NX10 per arm
F/U X1 month for biochemical X6 months for bone outcomes
PTx vs medical management
CKD stages 3–5, 5D, or 1–5T
RCTsa
NX25 per arm (X10 per arm for bone biopsy)
F/U X6 months
Same interventions as for adults (see above)
CKD stages 3–5, 5D, or 1–5T
RCTsa
N as specified above for adult studies(Studies with NX5 are discussed in narrative)
F/U as specified above for adult studies

CKD stages 3–5

CKD stage 5D CKD stages 1–5T

0

0

0

1

19 reports of
11 studies

0

7

3

5

1

5 reportsof 3 studies

0

0

0

0

3 Bisphosphonates
1 Teriparatide

1
Raloxifene

3
Bisphosphonates

0

0

0

0

0

0

0

2

0

Outcomes of interest for all questions of interventions
Biochemical outcomes Ca, P, PTH, 25(OH)Dd, 1,25(OH)2Dd, ALP, b-ALP, Bicarbonate
Other surrogate
Bone histology, BMD
Vascular and valvular calcification imaging
outcomes
Measures of GFRPatient-centered
Mortality, cardiovascular and cerebrovascular events, hospitalization, QOL, kidney or kidney graft failure, fracture, PTx, pain,
outcomes
clinical AEs
For studies in pediatric populations: growth and development, including school performance
1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; AE, adverse event; ALP, alkaline phosphatases; b-ALP, bone-specific alkaline phosphatase; BMD, bonemineral density; Ca, calcium; CKD, chronic kidney disease; F/U, minimum duration of follow-up; GFR, glomerular filtration rate; N, number of subjects; P, phosphorus; PTH,
parathyroid hormone; PTx, parathyroidectomy; QOL, quality of life; RCT, randomized controlled trial; RR, relative risk; SERM, Selective Estrogen Receptor Modulators.
aObservational studies of treatment effects would have been included if they examined a clinical outcome and had a RR of 42.0 or o0.5.
b
The question of Ca-based P binders vs placebo was reviewed in the 2003 KDOQI (Kidney Disease Outcomes Quality Initiative) bone guidelines.5cLarge RCTs of interventions and comparisons of interest in the general population that reported results on more than 500 patients with CKD stages 3–5 were included.
d25(OH)D and 1,25(OH)2D included as outcomes of interest in patients not receiving vitamin D supplementation.

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chapter 2

Table 4 | Questions for topics not related to treatments
Topic

Natural history ofbone and CVD
abnormalities

Question

What is the natural history of bone abnormalities, and vascularand valvular calcification in CKD, after transplantation and after
PTx?

What is the association between calcium, phosphorus, CaXP,
and PTH, and (a) morbidity and mortality, (b) bone abnormalities(histology, DXA, qCT), and (c) vascular and valvular calcification?
How do these vary by CKD stage?

Evaluation ofbiochemicalmarkers

Evaluation ofbone

CKD stages 3–5D and T
Prospective, longitudinal
F/U X6 months
NX50
Predictors: bone biopsy; DXA; qCT; Vascular/Valvular calcificationby echo, EBCT, MSCT, qCT, carotid IMT, aortic X-ray
Outcomes: change in predictor over time, with or without
interim transplantation or PTx
CKD stages 3–5D and T
Prospective, longitudinal
F/U X6 months
NX100, for bone biopsy NX20
Predictors: serum calcium (ionized, correct, total), serum
phosphorus, CaXP, second, third generation or ratio PTH
Outcomes: mortality, bone outcomes, CVD outcomes

What is the association between additional biomarkers ofbone turnover, and (a) morbidity and mortality, (b) boneabnormalities, and (c) vascular and valvular calcification?

CKD stages 3–5D and T
Prospective, longitudinal
F/U X6 months
NX100, for bone biopsy NX20
Predictors: total alkaline phosphatase, bone-specific alkaline
phosphatase, TRAP, OC, OPG, C-terminal cross links
Outcomes: mortality, bone outcomes, CVD outcomes

What is the association between vitamin D (25(OH)D and1,25(OH)2D), and (a) morbidity and mortality, (b) boneabnormalities, and (c) vascular and valvular calcification in
individuals not treated with vitamin D replacement?

CKD stages 3–5D and T, naı̈ve to treatment with vitamin D
Prospective, longitudinal
F/U X6 months
NX100, for bone biopsy NX20
Predictors: vitamin D, 25(OH)D for all, 1,25 (OH)2 D for non-dialysis
Outcomes: mortality, bone outcomes, CVD outcomesCKD stages 3–5D and T
Prospective, longitudinal
F/U X1 year, X6 months for transplant
NX50, for bone biopsy NX20
Predictors: bone biopsy, DXA, DXA in combination withbiochemical markers, change in DXA over 1 year, bone imaging
by qCT (spine, wrist), qUS (heel)
Outcomes: mortality, bone outcomes, CVD outcomesCKD stages 3–5D and T, or subgroups with CKD in general
population studies
Prospective, longitudinal
F/U X6 months
NX50, for vascular histology NX20; for general population
studies NX800, at least 50 with CKD
Predictors: imaging techniques – X-ray, US, echo, EBCT, MSCT
(separately by site), fistulogram; Physiological measures – PWV,
PP, PWA, AIX, applanation tonometry
Outcomes: mortality, bone outcomes, CVD outcomesHow do bone biopsy and DXA, andother bone imaging tests, including plain radiographs, qCT,
and quantitative US predict (a) clinical outcomes and (b)surrogate outcomes for bone and CVD?

How do imaging tests and physiological/hemodynamicalmeasures of vascular stiffening or calcification predict (a) clinicaloutcomes and (b) surrogate outcomes for bone and CVD?

Evaluation ofvascular andvalvularcalcification

Screening criteria

What is the sensitivity and specificity of the imaging tests(plain radiograph, US, echo) for detecting vascular andvalvular calcification by EBCT or MSCT?

CKD stages 3–5D and T
Diagnostic test study, cross-sectional
NX50
Index test: vascular or valvular calcification – X-ray, US, echo,
EBCT, MSCT
Comparison test: vascular or valvular calcification (respectively)
by EBCT and MSCT
Outcomes: sensitivity, specificity, ROC curves

How do physiological/hemodynamical measures of vascular
stiffening (PWV, PP) correlate with vascular or valvular
calcifications by imaging tests?

CKD stages 3–5D and T
Cross-sectional correlations
NX50
Determinant: physiological measures PWV, PWA, AIX, PP,applanation tonometry
Outcome: vascular and valvular calcification measures by EBCT,MSCTKidney International (2009) 76 (Suppl 113), S9–S21

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chapter 2

Table 4 | Continued
Topic

Question

Screening criteria

What is the correlation between imaging tests of valvular
calcification and imaging tests of vascular calcification?

CKD stages 3–5D and T
Cross-sectional correlations
NX50
Determinant: valvular calcification by echo, EBCT
Outcome: vascular calcification by EBCT, MSCT

1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D,25-hydroxyvitamin D; AIX, augmentation index; CaXP, calcium-phosphorus product; CKD, chronic kidney disease; CVD,
cardiovascular disease; Dx, diagnostic; DXA, dual energy X-ray absorptiometry; EBCT, electron-beam computed tomography; echo, echocardiogram; F/U, follow-up; IMT,
intimal-media thickness; MSCT, multislice computed tomography; N, number of subjects; OC, osteocalcin; OPG, osteoprotegerin; PP, pulse pressure; PTH, parathyroid
hormone; PTx, parathyroidectomy; PWA, pulse wave analysis; PWV, pulse wave velocity; qCT, quantitative computed tomography; ROC, receiver operating characteristic;
TRAP, tartrate-resistant acid phosphatase; US, ultrasonography.

were based on a systematic search of MEDLINE (1966–31
December 2000). This was supplemented by a MEDLINE
search for relevant terms, including kidney, kidney disease,renal replacement therapy, bone, calcification, and specifictreatments. The search was limited to English language
publications since 1 January 2001 (Supplementary Table 1).
Additional pertinent articles were added from the reference
lists of relevant meta-analyses and systematic reviews.7 11During citation screening, journal articles reporting
original data were used. Editorials, letters, abstracts, unpublished reports, and articles published in non-peer-reviewed
journals were not included. The Work Group also decided to
exclude publications from journal supplements because of
potential differences in the process of how they get solicited,
selected, reviewed, and edited compared with peer-reviewed
publications in main journals. However, one article publishedin a supplement12 was used for the clarification of adverse
events (AEs) related to a study for which primary results werereported elsewhere.13 Selected review articles and key metaanalyses were retained from the searches for backgroundmaterial. An attempt was made to build on or use existing
Cochrane or other systematic reviews on relevant topics(Supplementary Table 2).
EXCLUSION/INCLUSION CRITERIA FOR ARTICLE SELECTION
FOR TREATMENT QUESTIONS

Search results were screened by members of the ERT for
relevance, using predefined eligibility criteria in the following
paragraphs. For questions related to treatment, the systematic
search aimed at identifying RCTs with sample sizes andfollow-up periods as described in (Table 3).
Restrictions by sample size and duration of follow-up werebased on methodological and clinical considerations. Generally, trials with fewer than 25 people per arm would be
unlikely to have sufficient power to find significant
differences in patient-centered outcomes in individuals with
CKD. This is especially true for dichotomous outcomes, suchas deaths, cardiovascular clinical events, or fractures.
However, for specific topics in which little data wereavailable, lower sample-size thresholds were used to provide
some information for descriptive purposes.
The minimum mean duration of follow-up of 6 months
was chosen on the basis of clinical reasoning, accounting for
S14

the hypothetical mechanisms of action. For treatments ofinterest, the proposed effects on patient-centered outcomesrequire long-term exposure and typically would not be
evident before several months of follow-up.
Any study not meeting the inclusion criteria for a detailed
review could nevertheless be cited in the narrative.
Interventions of interest are listed in (Table 3). For dietaryphosphate restriction, the literature search identified no RCTs
comparing assignment to different levels of dietary phosphateintake and outcomes of CKD–MBD. There were studies thatcompared assignment to different levels of protein restriction, and some of them quantified phosphate intake as aresult of the dietary protein intervention. The question of
dietary protein restriction, however, has been systematicallyreviewed previously.5 Thus, the Work Group chose anarrative format to review this topic. For the question of
how alternative dialysis schedules affect serum calcium andphosphorus and parathyroid hormone, the Work Groupchose to restrict itself to describing only the effects of RCTs,
comparing different dialysis schedules on these laboratory
outcomes. A complete review of all outcomes from thesestudies was deemed to be beyond the scope of this guideline.
Interventions of interest for children included all interventions reviewed in the adult population as well as growth
hormone.
The use of observational studies for questions on theefficacy of interventions is a topic of ongoing methodologicaldebate, given the many potential biases in the observational
studies of treatment effects. The decision on how toincorporate this type of evidence in the development of thisguideline was guided by concepts outlined in the GRADE
approach.14 Observational studies of treatment effects start
off as ‘low quality’. Their quality, however, can be upgraded ifthey show a consistent and independent, strong association.
For the strength of the association, GRADE defines two
arbitrary thresholds: one for a relative risk of 42 or o0.5 toupgrade the quality of evidence by one level, and the second
for a relative risk of 45 and o0.2 to upgrade by two levels.14
As the quality of observational studies can be downgraded formethodological limitations or indirectness, they can yieldhigh- or moderate-quality evidence only if they have noserious methodological limitations and show a strong or verystrong association for a patient-relevant clinical outcome.
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chapter 2Thus, the Work Group was asked to identify the observational studies of treatment effects that were relevant to theguideline questions and that showed a relative risk of 42.0 oro0.5 for patient-relevant clinical outcomes. This process for
identifying observational studies was used instead ofsystematic searches on the basis of the assumption thathigh-quality observational studies of patient-relevant clinicaloutcomes with large effect sizes would be well known toexperts in the field. No observational studies meeting thesecriteria were identified. Observational studies with smaller
estimates of treatment effects for clinical outcomes could be
discussed and referenced in the rationale. The ERT cautioned
against interpreting observational studies with smaller effectsizes for treatments as high-quality evidence, especially inareas in which RCTs are feasible.
EXCLUSION/INCLUSION CRITERIA FOR ARTICLE SELECTION
FOR NONTREATMENT QUESTIONS

For studies related to questions of diagnosis, prevalence, andnatural history (Table 4), the ERT completed a search in
March 2007, screened the literature yield, and screened
abstracts for relevance on the basis of the list of topics andquestions. The yield of abstracts was tabulated by citation,
population, number of individuals, follow-up time, study
design (cross-sectional or longitudinal, prospective or retrospective), and by predictors and outcomes of interest. Theselists were reviewed by the Work Group at the second WorkGroup meeting on 6 March 2007. The Work Group, in
subgroups, made decisions to eliminate studies for a numberof reasons (including publication prior to 1995, study size,
poor study design, or not contributing pertinent information). The Work Group, with the assistance of the ERT, madethe final decision for the inclusion or exclusion of all articles.
These articles were either reviewed in a narrative form by theWork Group members or were tabulated into overview tables
by the ERT and interpreted by the Work Group members.
Articles pertinent to these nontreatment questions could be
added by the Work Group members after the literature searchdate of March 2006. This hybrid process of a systematic
search and selection of pertinent articles by experts was used
to find information that was relevant and deemed importantby the Work Group for the specific questions. The final yieldof studies for these topics cannot be considered to becomprehensive and thus does not constitute a systematic
review. The articles were not data extracted or graded.
The following sections apply to studies included in thesystematic reviews of treatment questions.
LITERATURE YIELD FOR SYSTEMATIC REVIEW TOPICS

The literature searches up to December 2007 yielded 15,921
citations. For treatment topics, 92 articles were reviewed infull, of which 49 publications of 38 trials were extracted andincluded in summary tables. The remaining 43 articles were
rejected by the ERT after a review of the full text. Details of
the yield can be found in Table 5. An updated search for
RCTs was conducted in November 2008. It yielded an
extension study of an earlier RCT15, which was added as anannotation to the respective summary table. Two other RCTs
in press were added by the Work Group.
There were no RCTs comparing treatment to different
targets of phosphorus or parathyroid hormone levels. Thus,
observational studies were reviewed for data on risk
relationship to define extreme ranges of risk, rather thantreatment targets.
For the question related to parathyroidectomy vs medical
management for secondary or tertiary hyperparathyroidism, asearch was run for ‘parathyroidectomy’ and ‘kidney disease’
published from 2001 to 2008. These dates were used to capture
citations published after the final search for the 2003 KDOQI
bone guidelines. This search did not reveal any RCTs. Observational studies also did not meet criteria in terms of relativerisk or odds ratio; therefore, a list of potential observational
studies comparing these two modalities was provided to theWork Group as references for a narrative review.
For the question of calcium supplementation vs otheractive or control treatments for preventing the developmentof hyperparathyroidism, the search did not yield any RCTs
that met the inclusion criteria. This question had not been
specifically addressed in the 2003 KDOQI Bone Guidelines;
thus, the literature search with key words pertaining to‘kidney’, ‘calcium’, and ‘parathyroid hormone’ was not
limited to a specific publication year (i.e., 1950 onward).
For the question of bisphosphonates as a treatment for
CKD–MBD, one RCT was identified that evaluated the useof bisphosphonates for the prevention of glucocorticoidinduced bone loss in patients with glomerulonephritis.16

Table 5 | Literature search yield of primary articles for systematic review topics
Articles included in summary tablesa
Intervention
Phosphate binders
Vitamin D
Calcimimetics
Other bone treatmentsc

CKD stages 3–5
b

1
7
1
4

CKD stage 5D
b

19
3
5
1

CKD stages 1–5T0503Ca, calcium; CKD, chronic kidney disease; PTH, parathyroid hormone; SERM, Selective Estrogen Receptor Modulators.
aExcludes articles in tables other than summary tables; includes each report for a particular study.
b
Not all reports of the Treat to Goal Study will be included in the summary tables.
cBisphosphonates, calcitonin, estrogen, progesterone, SERMs, intermittent PTH, Ca supplement, growth hormone, and diet.

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As this study predominately included patients with CKD
stages 1–2, and therefore, by definition, did not evaluate
CKD–MBD, it was not included in the systematic review tableof this topic.
For treatment topics in the pediatric population, 30
articles were reviewed in full. A total of 11 RCTs wereidentified. If treatment studies in children met the same
criteria as those for adult studies, including sample size andfollow-up, they were added to adult summary tables.17,18
Otherwise, they were described in the corresponding sectionin the narrative. Separate evidence profiles for studies inchildren were not generated.
For the topic of growth hormone, a Cochrane metaanalysis update published in January 200719 was found toinclude all studies identified by the ERT through to 16 July
2007. In this meta-analysis, RCTs were identified from the
Cochrane Central Register of Controlled Trials, MEDLINE,EMBASE through to July 2005, as well as from article
reference lists, and through contact with local and international experts in the field. The screening criteria were similar
to the criteria established by the ERT and Work Group, butwere more inclusive in that studies with less than fiveindividuals per arm were included. The ERT and the WorkGroup decided that a summary of this meta-analysis wasadequate for the question of growth hormone treatment inchildren with CKD.
DATA EXTRACTION

The ERT designed data extraction forms to capture
information on various aspects of primary studies. Data
fields for all topics included study setting, patient demographics, eligibility criteria, stage of kidney disease, numbersof individuals randomized, study design, study-funding
source, description of mineral bone disorder parameters,
descriptions of interventions, description of outcomes,
statistical methods, results, quality of outcomes (as describedin the following paragraphs), limitations to generalizability,and free-text fields for comments and assessment of biases.
The ERT extracted the baseline data. The Work Groupextracted results, including AEs, graded the quality of thedata, and listed the limitations to generalizability. Trainingof the Work Group members to extract data from primary
articles occurred during Work Group meetings and bye-mail. The ERT reviewed and checked the data extraction
carried out by the Work Group. Discrepancies in gradingwere resolved with the relevant Work Group members
or with the entire Work Group during Work Group
meetings. The ERT subsequently condensed the informationfrom the data extraction forms. These condensed forms aswell as the original articles were posted on a shared web sitethat all Work Group members could access to review theevidence. Data extraction of bone histology outcomes was
carried out by two Work Group members specialized in thatfield (Susan Ott and Vanda Jorgetti). The ERT could not
proof the results or evidence grades for this outcome. The
method applied for assessing bone histomorphometry data
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by the Work Group experts is described in detail in thenext section.
DATA EXTRACTION AND METHODS FOR CATEGORIZINGBONE HISTOMORPHOMETRY DATAThe KDIGO position statement about renal osteodystrophy2
recommended that bone biopsy results should be reported ona unified classification system that includes parameters ofturnover, mineralization, and volume. The clinical trials withbone histology outcomes reviewed for this guideline,
however, were written before this statement, and the bone
histomorphometry results were presented in a wide variety ofways. After reviewing the studies that met the inclusion
criteria, two Work Group members chose a method that
could be applied to most of the reported data. Most reports
presented enough information to determine whether patients
had changed from one category to another; sometimes thisrequired extrapolation from figures or graphs. The categories
are defined in Chapter 3.1, page S34.
The Work Group defined an improvement in turnover as achange from any category to normal, from adynamic or
osteomalacia to mild or mixed, from osteitis fibrosa to mild,or from mixed to mild. Worsening bone turnover was defined
as a change from normal to any category, from any category
to adynamic or osteomalacia, from adynamic or osteomalacia
to osteitis fibrosa, or from mild to osteitis fibrosa. Thesechanges are shown in Figure 3, left side.
The average change in the bone formation rate could not
be used to determine improvement, because a patient with ahigh bone-formation rate improves when it decreases,
whereas a patient with adynamic bone disease must increasebone-formation rate to show improvement. A categoricalapproach, however, is also not ideal, because a patient could
have substantial improvement but remain within a category,whereas another patient with a baseline close to the threshold
between categories may change into another category with asmall change. Another problem is variable definitions of themixed category. A better method would be to report themean change toward normal.20,21 Most of the reports,
however, did not provide enough detail to analyze biopsies
in this manner.
With some treatments, an overall index of improvement
does not convey all the important information, because theresults have to be interpreted in the context of the original
disease. For example, a medicine that decreased boneturnover could be beneficial if the original disease wasosteitis fibrosa, but harmful if the patient had adynamic
disease.
Assessing mineralization was more straightforward. An
increase in mean osteoid volume, osteoid thickness or
mineralization lag time indicates a worsening of mineralization. An increase indicates a worsening of mineralization.
Using categories, an improvement would be a change frommixed or osteomalacia to normal, adynamic, or osteitis
fibrosa; worsening would be a change to the osteomalacia or
mixed categories (Figure 3, right side).
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chapter 2

Turnover

Mineralization

InitialNormalFinal
NormalInitialNormalFinal
Normal

Mild

Mild

Mild

Mild

Mixed

Mixed

Mixed

Mixed

O. Fib.

O. Fib.

O. Fib.

O. Fib.

OM

OM

OM

OM

Ady.

Ady.

Ady.

Ady.

InitialFinal

InitialFinal

NormalNormalNormalNormal

Mild

Mild

Mild

Mild

Mixed

Mixed

Mixed

Mixed

O. Fib.

O. Fib.

O. Fib.

O. Fib.

OM

OM

OM

OM

Ady.

Ady.

Improved

Ady.

Improved

Worsened

Ady.

Worsened

Figure 3 | Parameters of bone turnover, mineralization, andvolume. Ady, adynamic bone disease; O. Fib, osteitis fibrosa;
OM, osteomalacia.

For bone volume, an increase is usually an indication of
improvement. Exceptions would be when patients develop
osteosclerosis, but this is unusual. Most reports did not takebone volume into account. The studies also did not usuallyreport differences in cortical vs cancellous bone, or reportother structural parameters.
SUMMARY TABLES

Summary tables were developed to tabulate data from studies
pertinent for each treatment question. Each summary
contains three sections: a ‘Baseline Characteristics Table’,an ‘Intervention and Results Table’, and an ‘Adverse Events
Table’. Baseline Characteristics Tables include a descriptionof the study size, the study population at baseline,
demographics, country of residence, duration on dialysis,
calcium concentration in the dialysis bath, diabetes status,
previous use of aluminum-based phosphate binders, andfindings on baseline MBD laboratory, bone, and calcification
tests. Intervention and Results Tables describe the studies
according to four dimensions: study size, follow-up
duration, results, and methodological quality. Adverse Events
Tables include study size, type of AEs, numbers of patients
who discontinued treatment because of AEs, number ofpatients who died, and those who changed modality(including those who received a kidney transplant). The
Work Group specified AEs of interest for each particularintervention (for example, hypercalcemia). Work Group
members proofed all summary table data and quality
assessments.
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To provide consistency throughout the summary tables,
data were sometimes converted or estimated. When followup times were reported in weeks, the results were converted
into months by estimating 1 month as 4 weeks. Conventional
units were converted into SI units, with the exception ofcreatinine clearance.
EVIDENCE PROFILES

Evidence profiles were constructed by the ERT to record
decisions with regard to the estimates of effect, quality ofevidence for each outcome, and quality of overall evidence
across all outcomes. These profiles serve to make transparent
to the reader the thinking process of the Work Group insystematically combining evidence and judgments. Eachevidence profile was reviewed by Work Group experts.
Decisions were taken on the basis of data and results from theprimary studies listed in corresponding summary tables, andon judgments of the Work Group. Judgments with regard to
the quality, consistency, and directness of evidence were often
complex, as were judgments regarding the importance of an
outcome or the net effect and quality of the overall quality ofevidence across all outcomes. The evidence profiles provided
a structured approach to grading, rather than a rigorous
method of quantitatively summing up grades. When the
body of evidence for a particular question or for acomparison of interest consisted of only one study, thesummary table provided the final level of synthesis and an
evidence profile was not generated.
EVIDENCE MATRICES

Evidence matrices were generated for each systematic review
for a treatment question. The matrix shows the quantity andquality of evidence reviewed for each outcome of interest.
Each study retained in the systematic review is tabulated withthe description of its authors, year of publication, sample
size, mean duration of follow-up, and the quality grade forthe respective outcome. Conceptually, information on the left
upper corner shows high-quality evidence for outcomes ofhigh importance. Information on the right lower cornershows low-quality evidence for outcomes of lesser importance. Evidence for AEs was not graded for quality, but stilltabulated in one column in the matrices.
An evidence matrix was not generated for a systematic
review topic when the yield for the topic was only one
study that met inclusion criteria, as the entire study issummarized in the summary table that contains all relevant
information.
An overall evidence matrix was generated to show theyield of all studies included in summary tables for all
interventions of interest. This overall evidence matrix showsthe entire yield for all treatment questions, both in terms ofoutcomes reviewed and the quality of evidence for eachoutcome in each study. Single studies that did not warrant an
individual evidence matrix (that is, they were the only studies
for a specific intervention question) were still included in theoverall evidence matrix.
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chapter 2

Table 6 | Grading of study quality for an outcome
A: Good quality: low risk of bias and no obvious reporting errors;complete reporting of data. Must be prospective. If study of intervention:must be RCT.
B: Fair quality: Moderate risk of bias, but problems with study/paper are
unlikely to cause major bias. If study of intervention: must be prospective.
C: Poor quality: High risk of bias or cannot exclude possible significant
biases. Poor methods, incomplete data, reporting errors. Prospective or
retrospective.
RCT, randomized controlled trial.

GRADING OF QUALITY OF EVIDENCE FOR OUTCOMES IN
INDIVIDUAL STUDIES
Study size and duration

The study (sample) size is used as a measure of the weight ofevidence. In general, large studies provide more precise
estimates. Similarly, longer-duration studies may be of better
quality and more applicable, depending on other factors.

to support a particular recommendation (GRADE Working
Group, 2008).24 Following GRADE, the quality of a bodyof evidence pertaining to a particular outcome of interest
is initially categorized on the basis of study design. For
questions of interventions, the initial quality grade is‘High’ if the body of evidence consists of RCTs, or ‘Low’
if it consists of observational studies, or ‘Very Low’ if itconsists of studies of other study designs. For questionsof interventions, the Work Group graded only RCTs. The
grade for the quality of evidence for each intervention/
outcome pair was then decreased if there were serious
limitations to the methodological quality of the aggregateof studies; if there were important inconsistencies in the
results across studies; if there was uncertainty about thedirectness of evidence including a limited applicability offindings to the population of interest; if the data were
imprecise or sparse; or if there was thought to be a highlikelihood of bias. The final grade for the quality of evidence
for an intervention/outcome pair could be one of thefollowing four grades: ‘High’, ‘Moderate’, ‘Low’, or ‘Very
Low’ (Table 7).

Methodological quality

Methodological quality (or internal validity) refers to thedesign, conduct, and reporting of the outcomes of a clinicalstudy. A three-level classification of study quality waspreviously devised (Table 6). Given the potential differencesin the quality of a study for its primary and other outcomes,
study quality was assessed for each outcome.
The evaluation of questions of interventions included
RCTs. The grading of the outcomes of these studies included aconsideration of the methods (that is, duration, type ofblinding, number and reasons for dropouts, etc.), population(that is, does the population studied introduce bias?),outcome definition/measurement, and thoroughness/precision of reporting and statistical methods (that is, was the study
sufficiently powered and were the statistical methods valid?).
Results

The type of results used from a study was determined by thestudy design, the purpose of the study, and the Work Group’s
question(s) of interest. Decisions were based on screening
criteria and outcomes of interest (Table 3).
Approach to grading

A structured approach, modeled after GRADE,14,22,23,27 andfacilitated by the use of Evidence Profiles and Evidence
Matrices, was used to determine a grade that described thequality of the overall evidence and a grade for the strength ofa recommendation. For each topic, the discussion on gradingof the quality of evidence was led by the ERT, and thediscussion regarding the strength of the recommendations
was led by the Work Group Chairs.
Grading the quality of evidence for each outcome

The ‘quality of a body of evidence’ refers to the extent towhich our confidence in an estimate of effect is sufficient
S18

Grading the overall quality of evidence

The quality of the overall body of evidence was thendetermined on the basis of the quality grades for all
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 were ‘A’, ‘B’, ‘C’, or ‘D’ (Table 8).14 This grade foroverall evidence is indicated behind the strength ofrecommendations. The summary of the overall quality ofevidence across all outcomes proved to be very complex.
Thus, as an interim step, the evidence profiles recorded thequality of evidence for each of three outcome categories:
patient-centered outcomes, other bone and vascular surrogate outcomes, and laboratory outcomes. The overall qualityof evidence was determined by the Work Group and is basedon an overall assessment of the evidence. It reflects that, formost interventions and tests, there is no high-quality
evidence for net benefit in terms of patient-centeredoutcomes.
Assessment of the net health benefit across all important
clinical outcomes

Net health benefit was determined on the basis of
the anticipated balance of benefits and harm acrossall clinically important outcomes. The assessment of net
medical benefit was affected by the judgment of the WorkGroup and ERT. The assessment of net health benefit
is summarized in one of the following statements: (i) Thereis net benefit from intervention when benefits outweighharm; (ii) there is no net benefit; (iii) there are tradeoffs
between benefits and harm when harm does not altogether
offset benefits, but requires consideration in decision
making; or (iv) uncertainty remains regarding net benefit(Table 9).
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Table 7 | GRADE system for grading quality of evidence for an outcome
Step 1: Starting grade for
quality of evidence basedon study design

Step 2: Reduce grade

Step 3: Raise gradeHigh for randomized trial

Study quality–1 level if serious limitations–2 levels if very serious limitations

Strength of association+1 level is strong,b no plausible confounders,consistent and direct evidence

Moderate for
quasi-randomized trial

Final grade for
quality of evidence
for an outcomea

High

c

+2 levels if very strong, no major
threats to validity and direct evidence

Consistency–1 level if important inconsistency

Low for observational study

Directness–1 level if some uncertainty
Very Low for any other evidence–2 levels if major uncertainty

Other+1 level if evidence of a dose–response
gradient

Other–1 level if sparse or imprecise data
–1 level if high probability of reporting bias

Moderate
Low
Very low+1 level if all residual plausible confounders
would have reduced the observed effect

GRADE, Grades of Recommendations Assessment, Development, and Evaluation; RR, relative risk.
a
The highest possible grade is ‘high’ and the lowest possible grade is ‘very low’.
bStrong evidence of association is defined as ‘significant RR of 42 (o0.5)’ based on consistent evidence from two or more observational studies, with no plausible
confounders.
cVery strong evidence of association is defined as ‘significant RR of 45 (o0.2)’ based on direct evidence with no major threats to validity.
Modified with permission from Uhlig (2006).22 and Atkins (2004)14

Table 8 | Final grade for overall quality of evidence23

Table 9 | Balance of benefits and harm23

Quality ofGrade evidence

When there was evidence to determine the balance of medical benefits andharm of an intervention to a patient, conclusions were categorized as follows:

A

High

B

Moderate

C

Low

D

Very low

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

GRADING THE STRENGTH OF THE RECOMMENDATIONSThe ‘strength of a recommendation’ indicates the extent towhich one can be confident that adherence to therecommendation will do more good than harm. The strengthof a recommendation is graded as Level 1 or Level 2.23
Table 10 shows the nomenclature for grading the strengthof a recommendation and the implications of each level forpatients, clinicians, and policy makers. Recommendations
can be for or against doing something.
Table 11 shows that the strength of a recommendation isdetermined not just by the quality of evidence, but also byother, often complex judgments regarding the size of the net
medical benefit, values and preferences, and costs. Formal
decision analyses, including cost analysis, were notconducted. Where there is doubt regarding the balance ofbenefits and harm with respect to patient centered outcomes,
or when the quality of evidence is too low to assess balance,
the recommendation is necessarily a ‘level 2’.
UNGRADED STATEMENTS

The Work Group felt that having a category that allows it
to issue general advice would be useful. For this purpose,
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Net benefits
Trade-offs
Uncertain trade-offs
No net benefits

The intervention clearly does more good thanharm.
There are important trade-offs between thebenefits and harm.
It is not clear whether the intervention does moregood than harm.
The intervention clearly does not do more goodthan harm.

the Work Group chose the category of a recommendationthat was not graded. Typically, this type of ungradedstatement met the following criteria: it provides guidanceon the basis of common sense; it provides reminders of theobvious; and it is not sufficiently specific enough to allow anapplication of evidence to the issue, and therefore it is notbased on a systematic evidence review. Common examples
include recommendations regarding the frequency of testing,referral to specialists, and routine medical care. The ERT andWork Group strove to minimize the use of ungradedrecommendations.
FORMULATION AND VETTING OF RECOMMENDATIONSThe selection of specific wording for each of the statements
was a time-intensive process. In addition to striving forthe recommendations to be clear and actionable, thewording also considered grammar, proper English-wordusage, and the ability of concepts to be translated accurately
into other languages. A final wording of recommendations
and the corresponding grades for the strength of therecommendations and the quality of evidence were voted
upon by the Work Group, and required a majority to
S19chapter 2

Table 10 | Implications of the strength of a recommendation
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 the recommended
course of action.

The recommendation can be adopted
as a policy in most situations.

Level 2‘We suggest’

The majority of people in yoursituation would want therecommended course of action,
but many would not.

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

The recommendation is likely to requiredebate and involvement of stakeholders
before policy can be determined.

Table 11 | Determinants of the strength of a recommendation23
FactorComment

Balance between desirable
and undesirable 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 the more uncertainty in values and preferences,the more likely a weak 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)

be accepted. The process of peer review was a serious
undertaking. It included an internal review by the KDIGO
Board of Directors and an external review by the public toensure widespread input from numerous stakeholders,
including patients, experts, and industry and nationalorganizations, and then another internal review by the
KDIGO Board of Directors.

would be the task of a local ‘guideline adoption group’ toreview and reconcile the recommendations of the KDIGO
guideline with those of other guidelines pertinent andapplicable to its country or context. Thus, this KDIGO
guideline does not contain a comparison of how therecommendations from this KDIGO Work Group differ
from those of other existing guidelines.

FORMAT FOR CHAPTERS

LIMITATIONS OF APPROACH

Each chapter contains one or more specific ‘recommendations’. Within each recommendation, the strength of therecommendation is indicated as level 1 or level 2, and thequality of the overall supporting evidence is shown as A, B, C,
or D. The recommendations are followed by a section that
describes the chain of logic, which consists of declarative
sentences summarizing the key points of the evidence base andthe judgments supporting the recommendation. This isfollowed by a narrative that provides the supporting rationale
and includes data tables where appropriate. In relevant
sections, research recommendations suggest future research
to resolve current uncertainties.

Although the literature searches were intended to becomprehensive, they were not exhaustive. MEDLINE
was the only database searched, and the search was limited
to English language publications. Hand searches ofjournals were not performed, and review articles andtextbook chapters were not systematically searched. However,important studies known to domain experts, which were
missed by the electronic literature searches, were added to theretrieved articles and reviewed by the Work Group.
Nonrandomized studies were not systematically reviewed.
The majority of the ERT and Work Group resources weredevoted to a detailed review of randomized trials, as thesewere deemed to most likely provide data to support
treatment recommendations with higher quality evidence.
Where randomized trials are lacking, it was deemed to be
sufficiently unlikely that studies previously unknown to theWork Group would result in higher quality evidence.
Evidence for patient-relevant clinical outcomes was low.
Usually, low-quality evidence required a substantial use ofexpert judgment in deriving a recommendation from theevidence reviewed.

COMPARISON WITH OTHER GUIDELINES

The reconciliation of a guideline with other guidelines
reduces potential confusion related to variability or discrepancies in guideline recommendations. At the beginningof the guideline process, the ERT searched for other current
guidelines on CKD–MBD and compiled them by topic. This
information was submitted to the Work Group to highlight
those topics that other guidelines had addressed and what
recommendations had been issued. However, given the global
nature of the KDIGO guidelines, it was felt that judging how
any guideline might be applicable in a particular setting
would require a process of ‘guideline adoption’, and that it
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SUMMARY OF THE PROCESS

Several tools and checklists have been developed to assess thequality of the guideline development process and to enhance
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chapter 2

the quality of guideline reporting. These include theAppraisal of Guidelines for Research and Evaluation(AGREE) criteria25 and the Conference on GuidelineStandardization (COGS) checklist.26 Supplementary Table 3
shows the key features of the guideline development processaccording to the COGS checklist.

Kidney International (2009) 76 (Suppl 113), S9–S21

SUPPLEMENTARY MATERIAL

Supplementary Table 1. Literature search strategy.
Supplementary Table 2. Use of other relevant systematic reviews andmeta-analyses.
Supplementary Table 3. Key features of the guideline.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki

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chapter 3.1

http://www.kidney-international.org& 2009 KDIGO

Chapter 3.1: Diagnosis of CKD–MBD: biochemical
abnormalities
Kidney International (2009) 76 (Suppl 113), S22–S49. doi:10.1038/ki.2009.191

Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

3.1.3

Biochemical abnormalities are common in chronic kidneydisease (CKD) and are the primary indicators by which thediagnosis and management of CKD–mineral and bonedisorder (CKD–MBD) is made. The two other components
of CKD–MBD (bone abnormalities and vascular calcification)
are discussed in Chapters 3.2 and 3.3.
3.1.4
RECOMMENDATIONS

3.1.1

We recommend monitoring serum levels of calcium, phosphorus, PTH, and alkaline phosphataseactivity beginning in CKD stage 3 (1C). In children,
we suggest such monitoring beginning in CKD
stage 2 (2D).
3.1.2 In patients with CKD stages 3–5D, it is reasonable
to base the frequency of monitoring serum calcium,
phosphorus, and PTH on the presence and magnitude of abnormalities, and the rate of progressionof CKD (not graded).
Reasonable monitoring intervals would be:
K In CKD stage 3: for serum calcium and phosphorus, every 6–12 months; and for PTH, basedon baseline level and CKD progression.
K In CKD stage 4: for serum calcium and phosphorus, every 3–6 months; and for PTH, every
6–12 months.
K In CKD stages 5, including 5D: for serum calcium
and phosphorus, every 1–3 months; and for PTH,
every 3–6 months.
K In CKD stages 4–5D: for alkaline phosphataseactivity, every 12 months, or more frequently inthe presence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for
CKD–MBD, or in whom biochemical abnormalities
are identified, it is reasonable to increase thefrequency of measurements to monitor for trends
and treatment efficacy and side-effects (not graded).
S22

3.1.5

3.1.6

In patients with CKD stages 3–5D, we suggestthat 25(OH)D (calcidiol) levels might be measured,and repeated testing determined by baseline values
and therapeutic interventions (2C). We suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for thegeneral population (2C).
In patients with CKD stages 3–5D, we recommendthat therapeutic decisions be based on trends rather
than on a single laboratory value, taking into
account all available CKD–MBD assessments (1C).
In patients with CKD stages 3–5D, we suggest that
individual values of serum calcium and phosphorus, evaluated together, be used to guide clinicalpractice rather than the mathematical construct of
calcium–phosphorus product (Ca  P) (2D).
In reports of laboratory tests for patients with CKD
stages 3–5D, we recommend that clinical laboratories inform clinicians of the actual assay method
in use and report any change in methods, sample
source (plasma or serum), and handling specifications to facilitate the appropriate interpretation ofbiochemistry data (1B).

Summary of rationale for recommendations

As the diagnosis of CKD–MBD depends on the measurement of laboratory and other variables, it is important toprovide a guide to clinicians regarding when to commence
measurement of those variables. Although changes in thebiochemical abnormalities of CKD–MBD may begin in
CKD stage 3, the rate of change and severity ofabnormalities are highly variable among patients.
K Thus,the recommendations and suggestions above
indicate that assessment of CKD–MBD should begin atstage 3, but the frequency of assessment needs to take into
account the identified abnormalities, the severity andduration of the abnormalities in the context of the degree

K

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chapter 3.1

and rate of change of glomerular filtration rate (GFR), andthe use of concomitant medications. Further testing andshorter time intervals would be dependent on the presence
and severity of biochemical abnormalities.
K Furthermore, the interpretation of these biochemical andhormonal values requires an understanding of assay type
and precision, interassay variability, blood sample handling, and normal postprandial, diurnal, and seasonalvariations in individual parameters.
K The serum phosphorus fluctuates more than the serum
calcium. As the mathematical construct of the calcium  phosphorus product (Ca  P) is largely driven by serum
phosphorus and generally does not provide any additional
information beyond that which is provided by individual
measures, it is of limited use in clinical practice.
BACKGROUND

The laboratory diagnosis of CKD–MBD includes the use oflaboratory testing of serum PTH, calcium (ideally ionized
calcium but most frequently total calcium, possibly corrected
for albumin), and phosphorus. In some situations, measuringserum ALPs (total or bone specific) and bicarbonate may be
helpful. It is important to acknowledge that the biochemicaland hormonal assays used to diagnose, treat, and monitor
CKD–MBD have limitations and, therefore, the interpretationof these laboratory values requires an understanding of assay
type and precision, interassay variability, blood sample
handling, and normal postprandial, diurnal, and seasonalvariations. Derivations of these assays compound the
problems with precision and accuracy. It is important forthe practicing clinician to appreciate the potential variations
in laboratory test results to avoid overemphasizing small or
inconsistent changes in clinical decision making. Educating
patients and primary-care physicians as to these subtleties isalso important to ensure the appropriate interpretation by nonnephrologists who may also receive the results of the tests.
This chapter is the result of a comprehensive literature
review of selected topics by the Work Group with assistancefrom the evidence review team to formulate the rationale forclinical recommendations. Thus, it should not be considered
as a systematic review.
RATIONALE

3.1.1 We recommend monitoring serum levels of calcium,
phosphorus, PTH, and alkaline phosphatase activity
beginning in CKD stage 3 (1C). In children, wesuggest such monitoring beginning in CKD stage 2 (2D).
Abnormalities in calcium, phosphorus, PTH, and vitamin D
metabolism (collectively referred to as disordered mineralmetabolism) are common in patients with CKD. Changes in
the laboratory parameters of CKD–MBD may begin in CKD
stage 3, but the presence of abnormal values, the rate ofchange, and the severity of abnormalities are highly variable
among patients. To make the diagnosis of CKD–MBD, one ormore of these laboratory abnormalities must be present.
Kidney International (2009) 76 (Suppl 113), S22–S49

Thus, measuring them once is essential for diagnosis.
Although the initial assessment should begin at this stage,
the frequency of assessment is based on the presence andpersistence of identified abnormalities, the severity ofabnormalities, all in the context of the degree and rate ofchange of GFR and the use of concomitant medications.
The interpretation of the biochemical and hormonal values
also requires an understanding of normal postprandial, diurnal,
and seasonal variations, with differences from one parameter tothe other. For example, serum phosphorus fluctuates more thanserum calcium within an individual, and is affected by diurnal
variation more than is serum calcium. Given the complexity ofchanges within any one parameter, it is important to take into
account the trends of changes rather than single values toevaluate changes in the degree of severity of laboratory
abnormalities of CKD–MBD.
The best available data to guide diagnostic monitoring
consist of that which is obtained from population-based orcohort-based prevalence studies. Although subject to specificbiases, these studies do guide the clinician with respect toexpected proportions of abnormal test results at specificlevels of CKD. However, even this is problematic, given theinconsistent definitions of ‘abnormal’ (be it insufficient,
deficient, or in excess). Moreover, there are additional issues
with specific assays, especially for PTH and 25(OH)D, whichfurther complicate and limit our ability to characterizespecific levels as pathological.
Limitations of current data sources

Most of the studies describing observational data andrelationships between individual parameters and clinicaloutcomes have been conducted in hemodialysis (HD)populations. Furthermore, those HD population studies are
generally from cohorts who did not always receive predialysis
care or early identification. In addition, the analysis of theobservational data uses cohort-specific cut points or KDOQI
recommendations from 2003.
Limited data exist regarding the prevalence of biochemicaland hormonal abnormalities in CKD stages 3–5, because of
the general absence of registry data, population-based
studies, or large cohort studies. There are increasingly
recognized differences in referred vs nonreferred populations,and in those with kidney transplants. Data are limited in allof these non-dialysis groups. Even in national dialysis
databases, a routine collection of data on MBD is
uncommon, and in those databases that do have theinformation, they are generally available only for a single
time point, such as dialysis initiation, or confounded bytreatment.
Thus, establishing diagnostic and management criteria on
the basis of data obtained from the sources described above,and in the context of individual person and assay variability,
is problematic. Nevertheless, utilizing trends, consistency ofdata direction, and biological plausibility, the Work Grouphas made recommendations and suggestions for the diagnosis and management of laboratory parameters.
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chapter 3.1

Examples of studies that describe the prevalence ofabnormalities
CKD stages 3–5. Levin et al.28 have described the prevalenceof abnormalities in serum calcium, phosphorus, and PTH ina cross-sectional analysis of 1800 patients with CKD stages
3–5 in North America (Study To Evaluate Early Kidney
Disease). Calcium and phosphorus values did not become
abnormal until GFR fell below 40 ml/min per 1.73 m2, andwere relatively stable until GFR fell below 20 ml/min per
1.73 m2 (Figure 4). However, 12% of patients with
GFR480 ml/min per 1.73 m2 had a high PTH (defined as
465 pg/ml, the upper limit of normal of the assay used)and nearly 60% of patients with GFRo60 ml/min
per 1.73 m2 had elevated PTH levels. Similar findings havebeen recently reported from a community-based screening
program sponsored by the National Kidney Foundation, theKidney Education and Evaluation Program.29 It is to be
noted that both cohorts were primarily nonreferred populations, with a diagnosis of CKD made on the estimated GFR.
CKD stage 5D. The Choices for Healthy Outcomes in
Caring for End-Stage Renal Disease study is a large,
prospectively collected national cohort of incident dialysis
patients with repeated measures of laboratory values. In
incident dialysis patients, serum levels of calcium andphosphorus at the start of dialysis were 9.35 mg/dl(2.34 mmol/l) and 5.23 mg/dl (1.69 mmol/l), respectively.
Mean serum levels increased over the initial 6 months ofrenal replacement therapy (calcium 9.51 mg/dl or 2.38 mmol/l;
phosphorus 5.43 mg/dl or 1.75 mmol/l).30
Although there are numerous cross-sectional reports ofserum levels of calcium, phosphorus, and PTH in CKD stage
5D population, the international Dialysis Outcomes andPractice Pattern Study provides the most comprehensive
global view of the prevalence of disorders of calcium(corrected for albumin), phosphorus, and PTH.33 Unfortunately, there is no standardization of PTH assays fromaround the world. Nevertheless, abnormalities were observedin parallel studies from large dialysis providers in the UnitedStates with central laboratories. Figure 5 provides a robust
depiction of not only the distribution of abnormalities inlaboratory values relevant to CKD–MBD but also a visual
representation of changes in international practice patterns aswell over the three phases of the Dialysis Outcomes andPractice Pattern Study observation (I ¼ 1996–2001,
II ¼ 2002–2004, and III ¼ 2005–present).
Recently, elevated serum total ALP (t-ALP) levels havebeen recognized as a possibly independent variable associatedwith an increase in the relative risk (RR) of mortality inpatients with CKD stage 5D.31,32 Regidor et al.31 havedescribed an association of serum t-ALP levels with mortality
Median values of serum calcium, phosphorus,
and intact PTH by GFR levels
45

100

40

Phosphorus >4.6 mg/dl
Intact PTH >65 pg/ml

35Serum calcium (mg/dl),
phosphorus (mg/dl)

Patients (%)

80

Calcium <8.4 mg/dl

60
40
20
0

150

Serum calcium (mg/dl)
Serum phosphorus (mg/dl)
Intact PTH (mg/dl)

30

100

25
20
15

50

Intact PTH (pg/ml)

Prevalence of abnormal serum calcium,
phosphorus, and intact PTH by GFR

10
5

80
79-70
69-60
59-50
49-40
39-30
29-20
< 20
(n =61) (n =117) (n =230) (n =396) (n =355) (n =358) (n =204) (n =93)

0

0
> 80

GFR level (ml/min)

79-70

69-60

59-50

49-40

39-30

29-20

< 20

GFR level (ml/min)Median values of 1,25 dihydroxyvitamin D,
25 hydroxyvitamin D, and intact PTH by GFR levels
1,25 Dihydroxyvitamin in D3 (pg/ml)
25 Hydroxyvitamin D (ng/ml)
Intact PTH (pg/ml)

45
40
35

150

100

30
25
20
50

15

Intact PTH (pg/ml)

1,25 Dihydroxyvitamin D (pg/ml),
25 Hydroxyvitamin D (ng/ml)

50

10
5
0

0
> 80

79-70 69-60 59-50 49-40 39-30 29-20
GFR level (ml/min)<20

Figure 4 | Prevalence of abnormal mineral metabolism in CKD. (a) The prevalence of hyperparathyroidism, hypocalcemia, andhyperphosphatemia by eGFR levels at 10-ml/min per 1.73 m2 intervals. (b) Median values of serum Ca, P, and iPTH by eGFR levels. (c) Medianvalues of 1,25 (OH)2D3, 25(OH)D3, and iPTH by GFR levels. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GFR,
glomerular filtration rate; iPTH, intact parathyroid hormone. Reprinted with permission from Levin et al.28
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chapter 3.1

Calcium(mg/dl)
12
95th

11

75th
10

50th
25th

9

5th
8
II IIIBEI II IIIFRI II IIIGE

I II IIIIT

I II IIISP

II IIISW

I II IIIUK

II IIIANZI II IIIJA

II IIICAI II IIII II III
US DOPPS AII

Phosphorus(mg/dl)
10
9
8
7
6
5
4
3
2
1
0

95th
75th
50th
25th
5th

II IIIBEI II IIIFRI II IIIGE

I II IIIIT

I II IIISP

II IIISW

I II IIIUK

II IIIANZI II IIIJA

II IIICAI II IIII II III
US DOPPS AIIOverall percentiles
DOPPS I, II, III

PTH (pg/ml)
1200
1000

95th
800
600
400

75th

200

50th
25th
5th

0
II IIIBEI II IIIFRI II IIIGE

I II IIIIT

I II IIISP

II IIISW

I II IIIUK

II IIIANZI II IIIJA

II IIICAI II IIII II III
US DOPPS AII

Figure 5 | Changes in serum calcium, phosphorus, and iPTH with time in hemodialysis patients of DOPPS countries. Distribution of
baseline serum calcium (a), phosphorus (b), and PTH (c) by country and the DOPPS phase. See text for details. DOPPS, Dialysis Outcomesand Practice Pattern Study; PTH, parathyroid hormone. Reprinted with permission from Tentori et al.33

among prevalent HD populations, in addition to U- or
J-shaped curves for calcium, phosphorus, and PTH, further
underscoring the complexity of the relationships of theselaboratory abnormalities with outcomes. High levels of ALPs
are associated with mortality, but there is no evidence that
reducing these levels leads to improved outcomes. The use of
ALPs to interpret other abnormalities of measured minerals
within an individual (for example, as an indicator of boneturnover or as an indicator of other conditions such as liverdisease, an so on) may be useful as detailed in Chapter 3.2.
Children. In children, one study showed that elevations
in PTH occur as early as CKD stage 2, especially in children
with slowly progressive kidney disease.34 Given the significant
associations of biochemical abnormalities of CKD–MBD withKidney International (2009) 76 (Suppl 113), S22–S49

growth and cardiac dysfunction35 in children, the Work Groupfelt it was reasonable to assess children for the biochemical
abnormalities of CKD–MBD initially at CKD stage 2.
3.1.2

In patients with CKD stages 3–5D, it is reasonable
to base the frequency of monitoring serum calcium,
phosphorus, and PTH on the presence and magnitude of abnormalities, and the rate of progressionof CKD (not graded).
Reasonable monitoring intervals would be:
In CKD stage 3: for serum calcium and phosphorus, every 6–12 months; and for PTH, basedon baseline level and CKD progression.

K

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chapter 3.1

In CKD stage 4: for serum calcium and phosphorus,
every 3–6 months; and for PTH, every 6–12 months.
K In CKD stages 5, including 5D: for serum calcium
and phosphorus, every 1–3 months; and for PTH,
every 3–6 months.
K In CKD stages 4–5D: for alkaline phosphataseactivity, every 12 months, or more frequently inthe presence of elevated PTH (see Chapter 3.2).
K

In CKD patients receiving treatments for
CKD–MBD, or in whom biochemical abnormalities
are identified, it is reasonable to increase thefrequency of measurements to monitor for trends
and treatment efficacy and side-effects (not graded).
There are no data showing that routine measurement
improves patient-level outcomes. Nevertheless, suggestions
can be made as to a reasonable frequency of measurement ofthese laboratory parameters of CKD–MBD. The clinician
should adjust the frequency on the basis of the presence andmagnitude of abnormalities, and on the rate of progression of
kidney disease. The frequency of measurement needs to be
individualized for those receiving treatments for CKD–MBD
to monitor for treatment effects and adverse effects.
Table 12 provides reasonable guidance as to the frequency
of monitoring, given the numerous caveats outlined above;clinical situations (stability and treatment strategies) andother factors will influence the frequency of testing, and thismust be individualized. As with any long-term condition,
longitudinal trends are important and some forms ofsystematic (for example, fixed interval) monitoring is likely
to be of greater value than random monitoring.
3.1.3

In patients with CKD stages 3–5D, we suggest that
25(OH)D (calcidiol) levels might be measured, andrepeated testing determined by baseline values andtherapeutic interventions (2C). We suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for thegeneral population (2C).

The Work Group acknowledged that there is emerging
information on the potential role of vitamin D deficiency andinsufficiency in the pathogenesis or worsening of multiple
diseases. In addition, vitamin D deficiency and insufficiency
may have a role in the pathogenesis of secondary hyperparathyroidism (HPT) as detailed in Chapter 4.2. The potential
risks of vitamin D repletion are minimal, and thus, despite
uncertain benefit, the Work Group felt that measurement
might be beneficial.

The prevalence of vitamin D insufficiency or deficiency
varies by the definition used. Most studies define deficiency
as serum 25(OH)D (calcidiol) values o10 ng/ml (25 nmol/l),
and insufficiency as values X10 but o20–32 ng/ml(50–80 nmol/l).36,37 However, there is no consensus on whatdefines ‘adequate’ vitamin D levels or toxic vitamin Dlevels,38 although some believe a normal level is that which is
associated with a normal serum PTH level in the general
population, whereas others define it as the level above which
there is no further reciprocal reduction in serum PTH upon
vitamin D supplementation.39,40 Numerous publications
have found associations of vitamin D deficiency, usually
defined as serum 25(OH)D valueso10 or 15 ng/ml (o25 or
37 nmol/l), to be associated with various diseases.41,42 In thegeneral population43,44 and in patients with CKD,45 there isan association of low 25(OH)D levels with mortality. There is
one prospective randomized controlled trial (RCT) in thegeneral population that shows that vitamin D supplementation reduces the risk of cancer.46 However, there are no data
showing that the repletion of vitamin D to a specific25(OH)D level reduces mortality.
Defining specific target or threshold levels in the current
era is likely to be premature (see Recommendation 3.1.4),37,42
and, in particular, using the criteria of a normal serum PTH
level as vitamin D adequacy in CKD is problematic becauseof the multiple factors that affect PTH synthesis, secretion,
target tissue response, and elimination in CKD. Studies in
CKD patients and in the general population show widespreadvitamin D deficiency; according to some definitions, almost
50% of those studied have suboptimal levels. In patients withCKD stages 3–4, some studies report lower 25(OH)D levels
with more advanced stages of CKD.28,47,48 However, theStudy To Evaluate Early Kidney Disease detailed above foundno relationship between the stage of CKD and calcidiol levels.
In the Study To Evaluate Early Kidney Disease, black
individuals had lower levels of calcidiol and higher levels of
PTH than did white individuals, despite higher levels of
calcium and phosphorus.49
Although position statements defining vitamin D deficiency exist, the definition of what level of vitamin D
represents sufficiency is the subject of an ongoing debate.
There are no data that the presence or absence of CKD would
alter recommended levels. From a practical perspective,
clinicians should also appreciate that—in the absence ofknowing the optimum level, and with all the issues related tothe measurement of serum levels of vitamin D sterols—thedecision of whether to measure, when to measure, howoften, and to what target level needs to be individualized.
Furthermore, considerations as to how the information

Table 12 | Suggested frequencies of serum calcium, phosphorus, and PTH measurements according to CKD stage

Calcium and phosphorus
PTH and alkaline phosphatases
Calcidiol

Progressive CKD stage 3

CKD stage 4

CKD stages 5 and 5D

6–12 months
Baseline
Baseline

3–6 months
6–12 months
Baseline

1–3 months
3–6 months
Baseline

CKD, chronic kidney disease; PTH, parathyroid hormone.

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chapter 3.1

would impact management and treatment decisions
should be considered on an individual patient basis, as well
as by considering the impact on health-care resources/costs,
where applicable. As detailed in Chapter 4.2, in patients withCKD stages 3 and 4, vitamin D deficiency may be anunderlying cause of elevated PTH, and thus there is arationale for measuring and supplementing in this population, although this approach has not been tested in aprospective RCT.
3.1.4

In patients with CKD stages 3–5D, we recommendthat therapeutic decisions be based on trends rather
than on a single laboratory value, taking into
account all available CKD–MBD assessments (1C).

The interpretation of biochemical and hormonal values inthe diagnosis of CKD–MBD requires an understanding of
assay type and precision, interassay variability, blood sample
handling, and normal postprandial, diurnal, and seasonalvariations. Owing to these assay and biological variation
issues, the Work Group felt that trends in laboratory values
should be preferentially used over single values for determining when to initiate and/or adjust treatments.
Table 13 describes the sources and magnitude of variationin the measurement of serum calcium, phosphorus, PTH,
and vitamin D sterols. This table serves as a guide forclinicians and forms the basis for the recommendation thatlaboratory tests should be measured using the same assays,
and at similar times of the day/week for a given patient.
Health-care providers should be familiar with assay problems
and limitations (discussed below). Furthermore, an appreciation of this variability further underscores the importance ofutilizing trends, rather than single absolute values, when
making diagnostic or treatment decisions.
3.1.5

In patients with CKD stages 3–5D, we suggest that
individual values of serum calcium and phosphorus, evaluated together, be used to guide clinicalpractice rather than the mathematical construct of
calcium–phosphorus product (Ca  P) (2D).

The mathematical construct of the calcium  phosphorus
product (Ca  P) is of limited use in clinical practice, as it islargely driven by serum phosphorus and generally does not
Table 13 | Sources and magnitude of the variation in themeasurement of serum calcium, phosphorus, PTH, andvitamin D sterols
Variable
Coefficient of variation
Diurnal variation
Seasonal variation
Variation with meals
Variation with dialysis time
Assay validity

Calcium Phosphorus PTH Vitamin D sterols
+
+

+
++

++
++

+
+
+++

+
+
+++

+

++

++


+

+

NS, no shading; PTH, parathyroid hormone; S, shading. þ , minimal or low; þ þ ,moderate; þ þ þ , high or good; , no variability; blank space, not tested.
Kidney International (2009) 76 (Suppl 113), S22–S49

provide any additional information beyond that which isprovided by individual measures.50,51 The measurement ofphosphorus is generally valid and reproducible, but isaffected by diurnal and postprandial variation. Values may
differ substantially (for example, up to 0.08 mg/dl;
0.026 mmol/l) in dialysis patients, depending on which shift
or which interdialytic interval is chosen.33 Furthermore, there
are multiple situations in which a normal product isassociated with poor outcomes, and the converse is similarly
true. Thus, the Work Group advised against a reliance on thiscombined measurement in clinical practice.
3.1.6

In reports of laboratory tests for patients with CKD
stages 3–5D, we recommend that clinical laboratories inform clinicians of the actual assay method
in use and report any change in methods, sample
source (plasma or serum), and handling specifications to facilitate an appropriate interpretation ofbiochemistry data (1B).

The use of biochemical assays for the diagnosis andmanagement of CKD–MBD requires some understanding of
assay characteristics and limitations, discussed by each assay
below. The understanding of these sources of variability
should allow clinicians and health-care providers to optimize
the performance and interpretation of laboratory tests in
CKD patients (for example, timing, location, laboratory used,and so on). Clinical laboratories should assist clinicians in theinterpretation of data by reporting assay characteristics andkits used.
Calcium

Serum calcium levels are routinely measured in clinicallaboratories using colorimetric methods in automatedmachines. There are quality control standards utilized byclinical laboratories. Thus, the assay is generally precise andreproducible. In healthy individuals, serum calcium is tightly
controlled within a narrow range, usually 8.5–10.0 or
10.5 mg/dl (2.1–2.5 or 2.6 mmol/l), with some, albeit
minimal, diurnal variation.52 However, the normal range
may vary slightly from laboratory to laboratory, dependingon the type of measurement used. In patients with CKD,
serum calcium levels fluctuate more, because of alteredhomeostasis and concomitant therapies. In those with CKD
stage 5D, there are additional fluctuations in association withdialysis-induced changes, hemoconcentration, and subsequent hemodilution. Moreover, predialysis samples collectedfrom HD patients after the longer interdialytic interval
during the weekend, as compared with predialysis samples
drawn after the shorter interdialytic intervals during theweek, often contain higher serum calcium levels. In theinternational Dialysis Outcomes and Practice Pattern Study,
the mean serum calcium measured immediately before the
Monday or Tuesday sessions was higher by 0.01 mg/dl(0.0025 mmol/l) than that measured before the Wednesdayor Thursday sessions.33
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chapter 3.1

The serum calcium level is a poor reflection of overall total
body calcium. Only 1% of total body calcium is measurable
in the extracellular compartment. The remainder is stored inbone. Serum ionized calcium, generally 40–50% of total
serum calcium, is physiologically active, whereas non-ionized
calcium is bound to albumin or anions such as citrate,bicarbonate, and phosphate, and is therefore not physiologically active. In the presence of hypoalbuminemia, there isan increase in ionized calcium relative to total calcium; thus,
total serum calcium may underestimate the physiologically
active (ionized) serum calcium. A commonly used formulafor estimating ionized calcium from total calcium is the
addition of 0.8 mg/dl (0.2 mmol/l) for every 1 g decrease inserum albumin below 4 g/dl (40 g/l). This ‘corrected calcium’
formula is routinely used by many dialysis laboratories and in
most clinical trials. Unfortunately, recent data have shownthat it offers no superiority over total calcium alone and isless specific than ionized calcium measurements.53 In
addition, the assay used for albumin may affect the correctedcalcium measurement.54 However, ionized calcium measurement is not routinely available and, in some instances, may
require additional costs for measuring and reporting.
Presently, most databases are already using the correctedcalcium formula and there is an absence of data showing
differences in treatment approach or clinical outcomes whenusing corrected vs total or ionized calcium. The Work Group
did not recommend that corrected calcium measurements beabandoned at present. Furthermore, the use of ionized
calcium measurements is currently not considered to bepractical or cost effective.
Phosphorus

Inorganic phosphorus is critical for numerous normal
physiological functions, including skeletal development,
mineral metabolism, cell-membrane phospholipid content
and function, cell signaling, platelet aggregation, and energy
transfer through mitochondrial metabolism. Owing to its
importance, normal homeostasis maintains serum concentrations between 2.5–4.5 mg/dl (0.81–1.45 mmol/l). The terms,
phosphorus and phosphate, are often used interchangeably,
but strictly speaking, the term phosphate means thesum of the two physiologically occurring inorganic ions inthe serum, and in other body fluids, hydrogenphosphate(HPO2
4 ) and dihydrogenphosphate (H2PO4 ). However,most laboratories report this measurable, inorganic component as phosphorus. Unlike calcium, a major component ofphosphorus is intracellular, and factors such as pH andglucose can cause shifts of phosphate ions into or out of cells,
thereby altering the serum concentration without changing
the total body phosphorus.
Phosphorus is routinely measured in clinical laboratories
with colorimetric methods in automated machines. There are
quality control standards used by clinical laboratories. Thus,
the assay is generally precise and reproducible. Levels will be
falsely elevated with hemolysis during sample collection. In
healthy individuals, there is a diurnal variation in both serum
S28

phosphorus levels and urinary phosphorus excretion. Serum
phosphorus levels reach a nadir in the early hours of themorning, increasing to a plateau at 1600 hours, and further
increasing to a peak from 0100 to 0300 hours.55,56 Similar
results were found in patients with hypercalcuria andnephrolithiasis.57 However, another study found no diurnal
variation in patients on dialysis when studied on a nondialysis day.58 There are usually higher levels after a longer
period of dialysis. In the international Dialysis Outcomes andPractice Pattern Study, samples collected from HD patients
immediately before a Monday or Tuesday session vs a
Wednesday or Thursday session were higher by 0.08 mg/dl(0.025 mmol/l).33
Thus, the measurement of phosphorus is generally valid
and reproducible, but may be affected by normal diurnal andpostprandial variation. Again, trends of progressive increaseor decrease may be more accurate than small variations inindividual values.
Parathyroid hormone

PTH is cleaved to an 84-amino-acid protein in theparathyroid gland, where it is stored with fragments insecretory granules for release. Once released, the circulating
1–84-amino-acid protein has a half-life of 2–4 min. The
hormone is cleaved both within the parathyroid gland andafter secretion into the N-terminal, C-terminal, and midregion fragments of PTH, which are metabolized in the liverand in the kidneys. Enhanced PTH synthesis/secretion occurs
in response to hypocalcemia, hyperphosphatemia, and/or adecrease in serum 1,25-dihydroxyvitamin D (1,25(OH)2D),
whereas high serum levels of calcium or calcitriol—and, as
recently shown, of FGF-2359—suppress PTH synthesis/
secretion. The extracellular concentration of ionized calciumis the most important determinant of the minute-to-minutesecretion of PTH, which is normally oscillatory. In patientswith CKD, this normal oscillation is somewhat blunted.60
There has been a progression of increasingly sensitive
assays developed to measure PTH over the past few decades(Figure 6). Initial measurements of PTH using C-terminalFirst-generation PTH assays
N-PTH RIA
Mid/C-PTH RIA
1

34

84

Second-generation PTH assays
Third-generation PTH assays

Figure 6 | PTH assays. The figure shows the entire parathyroid
hormone molecule, composed of 84 amino acids. Mid/C-PTH,
mid/carboxyl-terminus of parathyroid hormone; N-PTH,
amino-terminus of parathyroid hormone; PTH, parathyroid
hormone; RIA, radioimmunoassay. Reprinted with permission
from Moe and Sprague.70
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chapter 3.1

assays were inaccurate in patients with CKD because of theimpaired renal excretion of C-terminal fragments (and thus
retention) and the measurement of these probably inactive
fragments. The development of the N-terminal assay was
initially thought to be more accurate but it also detected
inactive metabolites.
The development of a second generation of PTH assays(Figure 6), the two-site immunoradiometric assay—commonly called an ‘intact PTH’ assay—improved the detectionof full-length (active) PTH molecules. In this assay, acaptured antibody binds within the amino terminus and asecond antibody binds within the carboxy terminus.61
Unfortunately, recent data indicate that this ‘intact’ PTH
assay also detects accumulated large C-terminal fragments,
commonly referred to as ‘7–84’ fragments; these are a mixtureof four PTH fragments that include, and are similar in size to,
7–84 PTH.62 In parathyroidectomized rats, the injection of atruly whole 1- to 84-amino-acid PTH was able to inducebone resorption, whereas the 7- to 84-amino-acid fragment
was antagonistic, explaining why patients with CKD may
have high levels of ‘intact’ PTH but relative hypoparathyroidism at the bone-tissue level.6365 Thus, the majordifficulty in accurately measuring PTH with this assay is
the presence of circulating fragments, particularly in thepresence of CKD. Unfortunately, the different assays measuredifferent types and amounts of these circulating fragments,
leading to inconsistent results.66
More recently, a third generation of assays has become
available that truly detect only the 1- to 84-amino-acid, fulllength molecule: ‘whole’ or ‘bioactive’ PTH assays (Figure 6).
However, they are not yet widely available and have not beenshown convincingly to improve the predictive value for the
diagnosis of underlying bone disease67 or other serum
markers of bone turnover,68 in contrast to at least one reportthat suggested that levels of 1–84 PTH or the 1–84 PTH/large
C-PTH fragment ratio may be a better predictor of mortality
in CKD stage 5 than standard ‘intact’ PTH values.69
Therefore, the Work Group felt that the widely available
second-generation PTH assays should continue to be used inroutine clinical practice at present.
There are a number of commercially available kits thatmeasure so-called ‘intact’ PTH with second-generation
assays. Much of the literature and recommendations fromKDOQI Bone and Mineral guidelines5 were based on thesecond-generation Allegro assay from Nichols, which is not
currently available. A study evaluated these other assays incomparison with the Allegro kit, using pooled human serum,
and found intermethod variability in results because ofstandardization and antibody specificity. The different assays
measured different quantities of both 7–84 and 1–84 PTH(when added to uremic serum).66 In addition, there are differences in PTH results when samples are measured in plasma,serum, or citrate, and depending on whether the samples areon ice, or are allowed to sit at room temperature.71,72
Thus, these data—which describe problems with sample
collection and assay variability—raise significant concerns
Kidney International (2009) 76 (Suppl 113), S22–S49

with regard to the validity of absolute levels of PTH and theirstrict use as a clinically relevant biomarker for targeting
specific values. Nevertheless, the clinical consequences of notmeasuring PTH and treating secondary HPT are of equal
concern. In an attempt to balance the methodological issuesof PTH measurement with the known risks and benefits ofexcess PTH and treatment strategies, the Work Group feltthat PTH should be measured, with standardization withinclinics and dialysis units in the methods of sample collection,
processing, and assay used. In addition, the Work Group feltthat trends in serum PTH, rather than single values, should
be used in the diagnosis of CKD–MBD and in the treatmentof elevated or low levels of PTH. However, ‘systematic’unidirectional trends observed in the majority of patients in asingle center should prompt suspicion that the central
laboratory may have changed the assay. The Work Groupalso felt that using narrow ranges of PTH defining an‘optimal’ or ‘target’ range was neither possible nor desirable.
Vitamin D2 and D3 and their derivatives

To ensure that the reader of this guideline is clear on the
difference between these compounds, and to ensure the useof consistent nomenclature in clinical practice, Table 14 isprovided. Following the table is an in-depth discussion
relating to the assays and measurement of these compounds.
Assays of serum vitamin D metabolites
25(OH)D. The parent compounds ofvitamin D—D3
(cholecalciferol) or D2 (ergocalciferol)—are highly lipophilic.
They are difficult to quantify in the serum or plasma. They
also have a short half-life in circulation of about 24 h. These
parent compounds are metabolized in the liver to 25(OH)D3(calcidiol) or 25(OH)D2 (ercalcidiol). Collectively, they arecalled 25(OH)D or 25-hydroxyvitamin D. The measurementof serum 25(OH)D is regarded as the best measure of vitaminD status, because of its long half-life of approximately
3 weeks. In addition, it is an assessment of the multiple
sources of vitamin D, including both nutritional intake andskin synthesis of vitamin D. There is a seasonal variation in
calcidiol levels because of an increased production ofcholecalciferol by the action of sunlight on skin during
summer months.
There are three types of assays for measuring calcidiol.
Fortunately, unlike PTH, the specimen collection process iswell standardized and the sample is stable over time.
However, there are real differences in measurement methods.
The gold standard of calcidiol measurement is highperformance liquid chromatography (HPLC), but this is
not widely available clinically. This is because HPLC is time
consuming, requires expertise and special instrumentation,and is expensive. In early 1985, Hollis and Napoli73
developed the first radioimmunoassay (RIA) for total
25(OH)D, which was co-specific for 25(OH)D2 and25(OH)D3. The values correlated with those obtained from
HPLC analysis, and DiaSorin RIA became the first test to beapproved by the Food and Drug Administration for use in
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chapter 3.1

Table 14 | Vitamin D2 and D3 and their derivatives
D2 and derivatives

D3 and derivatives

Collective terminology

Parent compound
Abbreviation
Full term
Synonym

D2
Vitamin D2
Ergocalciferol

D3
Vitamin D3
Cholecalciferol

D
Vitamin D

Product of first hydroxylation
Abbreviation
Full term
Synonym25(OH)D2
25-Hydroxyvitamin D2
Ercalcidiol

25(OH)D3
25-Hydroxyvitamin D3
Calcidiol

25(OH)D
25-Hydroxyvitamin D

Product of second hydroxylation
Abbreviation
Full term
Synonym

1,25(OH)2D2
1,25-Dihydroxyvitamin D2
Ercalcitriol

1,25(OH)2D3
1,25-Dihydroxyvitamin D3
Calcitriol

1,25(OH)2D
1,25 Dihydroxyvitamin D

clinical settings.73 Subsequent developments led to theautomation of the test. Nichols developed a fully automatedchemiluminescence assay in 2001, allowing clinical laboratories the ability of rapid and large-volume detection.
However, this assay was removed from the market in 2006.
In 2004, DiaSorin (Stillwater, MN, USA) introduced its fully
automated chemiluminescence assay, which, similar to its
RIA, is co-specific for 25(OH)D2 and 25(OH)D3, reporting‘total’ 25(OH)D concentration. This assay has recently been
updated as a ‘second-generation’ assay with an improved
assay precision.37,74 Additional manufacturers, IDS (Fountain
Hills, AZ, USA) and Roche Diagnostics (Burgess Hill, West
Sussex, UK) also make automated RIAs and/or enzymelinked immunosorbent assay tests, but there are only limited
publications thus far. In the majority of reports in this field,
the DiaSorin assay was used.
Another method now carried out is liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar to
HPLC, the LC-MS/MS method also has the ability to quantify
25(OH)D2 and 25(OH)D3 separately, which distinguishes itfrom RIA and enzyme-linked immunosorbent assay technologies. This method is very accurate and has been shown tocorrelate well with DiaSorin RIA.75,76 Next to DiaSorin
assays, LC-MS/MS is the most frequently used procedure forthe clinical assessment of circulating 25(OH)D.37 However,most clinical laboratories do not use this technique becauseof the substantial cost and need for highly trained operators.
Only HPLC and LC-MS/MS can differentiate 25(OH)D2 and25(OH)D3, whereas RIA and automated chemiluminescence
technologies only measure total 25(OH)D—the sum of25(OH)D2 and 25(OH)D3. There is controversy as towhether the ability to differentiate these metabolites isimportant, as they have similar biological effects.77,78
A recent study by Binkley et al.79 analyzed blood obtained
from 15 healthy adults for 25(OH)D. Aliquots of serum fromall volunteers and a calibrator (known to contain 30 ng/ml(75 nmol/l) 25(OH)D by HPLC) were sent to four laboratories. The methods used for 25(OH)D measurement
included HPLC, LC-MS/MS in two laboratories, and RIA(DiaSorin). A good correlation was observed for 25(OH)D
measurement among the laboratory using HPLC, the two
S30

laboratories using LC-MS/MS, and the laboratory using RIA(R2 ¼ 0.99, 0.81, and 0.95, respectively). The classification ofclinical vitamin D status as optimal or low was identical for
80% of the 15 individuals in all four laboratories. However,
20% would be variably classified depending on the laboratory
used. A modest interlaboratory variability was noted, with amean bias of the laboratories using LC-MS/MS and RIA
being from þ 2.9 to þ 51 ng/ml ( þ 7.2 to þ 127 nmol/l)when compared with the laboratory using HPLC. They foundthat a systematic bias led to 89% of values being higher in the
non-HPLC laboratories, and that a correction of the25(OH)D value using a single calibrator at all sites for all
assays reduced the mean interlaboratory bias. This suggeststhat the use of a standard calibrator may increase agreement
among laboratories.
Thus, the Work Group advises that clinicians should beaware of the assay methods when assessing vitamin D status.
Currently, the assays for 25(OH)D are not well standardized,
and the definition of deficiency is not yet well validated. At
best, clinicians should ensure that patients use the samelaboratory for measurements of these levels, if carried out.
The most appropriate vitamin D assays presently available
seem to be those that measure both 25(OH)D2 and25(OH)D3. Presently, approximately 20–50% of the general
population has low vitamin D levels, irrespective of CKD
status. However, the benefits from replacing vitamin D havenot been documented in patients with CKD, particularly ifthey are taking calcitriol or a vitamin D analog. Therefore,
the utility of measurement is unclear, outside of clinical trial
or research situations. Furthermore, there are no data
indicating that the measurement is helpful in guiding therapy
or in predicting outcomes in CKD, although vitamin D
deficiency may be a treatable cause of secondary HPT,
especially early in the course of CKD. The risk, benefit, andcosts of testing in patients should be balanced with practicalissues related to treatment trials.
1,25(OH)2D. 1,25(OH)2D is used to describe both hydroxylated D2 (ercalcitriol) and D3 (calcitriol) compounds, bothof which have a short half-life of 4–6 h. Commerciallyavailable assays do not distinguish between 1,25(OH)2D2 and1,25(OH)2D3, and there are insufficient data to support the
Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.1

different biological effects of these compounds. The gold
standard for assessment of 1,25(OH)2D is HPLC, and only asmall number of kits are available for routine measurement.
Circulating levels of 1,25(OH)2D are approximately 1/1000ththat of 25(OH)D. The measurement of 1,25(OH)2D will beaffected by both the stores of 25(OH)D and the multiple
factors that convert 25(OH)D to 1,25(OH)2D by the25(OH)D-1a-hydroxylase enzyme (CYP27B1), as well as its
inactivation by the 24(OH)D hydroxylase enzyme(CYP24A1) to 1,24,25(OH)3D and other inactivation steps.
The renal CYP27B1 is regulated by nearly every hormone
involved in calcium homeostasis. Its activity is stimulated by
PTH, estrogen, calcitonin, prolactin, growth hormone, lowcalcium, and low phosphorus, and is inhibited by its product1,25(OH)2D, FGF-23, and metabolic acidosis. Recent data
show that multiple other tissues and cells also have CYP27B1
activity, which is believed to have autocrine/paracrine
functions.80 This extrarenal 1a-hydroxylase does not seemto be regulated by factors related to calcium homeostasis,suggesting a role for the extrarenal production of
1,25(OH)2D other than that involved in mineral metabolism.
Furthermore, in patients with earlier stages of CKD
and in the general population, mild-to-moderate vitamin D
deficiency, or partly treated vitamin D deficiency, isfrequently associated with increased levels of 1,25(OH)2D.
Thus, even accurate levels can be misleading. The serum
levels of 1,25(OH)2D are uniformly low in late stages of
CKD–MBD, at least in patients not treated with vitamin D
derivatives.
Thus, the Work Group did not recommend a routine
measurement of 1,25(OH)2D levels, as the assays are not wellstandardized, the half-life is short, the measurement will be
artificially altered by the exogenous administration of
calcitriol and vitamin D analogs, and there are no data
indicating that the measurement is helpful in guiding therapy
or predicting outcomes.
Alkaline phosphatases

Alkaline phosphatases are enzymes that remove phosphatefrom proteins and nucleotides, functioning optimally at
alkaline pH. Measurement of the level of t-ALP is acolorimetric assay that is routinely used in clinical laboratories in automated machines, with quality control standards
routinely used. The enzyme is found throughout the body inthe form of isoenzymes that are unique to the tissue of origin.
Highest concentrations are found in the liver and bone, but
the enzyme is also present in the intestines, placenta, kidneys,
and leukocytes. Specific ALP isoenzymes to identify the tissuesource can be determined after fractionation and heat
inactivation, but these procedures are not widely available inclinical laboratories. Bone-specific ALP (b-ALP) is measured
with an immunoradiometric assay. Elevated levels of t-ALP are
generally due to an abnormal liver function (in which case,other tests are also abnormal), an increased bone activity, orbone metastases. Levels are normally higher in children withgrowing bones than in adults, and often are increased after
Kidney International (2009) 76 (Suppl 113), S22–S49

fracture. In addition, t-ALP and b-ALP can be elevated in bothprimary and secondary HPT, osteomalacia, and in the presenceof bone metastasis and Paget’s disease.
The Work Group recommended that the measurement of
t-ALP in the diagnosis and assessment of CKD–MBD may be
used as an adjunct test, but if values are high, then liverfunction tests should be checked. t-ALP could reasonably be
used as a routine test to follow response to therapy. The more
expensive testing for b-ALP can be used when the clinicalsituation is more ambiguous. Relationships between b-ALP
and bone turnover are discussed in the following chapter.
However, testing for t-ALP is inexpensive and therefore may
be helpful for following patients’ response to therapy ordetermining bone turnover status when the interpretation of
PTH is unclear. The use of b-ALP, an indicator of bonesource, may provide additional and more specific information, although it is not readily available. Clinicians should
consider the adjunct value of these tests in treating individual
patients in the context of the caveats described above.
RESEARCH RECOMMENDATIONS

It is important to emphasize that CKD–MBD is a complex
disorder affecting those at all stages of CKD. An understanding of the complex biology in combination with thecomplexity of measurement issues is of tantamount importance, if eventually the appropriate RCTs of treatment are
to be conducted. Many different kinds of studies are required
to further our knowledge. As it pertains to the recommendations and suggestions described in this chapter of diagnosis
and monitoring, the key areas for research to address in thearea of measurement and assay variability are listed below:
K To increase the understanding of inter- and intraindividual
variations in the laboratory parameters of CKD–MBD,
registries (for those in stages 3–4, on dialysis, and thosewith kidney transplants) should endeavor to collect serial
data on CKD–MBD laboratory information.
K To ensure comparability between and within cohorts/
facilities and countries and thus ensure the transferabilityof knowledge, there is a need to establish standards for all
relevant laboratory parameters, including assays, handling,
and timing of specimen collection.
K To conduct international trials (cohort, observational, or
treatment), and to facilitate the appropriate uptake of study
information, there is a need for the creation of aninternational registry to oversee and review the standardization of measurement methods. This group would necessarily
work with pathology/laboratory medicine organizations tofacilitate the implementation of these standards.
K To establish CKD cohort-specific ranges of normal andpathological values, there is a need to ensure the systematiccollection of longitudinal prospective observational dataand outcomes. Specific cohorts, about whom little is
known about initial and serial ‘expected’ or acceptablevalues, include those initiating dialysis (with and withoutearlier CKD care), those receiving kidney transplants, andthose on home-based therapies.
S31

chapter 3.2

http://www.kidney-international.org& 2009 KDIGO

Chapter 3.2: Diagnosis of CKD–MBD: bone
Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

The bone-disease component of CKD–MBD may result in
fractures (including asymptomatic fractures seen on vertebral
radiographs), bone pain, deformities in growing children,
reduced growth velocity, and abnormal height. Complicationsof hip fractures include bleeding, infection, loss of independence, and increased mortality. Vertebral fractures lead to height
loss, reduced pulmonary function, gastrointestinal reflux, andchronic disability. In children, growth retardation and skeletal
deformities reduce quality of life. In clinical studies of bonedisease, surrogate outcomes are bone density and findings onbone biopsies. Potential surrogate outcomes are serum
biochemical markers of bone resorption and bone formation.
It is important to recognize that most patients with
postmenopausal or age-related osteoporosis also have earlystages of CKD (stages 1 through, perhaps, to early stage 3).
Patients with more advanced stages of CKD (stages 3–5D), in
whom the biochemical abnormalities of mineral metabolismthat define CKD–MBD are present, have renal osteodystrophy. Both idiopathic osteoporosis and renal osteodystrophy
can lead to increased bone fragility and fractures, but these
diseases have different pathophysiological backgrounds. Bonefragility is due to varying combinations of low bone mineralcontent and abnormal bone quality. CKD–MBD can lead toan abnormal bone quality even in the setting of a normal orhigh bone-mineral content, and the gold standard diagnosis
for the bone component of CKD–MBD is bone biopsy-based
histologic analysis. Osteoporosis is traditionally diagnosed as
low BMD. Given these pathophysiological and diagnostic
differences, the definition of ‘osteoporosis’ in adults is mostappropriate only for those with CKD stages 1–3; in later CKD
stages, those with low BMD should be designated as having‘CKD–MBD with low BMD.’
RECOMMENDATIONS

3.2.1

S32

In patients with CKD stages 3–5D, it is reasonable toperform a bone biopsy in various settings including,but not limited to: unexplained fractures, persistentbone pain, unexplained hypercalcemia, unexplained
hypophosphatemia, possible aluminum toxicity, and

3.2.2

3.2.3

3.2.4

3.2.5

prior to therapy with bisphosphonates in patientswith CKD–MBD (not graded).
In patients with CKD stages 3–5D, with evidence ofCKD–MBD, we suggest that BMD testing not be
performed routinely, because BMD does not predict
fracture risk as it does in the general population,
and BMD does not predict the type of renal
osteodystrophy (2B).
In patients with CKD stages 3–5D, we suggestthat measurements of serum PTH or bone-specificalkaline phosphatase can be used to evaluate bonedisease because markedly high or low values predict
underlying bone turnover (2B).
In patients with CKD stages 3–5D, we suggest not toroutinely measure bone-derived turnover markers
of collagen synthesis (such as procollagen type I
C-terminal propeptide) and breakdown (such astype I collagen cross-linked telopeptide, cross-laps,
pyridinoline, or deoxypyridinoline) (2C).
We recommend that infants with CKD stages 2–5D
have their length measured at least quarterly, whilechildren with CKD stages 2–5D should be assessed
for linear growth at least annually (1B).

Summary of rationale for recommendations

Patients with CKD stages 3–5, 5D, and 1–5T have an
increased risk of fracture compared with the general
population. These fractures are associated with increased
morbidity and mortality.
K Fracture risk relates to bone mineral density and bonequality, together with risk for falling and trauma.
K Bone biopsies provide measurements of bone turnover,mineralization, and volume. These help to assess bonequality and the underlying physiology. The histology isvariable and influenced by many factors, including stage of
CKD, serum biochemistries, age, and treatments. The
different types of renal osteodystrophy have only modest
relationships with clinical outcomes.
K In patients with CKD stages 4–5D, BMD of the hip andradius is generally lower than that in the general

K

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chapter 3.2

population; lumbar spine BMD is similar to that in thegeneral population.
K In the general population, a low BMD predicts fracture
and mortality. The ability of BMD to predict fractures orother clinical outcomes in patients with CKD stages 4–5D
is weak and inconsistent. BMD in patients with CKD
stages 3–5D does not distinguish among types of renal
osteodystrophy, as seen with bone histology.
K There are no longitudinal studies of changes in BMD inpatients with CKD stages 4–5.
K PTH is one important factor that affects bone physiology.
ALP may reflect osteoblast activity. Serum measurementsof PTH and ALP are related to clinical outcomes,
including relative risk of mortality. They also correlatewith some of the histomorphometric measurements.
K Serum biochemical markers of bone turnover showcorrelations with findings on bone biopsies, but theirdiagnostic utility is limited and these serum tests have notbeen directly related to clinical outcomes, except ALPs
and extreme values of PTH.
K An alteration in growth in infants and children is asensitive indicator of the presence of CKD–MBD.

groups of clinical trials.85 The World Health Organization
fracture assessment tool includes earlier fracture after
50 years of age as one of the clinical risk factors, with arisk ratio for hip fracture of 1.85 without BMD, and 1.62
including BMD in the model.87 The risk of a new vertebral
fracture increases with the higher number and severity offractures seen on spine radiographs, but even a mild
asymptomatic fracture of one vertebra is associated with asignificantly increased risk.83 However, it is important forclinicians to appreciate that these vertebral fractures do notcause increased back pain in about 60% of cases, and that asevere loss of vertebral height can be asymptomatic.88
In patients with CKD stage 5D, one study89 found that avertebral fracture identified on a radiograph increased therisk of a new fracture by over sevenfold.
Mortality

Abnormal bone quality and quantity can lead to increasedbone fragility, resulting in fracture. In 1966, Pendras andErickson81 reported their experience with the first 22 patientsto receive long-term HD. Bone and mineral disorders
emerged as one of the most troublesome complications;fractures occurred in 47% of the patients. Since then, several
studies of fracture prevalence and incidence have beenreported, with a prevalence from 10 to 40% in general
dialysis populations and in approximately half of patientsolder than 50 years (Supplementary Table 4). The incidence
rate of hip fractures in all patients who started dialysis in the
United States from 1989 to 1996 was 4.4 times higher thanthat in the residents of Olmstead County.82 Fractures occur
more commonly in elderly patients, in women, in diabetic
patients, in those using glucocorticoids, and in those with alonger exposure to dialysis. Fractures are also common inelderly patients with CKD stages 3–4 (Supplementary Table 5).
Hip fractures were seen two to three times more often than inpersons without CKD.

Mortality in patients with CKD stage 5 who have had a hip
fracture is about twice as high as that in patients of similar
age and gender who have not had a fracture (Supplementary
Table 7). Coco et al. followed up 1272 HD patients over
10 years and observed that the mortality for CKD stage
5 patients with a hip fracture was 2.7 times higher than thatin fracture-free HD patients and 2.4 times higher than thatin patients without CKD who had a fractured hip.90 Threestudies used data from the US Renal Data System.
Mittalhenkle et al.91 recorded hip fracture cases over
5.5 years, and the mortality incidence was 2.15 times higher
in cases than in controls matched for age, duration of
dialysis, and cardiovascular risk scores. Adjusting for multiple
risk factors resulted in an RR of 1.99 for mortality associatedwith hip fracture. Danese et al.89 evaluated 9007 patients andfound that a history of hip, vertebral, or pelvic fracture wasassociated with an age- and sex-adjusted mortality rate thatwas 2.7 times higher than that for the other dialysis patients.
Kaneko et al.92 found that the adjusted hazard ratio formortality was 1.95 in patients with long bone fractures, using
data from 7159 individuals in the Dialysis Morbidity andMortality Study.
This topic represents a comprehensive review of theliterature of selected topics by the Work Group withassistance from the evidence review team to formulate therationale for clinical recommendations. Thus, this should not
be considered to be a systematic review.

Increased risk of another fracture

RATIONALE

In the general population, previous fractures as an adult arestrongly associated with the risk of a subsequent fracture.
This is independent of age, bone density, or other identified
risk factors.8385 Among US women older than 65 years,
those who had a vertebral fracture as seen on a spine
radiograph were 5.4 times more likely to experience a newvertebral fracture in the next 3.7 years compared with women
without a prevalent fracture. Even when adjusted for age andbone density, the risk was 4.1 times higher.86 Similar findings
are reported in several cohort studies and in the placebo

3.2.1

BACKGROUND: FRACTURES IN CKD PATIENTSPrevalence

Kidney International (2009) 76 (Suppl 113), S22–S49

In patients with CKD stages 3–5D, it is reasonable
to perform a bone biopsy in various settings,
including, but not limited to: unexplained fractures,persistent bone pain, unexplained hypercalcemia,
unexplained hypophosphatemia, possible aluminum
toxicity, and prior to therapy with bisphosphonates in patients with CKD–MBD (not graded).

Abnormal bone histology, diagnosed by bone biopsy withhistomorphometry, has been the primary tool used to diagnose
S33

chapter 3.2

and classify renal osteodystrophy. Although bone biopsy isinvasive and thus cannot be performed easily in all patients, it is
the gold standard for the diagnosis of renal osteodystrophy. As
detailed below, renal osteodystrophy is a complex disorder andbiochemical assays do not adequately predict the underlying
bone histology. Thus, bone biopsy should be considered inpatients in whom the etiology of clinical symptoms andbiochemical abnormalities is not certain. Aluminum bonedisease, although less common in the current era, also requires
a bone biopsy for diagnosis in many individuals, as detailed in
the KDOQI Bone and Mineral guidelines.5 A bone biopsy
should be considered in patients before treatment withbisphosphonates, because bone biopsy is the most accurate
test for the diagnosis of adynamic bone disease, and thepresence of adynamic bone disease is a contraindication tobisphosphonates. Thus, the Work Group encourages thecontinued training of nephrologists in the performance andinterpretation of bone biopsies.
Classification of renal osteodystrophy by bone biopsy

Bone biopsies are performed to understand the pathophysiology and course of bone disease, to relate histologicalfindings to clinical symptoms of pain and fracture, and to
determine whether treatments are effective. The traditional
types of renal osteodystrophy have been defined on the basisof turnover and mineralization as follows: mild, slightincrease in turnover and normal mineralization; osteitis
fibrosa, increased turnover and normal mineralization;
osteomalacia, decreased turnover and abnormal mineralization; adynamic, decreased turnover and acellularity; mixed,
increased turnover with abnormal mineralization.
A recent Kidney Disease: Improving Global Outcomes
report2 has suggested that bone biopsies in patients withCKD should be characterized by determining bone turnover,mineralization, and volume (TMV). Thus, in this guideline
document, we have endeavored to examine data frompublished literature and report it using this TMV system.
Turnover. Patients with CKD display a spectrum of boneformation rates from abnormally low to very high. Other
measurements that help to define a low or high turnover(such as eroded surfaces, number of osteoclasts, fibrosis, or
woven bone) tend to be associated with the bone-formation
rate as measured by tetracycline labeling. This is the mostdefinite dynamic measurement, hence it was chosen to
represent bone turnover. It should be noted that an
improvement of a bone biopsy cannot be determined on
the basis of a simple change in the bone-formation rate,
because the restoration of normal bone may require either anincrease or a decrease in bone turnover, depending on thestarting point.
Mineralization. The second parameter is mineralization,
which reflects the amount of unmineralized osteoid. Mineralization is measured by the osteoid maturation time or bymineralization lag time, both of which depend heavily on theosteoid width as well as on the distance between tetracycline
labels. The classic disease with an abnormality of mineraliS34

zation is osteomalacia, in which the bone-formation rate is
low and the osteoid volume is high. Some patients have amodest increase in osteoid, which is a result of high boneformation rates. They do not have osteomalacia because themineralization lag time remains normal. The overall mineralization, however, is not normal because unmineralized
osteoid is increased. Patients with low bone-formation rates
and a normal osteoid have adynamic disease (they do noteven form the osteoid matrix, hence they do not manifest a
problem with mineralization).
Volume. The final parameter is bone volume, which has
not traditionally been included in previous schemes fordescribing renal osteodystrophy. Bone volume contributes tobone fragility and is separate from the other parameters. The
bone volume is the end result of changes in bone-formation
and resorption rates: if the overall bone formation rate ishigher than the overall bone resorption rate, the bone is in
positive balance and the bone volume will increase. If
mineralization remains constant, an increase in bone volume
would also result in an increase in BMD and should be
detectable by dual-energy X-ray absorptiometry (DXA).
Although both cortical and cancellous bone volumes decreasein typical idiopathic osteoporosis, these compartments are
frequently different in patients with CKD. For example, in
dialysis patients with high PTH levels, the cortical bonevolume is decreased but the cancellous volume is increased.93
Prevalence of abnormalities on bone biopsies

A systematic literature review of the prevalence of types ofbone disease in CKD is shown in Figure 7. The review
analyzed studies carried out between 1983 and 2006.
Differing prevalences of bone disease types observed between
studies are due to differing classification methods, inaddition to differences related to geographical areas, genetic
background, and treatment modalities. One of the mostproblematic differences in classification relates to the boneformation rate. This requires tetracycline labeling, and thus
normal ranges cannot be determined on autopsy or surgicalseries. The reported normal bone-formation rates show
inconsistencies and variations.20
The prevalence of bone histology types in children withCKD–MBD is similar to that observed in adults. Figure 8
shows the results from 325 children who had CKD stages
5–5D.18,34,9496
Natural history of bone biopsy findings

The distribution of histological types in patients with CKD
stage 5 was compared in studies before 1995 and after 1995
(Figure 9). The studies also revealed a decreased aluminum
intoxication, from 40% of biopsies carried out before 1995 to
20% in patients biopsied after 1995.
The natural history of bone disease evaluated throughbone histomorphometry is variable. The placebo groups
from RCTs and from one longitudinal study are shown in
Table 15. The overall trend is toward a worsening turnover(either getting too high or too low) and stable mineralization.
Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.2

CKD stages 3–5

Peritoneal dialysis
Normal16%

AD
18%

Hemodialysis

Normal
2%

Mild
6%

OM
8%

AD
19%

Mild
20%

Normal
Mild
2%
3%

OF
34%

OM
10%
AD
50%
OF
18%

Mixed
20%

OF
32%

OM Mixed
5% 5%

Mixed
32%

Figure 7 | Prevalence of types of bone disease as determined by bone biopsy in patients with CKD–MBD. Bone formation (turnover) is
high in those with osteitis fibrosa and mild disease, and low in those with osteomalacia and adynamic bone disease. Mineralization isabnormal in those with osteomalacia and mixed disease. AD, adynamic bone; OF, osteitis fibrosa; OM, osteomalacia.

Relationship between bone biopsy findings
and clinical outcomesChildrenAD
16%

Normal
17%

OM
6%
Mild
10%

Mixed
10%

OF
41%

%

Figure 8 | Prevalence of histological types of renal
osteodystrophy in children with CKD stages 5–5D.
AD, adynamic bone; OF, osteitis fibrosa; OM, osteomalacia.

45
40
35
30
25
20
15
10
5
0

Normal
Mild
OF
Mixed
OM
Adynamic< 1995> 1995Figure 9 | Types of renal osteodystrophy before and after
1995. OF, osteitis fibrosa; OM, osteomalacia.

The wide variability in the natural history of bone histology
reflects the complex pathophysiology of CKD–MBD(Supplementary Table 6). Another way to evaluate the natural
history of bone disease in CKD is to compare bonevolume by bone biopsy in predialysis patients with thatin dialysis patients. Studies dating from 1969 to 2007
show that bone volume/trabecular volume (BV/TV) is
generally lower in dialysis patients compared with that in
non-dialysis CKD patients across all renal osteodystrophy
categories.105112
Kidney International (2009) 76 (Suppl 113), S22–S49

Symptoms. A further analysis was carried out on 20 of theabove studies conducted in HD patients to examine therelationship of bone biopsy histology findings to clinicalsymptoms and changing trends over time (Figure 10). Mostof these patients had been referred for some clinical reason(6505 patients), whereas the remaining patients wereapparently asymptomatic (863 patients). There did not seemto be differences in the prevalence of histological types
between referred and asymptomatic patients.
Fractures. Most of the studies of bone histomorphometry
have not been designed to fully evaluate the relationshipbetween fractures and types of renal osteodystrophy. One
study of 31 dialysis patients found that those with lowturnover osteodystrophy had fracture rates of 0.2 per year
compared with 0.1 per year in those with osteitis fibrosa; thiswas because of a high number of rib fractures in the lowturnover patients.113 A review of 2340 biopsies carried out in
Brazilian patients for clinical indications found that thefrequency of fractures was significantly higher in those withosteomalacia compared with that in other forms. There were
no differences in fracture history between those withadynamic bone disease, high bone turnover, or mixed bonedisease.114 A study that followed up 62 patients for 5 years
after bone biopsy found a higher rate of fractures in thosewith adynamic bone disease.115
Theoretically, we would expect that persons with a lower
bone volume would be more likely to suffer fractures.
However, we could locate no reports of prospective studies ofpatients with a low bone volume to determine the subsequent
fracture rate.
Cardiovascular calcification. Several studies have examined
this issue. London et al.116 found that aortic calcification wasincreased in HD patients with adynamic bone disease. They
subsequently, with an expanded cohort, reported a significant
interaction between the dosage of calcium-containing
phosphate binders and bone activity, such that calcium load
had a significantly greater influence on aortic calcifications
and stiffening in the presence of adynamic bone disease.117 In
contrast, Barreto et al.,118 in their series of 98 HD patients,
did not observe an association between type of bone disease
S35

chapter 3.2

Table 15 | Changes in bone histomorphometric measurements from patients in placebo groups of clinical trials or longitudinalstudies
Turnover
Worse
HigherAuthor, year

Other RxCKD stages

N

Hamdy (1995)97 a
Spasovski (2006)98
Joffe (1994)99
Sanchez (2004)100
Baker (1986)101
Freemont (2005)13
Nordal (1988)102
Malluche (2008)103
Ferreira (2008)104

Ca, bindersCa, vit D
None
Ca, Al, vit D
Aluminum
Calcium
AluminumStandard
Calcium

3–4
5D, new
5D, PD
5D, PD
5D
5D
5
5D
5D

62
10
10
10
10
30
12
32
35

Lower

BetterHigherLower

Mineralization
Worse% of patients
6.5
0
10
0
50
10

6.5
30
0
10
0
20
NR
16
17

d

29
2.8

3.2
0
10
33c
0
13.5
NR
3
17

BetterChangeVolume change% of TV% of patients
0
0
10
0
0
6.5
NR
0
8.6

a

a

NR
10
0
40
0
0
0
3

NR
0
0
0
3
0
0
0

a

4.3% [OV]157b [MLT]
0.51 mm [Oth]NR
35b [MLT]
1b [MLT]40b [MLT]
14b [MLT]

0.95
NR
4.0
NR
NR
NR
0
1.2
2.3

BFR, bone-formation rate; CKD, chronic kidney disease; MLT, mineralization lag time; N, number of subjects; NR, not reported; OTh, osteoid thickness; OV, osteoid volume;
Rx, prescription; TV, trabecular volume.
a
Inconsistencies in mineralization values; bone volume average of two groups.
b
MLT, mineralization lag time in days.
cChange from adynamic to ‘high turnover’ but measurements were not above normal controls.
d
As group, BFR increase from average of normals to above normal range.

40

Normal
Mild

30

OF

%

Mixed

20

OM
Adynamic

10
0
No

Yes
Symptomatic

Figure 10 | Prevalence of bone histology types by symptoms
in patients with CKD stage 5D receiving HD treatment.
CKD, chronic kidney disease; HD, hemodialysis; mixed, mixed renal
osteodystrophy; OF, osteitis fibrosa; OM, osteomalacia.

and coronary artery calcification (CAC) on cross sectional
analysis. A more recent prospective study in HD patientsfound that lower trabecular bone turnover was associatedwith CAC development, whereas an improvement in boneturnover was associated with lower CAC progression inpatients with both high- and low-turnover bone disorders atbaseline.119
3.2.2

In patients with CKD stages 3–5D with evidence ofCKD–MBD, we suggest that BMD testing not be
performed routinely, because BMD does not predict
fracture risk as it does in the general population,
and BMD does not predict the type of renal
osteodystrophy (2B).

Bone density does not predict fractures very well in patientswith CKD stages 4–5. In addition, no treatments have beenshown to reduce fracture risk in those patients with CKD
stages 3–5 who have low BMD and biochemical abnormalities
of CKD–MBD (discussed in Chapter 4.3). Spine BMD
S36

measurements can be misleading if there are anatomic
abnormalities in the bone, if there is extensive osteophyte
formation, or if there is aortic calcification; hip measurements also can have positioning errors. Although forearm
measurements provide the least ability to predict fractures inolder persons without CKD, the meta-analysis by Jamal
et al.120 found that the forearm was the most sensitive site inpatients with CKD stage 5D. The Work Group acknowledges
that having a low DXA or a decreasing DXA value isindicative of abnormal bones. However, as detailed below, theetiology of the abnormal bone in CKD–MBD is complex, andpatients with CKD–MBD and osteoporosis should not beassumed to benefit from therapies such as bisphosphonates
provided in the general population. Thus, the Work Group
could not recommend the routine use of DXA in thesepatients.
BMD measurements

Noninvasive techniques for measuring BMD include DXA
and quantitative computed tomography (CT). Other methods have been used in some studies, but they do not have thesame extensive reference database or utility in clinical trials as
does DXA.
The skeleton is composed of cortical and trabecular(cancellous) bone. The trabecular bone is very porous: about
20% of the tissue is bone and the rest is marrow or fat. DXA
cannot differentiate between cortical and trabecular bone.
Certain sites, however, contain higher percentages oftrabecular bone (by weight). The forearm is almost all
cortical bone, the vertebral body is 42% trabecular bone,121
the proximal femur is about 25% trabecular, and the total
body about 80% cortical. These distinctions are importantbecause bone remodeling in patients with CKD–MBD isdifferent in trabecular bone compared with cortical bone.
Quantitative CT can separately measure cortical and trabecular bone because it is a three-dimensional measurement.
Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.2

Females (age 20–80+ years)
14,000,000

Estimated US population

12,000,000

10,000,000

8,000,000
Normal
Osteopenia

6,000,000

Osteoporosis

4,000,000

2,000,000

235–245

245–255

255–265275+

255–265

265–275275+

225–235

245–255

215–225

205–215

195–205

185–195

175–185

165–175

155–165

145–155

135–145

125–135

115–125

105–115

85–95

95–105

75–85

65–75

55–65

45–55

35–45

25–35

15–25

0–5

5–15

0

Creatinine clearance (ml/min)Males (age 20–80+ years)
14,000,000

Estimated US population

12,000,000

10,000,000
Normal
Osteopenia
8,000,000

Osteoporosis

6,000,000

4,000,000

2,000,000

235–245

225–235

215–225

205–215

195–205

185–195

175–185

165–175

155–165

145–155

135–145

125–135

115–125

105–115

95–105

85–95

75–85

65–75

55–65

45–55

35–45

25–35

15–25

0–5

5–15

0

Creatinine clearance (ml/min)Figure 11 | Distribution of osteoporosis, osteopenia, and normal bone density by creatinine clearance in general US population.
Reprinted with permission from Klawansky et al.122

DXA measurements of the spine may also be inaccurate
because of height. In children or short adults, DXA measurements seem lower than those in larger adults because the volume
of bone increases at a faster rate than does the projected area ofthe bone. Thus, the interpretation of DXA results in children
with growth delays must take into account the size of the bone.
BMD in patients with CKD stages 3–4

The Third National Health and Nutrition Examination
Survey, 1988–1994, measured BMD and serum creatinine in
13,831 adults older than 20 years. On the basis of the
Cockcroft–Gault equation, 23% of adult women with CKD
stages 3–4 had osteoporosis (BMD at total hipo0.64
g/cm2).122 As seen in Figure 11, the percentage of people
with low BMD was much greater in those with CKD than inthose with normal kidney function.
Kidney International (2009) 76 (Suppl 113), S22–S49

Not only do patients with CKD stages 3–4 have a highprevalence of low bone density but elderly patients withosteoporosis usually have CKD stage 3 or 4 (Figure 12). In the
US population, 61% of women with osteoporosis had CKD
stage 3 and 23% had CKD stage 4. Most of this overlap is seen
because both CKD and bone loss increase considerably withaging. In osteoporotic women younger than 60 years of age,the prevalence of CKD stage 4 was very low.122
A cross-sectional and longitudinal study of 1713 older
men and women found a significant linear association
between estimated GFR and hip bone density. The bone loss
over 4 years was associated with estimated GFR as measured
by the Cockcroft–Gault equation, but not by the Modificationof Diet in Renal Disease equation.124
Clinical trials of postmenopausal osteoporosis therapy
generally exclude patients with known kidney disease, hence
S37

chapter 3.2

the proportion of patients with CKD in the trials is lower thanthat in the general population. Measurement of estimated GFR
was lower than 45 ml/min per 1.73 m2 in 3.8% of theindividuals in the teriparatide trial,125 in 52% of the individuals
in the pooled risedronate trials,126 and in 9% of the individuals
in the alendronate Fracture Intervention Trial.127

Z-scores, which compare BMD in patients with BMD fromthe reference values of age- and gender-matched persons in
the community. The prevalence of low BMD is influenced by
the age of the cohort, the number of men, the proportion of
non-Caucasians, the average duration of dialysis, and theskeletal sites used to define osteoporosis.

BMD in patients with CKD stage 5D

BMD and fractures in the general population

Figure 13 shows the average values of BMD in studies ofpatients with CKD stage 5D. These values are expressed as

In 1994, the World Health Organization proposed
guidelines for the diagnosis of osteoporosis on the basis ofmeasurements of BMD.183 Osteoporosis was defined as BMD
lower than 2.5 s.d. from that of a young white female. In
2005, they reported a meta-analysis of data from 39,000
persons and found that BMD strongly predicted fractures.
For example, at the age of 50 years, the RR of a hip fracture
was 3.68 for each s.d. of hip BMD.184 Although BMD is an
important factor that predicts fracture, it does have
limitations and it is not the only significant factor. In
patients with osteoporosis, the degree of trauma and thequality of the bone also determine whether bones will
fracture. The World Health Organization recently developed
a method of assessing fracture risk on the basis of BMD andclinical risk factors: age, gender, race, weight, previous adultfracture, parental history of hip fracture, history of cigarettesmoking, alcohol use, rheumatoid arthritis, and glucocorticosteroid use.185 The equations used to calculate the risk
score are derived from international studies of 46,340 persons
and were validated in 230,486 persons, with a mean age of 63
years. The risk of a hip fracture was 4.2 times higher for everys.d. increase in the risk score.186 These calculations ofNormal

CKD
Osteostages 3-4 porosis

Figure 12 | Overlap between osteoporosis and CKD stages 3–4.
This graph shows the overlap between osteoporosis and CKD
stages 3–4 in women from the United States, using data from the
NHANES III survey. The kidney function was estimated using the
Cockcroft–Gault equation, which results in a greater prevalence of
CKD stage 3–4 than when other methods are used.123
CKD, chronic kidney disease; NHANES III survey, The Third
National Health and Nutrition Examination Survey.
1

0.5

0

Z-score

–0.5

–1

–1.5

–2

Spine
Hip
Forearm
Body

–2.5

2

197

3

198

3

199

6

199

1

200

3

200

6

200

Figure 13 | Bone mineral density in patients with CKD stage 5D. The graph is a summary of studies arranged in chronological order;
each point is the mean value for a study. When more than one skeletal site or gender was measured in a study, the points areconnected by a vertical line. If data from men and women were reported separately, the points for women are in a lighter shade. The size ofpoints is larger in studies with greater numbers of individuals. Data from studies that reported g/cm2 were converted to Z-scores (hipand forearm) using the average age of the group of individuals and published normal reference ranges. Overall, the average cortical bonedensity for patients with CKD stage s.d. was about 0.5–1 s.d. below that expected for age and gender, but at the spine, the bone density
measurements were closer to the average in persons without known CKD.115,128182 CKD, chronic kidney disease.
S38

Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.2

absolute fracture risk will apply to patients with CKD
stages 1–3 but have not been studied in patients with CKD
stages 4 and 5.
A definition of osteoporosis based on BMD does notdistinguish among different etiologies. The ability of a BMD
measurement to diagnose osteoporosis is similar to that of ahematocrit measurement to diagnose anemia. Just as there
are different causes of anemia (such as iron deficiency orhemolytic anemia), there are different causes of low BMD(such as corticosteroid-induced osteoporosis, osteomalacia,
myeloma, or renal osteodystrophy).
A relationship between BMD by DXA and fractures has
also been recently shown in children without CKD. In over7000 10-year-old children, a low BMD adjusted for size
parameters was associated with an 89% increased risk offractures in the subsequent 2 years.187 In young adults andmiddle-aged men and women, there are no large studies
relating fractures to DXA results.
BMD and fractures in CKD patients

In patients with CKD stage 5, the relationship between BMD
and fractures is not as strong as that in the general
population. We identified 13 cross-sectional studies thatmeasured BMD and prevalent fractures; there were noprospective studies. The results were variable: five studies
found no relationship between BMD and fracturerate,113,115,181,188,189 whereas eight studies found a relationship in at least one skeletal site.153,157,169,175,180,190192 A
meta-analysis by Jamal et al.120 included six of these studies
and found no increased risk of hip fracture related to BMD at
the hip. The spine and distal radius BMD values, however,were significantly lower in patients who had a fracture thanin those who did not. In a study of 187 men, Atsumi et al.157
found that each s.d. lowering of spine bone density increased
the odds ratio of a spine fracture by 2.0. Elder and Mackun180
studied 242 patients and found a lower BMD at the hip incases with fragility fractures, and a trend toward a lower spine
BMD. Ersoy et al.181 studied 292 patients receiving peritoneal
dialysis and found no relationship between BMD and
fractures.
The reasons for the poor performance of DXA in patientswith CKD are not defined. Partially, this is because themeasurements may overestimate BMD due to arthritic
conditions, scoliosis, and aortic calcifications, but thosewould apply mainly to the lumbar spine and not to the total
hip. Another reason is that CKD patients have poor bonequality that cannot be measured by absorptiometry. Abnormal microarchitecture, mineralization density, crystal deposition in the bone matrix, or abnormalities in the matrix itself
could all contribute to the loss of bone strength. Patients with
CKD, especially those with a high serum PTH, have increased
cancellous bone volume but decreased cortical thickness;93
this can alter the relationship between the overall bonestrength and BMD findings. Furthermore, patients with CKD
may experience more trauma to the skeleton if they havemore frequent falls.193196
Kidney International (2009) 76 (Suppl 113), S22–S49

BMD and relationship with bone biopsy findings in CKD

The relationship between BMD and bone biopsy is notwell defined. In patients with postmenopausal osteoporosis,
there is a significant but weak correlation between bonevolume on biopsy and BMD measured by DXA. In patientswith CKD, Lindergard93 measured BV/TV on 71 biopsies fromdialysis patients, and did not see a correlation with BMD at theradius. Similar results were seen by Gerakis et al.115 in a studyof 62 patients. Torres et al.,197 on the other hand, found acorrelation coefficient of 0.82 between BV/TV and quantitative
CT of the spine, and Van Eps et al.198 found lower DXA values
in patients with low BV on biopsy.
Is BMD different among the different types of renal
osteodystrophy? Studies of 20–30 patients found similar
BMD in all the types.146,167,199201 Boling et al.201 examined
27 patients; the types had similar values for BMD measured
by DXA, but the spine quantitative CT was 5% above thenormal mean in patients with a high bone turnover and 30%
below the mean in those with a low turnover. In a study of 62
patients, Gerakis et al.115 found that BMD by DXA was lower
in osteitis fibrosa than in adynamic bone, but there were wide
ranges in both types. The BMD by DXA was lower in thosewith severe osteitis fibrosa in the study by Fletcher et al.202 in
73 patients, particularly at the proximal forearm, in which the
BMD Z-score was 1.94 in severe osteitis fibrosa comparedwith 0.17 in mild disease. The patients with adynamic
disease also had a low forearm BMD with a Z-score of 1.85.
At the spine, those with mixed lesions were 2.85 s.d. higher
than normal, compared with 0.77 s.d. lower in those withsevere osteitis fibrosa.
BMD and mortality

In the general population, low BMD is associated withmortality. In CKD, low BMD was also associated with mortality,
as shown in a single study by Taal et al.203 (Supplementary Table 7)
in 88 HD patients. The risk was 4.3 times higher in thosewith hip BMD T-scores lower than 2.5 (the World HealthOrganization criteria for diagnosis of osteoporosis).
3.2.3

In patients with CKD stages 3–5D, we suggest thatmeasurements of serum PTH or bone-specificalkaline phosphatase can be used to evaluate bonedisease because markedly high or low values predict
underlying bone turnover (2B).

HPT is one of the most important causes of bone disease inpatients with CKD. The circulating PTH is related to bonebiopsy findings, but a prediction of the type of renal
osteodystrophy may be inaccurate. Bone biopsy remains thegold standard for the assessment of bone turnover, and asdetailed below, measurements of circulating PTH or b-ALP
have limited sensitivity and specificitiy, especially in detecting
adynamic bone. In addition, as detailed in Chapter 3.1, theavailability of various assay kits for PTH is another problem.
However, bone biopsy is not practical in the majority ofclinical patients, and when these serum markers are above orS39

chapter 3.2

below thresholds, they can be used to estimate bone turnover.
Large discrepancies between serum PTH and ALP measurements should prompt further investigation.
Serum PTH and ALPs and bone outcomes
Fractures. There have been several large prospective studies

in CKD stage 5D patients relating serum PTH to fractures(Supplementary Table 8), with inconsistent results, as shownin Table 16.
Several other cross-sectional studies157,175,180,189,191,192,208
have also evaluated this relationship and, in general,
were negative. However, a case-controlled cohort study
did find a 31% (95% confidence interval 0.57–0.83,
Po0.001) reduction in global fracture risk afterparathyroidectomy.209
An association between high serum t-ALP levels and the
RR of fractures has been reported in dialysis patients by
Blayney et al.32
PTH and b-ALP relationship with bone histology. The classic
findings of HPT in patients with CKD are high turnover withperitrabecular fibrosis, active osteoclasts and increased
numbers of multi-nucleated osteoclasts, woven bone, blurry
tetracycline labels, increased cancellous bone volume but
decreased cortical thickness, and intratrabecular tunneling.
The bone response to PTH, however, is not consistent, andthere is evidence for skeletal resistance to PTH in patientswith CKD–MBD.
The results of studies that reported correlations between
PTH and bone-formation rates are shown in Figure 14,
which shows the wide variabilities seen in different
situations.69,99,108,111,146,210224 The older studies tended
to find better correlations between PTH and bone-formation
rates, whereas more recent studies show poorcorrelations. This follows a trend for associating findingsof adynamic bone disease with high PTH levels. The
reasons for poor correlations between PTH and boneformation are not clear, but could involve differences in
the assays for PTH, secular changes in the dialysis
population with more diabetic and elderly patients,
differences in therapies, and differences in the racialcomposition of the studies. This figure also shows correlations with several bone turnover markers. Osteocalcin is
generally no better than intact PTH (iPTH), whereas b-ALP
shows a higher correlation with tetracycline-based bone-formation rates and has a better correlation to boneformation rate than does PTH. b-ALP also has somepredictive value for the diagnosis of high or low boneturnover (Table 17).
Even though there is usually a significant but weakcorrelation between serum PTH or other markers and boneformation rates, the ability to correctly classify an individual
patient is limited. As with any diagnostic test, there is a tradeoff between the sensitivity and the specificity of the test. The
predictive value depends on the sensitivity and specificity,and on the overall prevalence of the condition. It also
depends on which cutoff was used and how the diseases were
defined. Some of the differences among studies could becaused by a different exposure to aluminum, which increases
the skeletal resistance to PTH. The studies also used different
PTH assays, which may confound interpretation as detailedin Chapter 3.1. Table 17 shows the results that were reported
in studies that measured PTH and types of bone disease inpatients with CKD stage 5D. The positive predictive value isthe percentage of patients with a positive result on a test who
actually have the disease (either high or low turnover), andthe sensitivity is the percentage of patients with the disease
who have a positive test result.
Much of the focus of renal osteodystrophy has been onbone turnover, but bone volume is another important factor
in bone physiology. The correlations between BV/TV andPTH are not consistent among studies; four studies found nocorrelation,220,230232 one reported a correlation coefficientof 0.51,219 and another of 0.56.213 b-ALP showed no
relationship with bone volume in three studies;220,230,231 inanother, the correlation was 0.54;219 and in one, thecorrelation between b-ALP and BV/TV was not significant,but the b-ALP was lower in those who had histological signsof osteopenia.232
1

0.8
PTH

0.6

0.4

BAP
OC
X-link

0.2

Table 16 | Relationship between fractures and PTH in patientswith CKD–MBD
Author, year
90

Coco (2000)
Stehman-Breen (2003)204
Block (2004)205
Danese (2006)89
Jadoul (2006)206
Mitterbauer (2007)207

N
1272
4952
40,5389007
12,782
1774

Relationship between
fractures and PTH
High risk with low PTH
No relation
Weak direct association, P=0.035
Higher risk with low or high PTH
RR=1.7 if PTH4900
No relation

CKD–MBD, chronic kidney disease–mineral and bone disorder; PTH, parathyroid
hormone; RR, relative risk.

S40

0

Figure 14 | Correlation coefficients between bone formation
rate as seen on bone biopsies and serum markers of PTH,
bone-specific ALP (BAP), osteocalcin (OC), and collagencross-linking molecules (x-link) in patients with CKD stages
5–5D. Each point represents a study, and they are arranged inchronological order from 1981 to 2006 from left to right. Studies
that measured more than one marker are joined by a verticalline. The small symbols are studies of 20–50 patients, medium
symbols 51–100 patients, and large symbols 4100 patients.
CKD, chronic kidney disease; PTH, parathyroid hormone.
Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.2

Table 17 | Positive predictive value for iPTH and b-ALP to predict bone turnover in patients with CKD stage 5High bone turnover
Author, year

N
225

Cutoff

PPVa

Low bone turnover
Sensitivity

Cutoff

PPV

Sensitivity

92
83
43
88
89

a

o490
o65
o120
o150

76
78
89
83

93
88
48
91

o150
b-ALP
o150
b-ALP
o65

65
75
51
58
45

81
78
70
70
69

o150
o150
o237
b-ALP

97
54
47
57

92
81
78
83

o150

83

50

McCarthy (1989)
Hutchison (1993)146
Torres (1995)215
Wang (1995)216 b
Qi (1995)226 b
Couttenye (1996)227

41
30
119
175
79
103

41200
4200
4450
4200
4250

Urena (1996)219

42

Gerakis (1996)218
Fletcher (1997)202 b

114
73

Carmen Sanchez (2000)221
Coen (2002)108
Bervoets (2003)222

57
107
84

4200
b-ALP
4200
4100
b-ALP
4250

92
90
78
89
97
92

72
84
87
81
70
57

Lehmann (2008)228

132

Barreto (2008)229

97

4161
b-ALP
4300

89
91
62

75
71
69

79
88
100
58
80

b-ALP, bone-specific alkaline phosphatase; iPTH, intact parathyroid hormone; N, number of subjects; PPV, positive predictive value.
aC-terminal assay.
b
Calculated from sensitivity, specificity, and prevalence.

Table 18 | Correlation between PTH or other serum markers and BMD
Author, year

N

Patients% MaleStudy design

PTH

233

Rix (1999)
Tsuchida (2005)234
Obatake (2007)235

113
85
53

CKD 3–5
CKD 5
CKD 5

70
60
70

xs
xs
long

InverseTaal (1999)159
Atsumi (1999)157

88
187

HD
HD

88
100

xs
xs

Gerakis (2000)115
Kokado (2000)162
Barnas (2001)163
Pecovnik (2002)170
Ueda (2002)236

62
293
90
50
195

HD
HD
HD
HD
HD

66
60
60

xs
xs
xs
xs
long

Urena (2003)175
Nakashima (2003)174
Negri (2004)189
Nakashima (2006)182

70
83
65
201

HD
HD
PD
HD

60
53
60

xs
xs
xs
long

Jamal (2006)192
Wittersheim (2006)237
Ersoy (2006)181
Elder (2006)180
Sit (2007)238
Doumouchtsis (2008)239

52
79
292
242
70
54

HD
HD, PDPD
HD, PD
HD
HD

71
48
56
61
52
50

xs
xs
xs
xs
xs
xs

InverseInverse (body,not spine)
InverseInverseNot related
InverseInverse tochange in BMD
InverseInverseInverseInverse tochange in BMD
InverseInverseNot related
InverseNot related
Not related

100

Other markers
OC, PINP, b-ALP: inverse; NTX, DPD, PYD: not related
Higher OC had more bone loss; b-ALP, NTX,PINP not significant

OC: inverse

Radial BMD change inverse to PINP,
b-ALP, OC, CTX, NTX, and DPD
CTX, b-ALP: inverse

BMD change positive with OPG;
b-ALP, NTX, OC, TRAP: inverse
OPG, RANK-L not correlated; CTX: inverse

OPG, ALP: inverse; OC, TRAP: not related

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; BMD, bone mineral density; CKD, chronic kidney disease; CTX, carboxyterminal cross-linking telopeptideof bone collagen; DPD, deoxypyridinoline; HD, hemodialysis, long, longitudinal; N, number of subjects; NTX, aminoterminal cross-linking telopeptide of bone collagen;OC, osteocalcin; OPG, osteoprotegerin; PD, peritoneal dialysis; PINP, procollagen type I N propeptide; PTH, parathyroid hormone; PYD, pyridinoline; RANK-L, Receptor
Activator for Nuclear Factor kB Ligand; TRAP, tartrate-resistant acid phosphatase; xs, cross-sectional.

PTH relationship with BMD. Table 18 shows the resultsfrom studies that measured BMD and serum markers in atleast 50 patients with CKD–MBD. None of the studies founda positive effect of PTH on BMD; either the relationship was
not significant or there was a significant inverse correlation.
PTH and combinations of biochemistries in the prediction ofbone histology. None of the studies published to date in
Kidney International (2009) 76 (Suppl 113), S22–S49

CKD patients have been adequately powered to assess if
combinations of PTH and other bone-derived circulating
biomarkers would be more predictive than individual
markers. Kidney Disease: Improving Global Outcomes iscoordinating an ongoing international collaborative effort todetermine the predictive value of whole (1–84) PTH assays
compared with currently used iPTH assays, with or without
S41

chapter 3.2

other biomarkers, to predict underlying bone histology using
the TMV classification system.
3.2.4

In patients with CKD stages 3–5D, we suggest not toroutinely measure bone-derived turnover markers
of collagen synthesis (such as procollagen type I
C-terminal propeptide) and breakdown (such astype I collagen cross-linked telopeptide, cross-laps,
pyridinoline, or deoxypyridinoline) (2C).

Collagen-based markers of bone turnover, measured in theserum, have not been extensively evaluated in patients withCKD stages 4–5. The available studies show that thesemarkers do not predict clinical outcomes or bone histology
any better than does circulating PTH or b-ALP. Therefore, at
this time, they are not recommended for diagnostic purposesin patients with later stages of CKD–MBD. In earlier stages of
CKD, some of these markers seem promising for monitoring
the treatment of osteoporosis, but they currently are notsufficiently validated to recommend their use.
Bone markers
Collagen based.

Active osteoblasts secrete procollagen type I,
and the propeptides at both C- and N-terminal ends are
immediately cleaved and can be measured in the circulation(PICP and PINP). The collagen molecules are then covalently
bonded through pyridinoline cross-linking. The fragments
containing these pyridinoline links (at both the C- and Nterminal ends of the peptides) are released during bone
resorption: carboxyterminal (CTX) and aminoterminal(NTX) cross-linking telopeptide of bone collagen, respectively. These collagen-based markers have been studied innormal populations, wherein there are significant but
moderate correlations with bone-formation/resorption
rates.240 The markers are increased after a fracture.241
Other bone markers. Osteoblasts secrete other proteinsthat have been used to assess their function, including b-ALP(discussed in the previous section), osteocalcin, osteoprotegerin, and receptor activator for nuclear factor kB ligand.242
Osteoclasts secrete tartrate-resistant acid phosphatase. Osteocytes secrete FGF-23 in response to phosphate andcalcitriol. High levels of FGF-23 are seen in patients with
CKD, but this is a new measurement, and clinical significanceremains to be determined. FGF-23 was recently shown to be
associated with an increased RR of mortality in dialysis
patients,243 but this may be related to phosphate or vitamin
D metabolism and not to bone disease per se. Thus, althoughsynthesized in bone, it seems premature to use FGF-23 as abone biomarker.
Some of these markers are excreted by the kidneys, so in
CKD, the serum concentrations may merely represent
accumulation instead of bone turnover.
Markers of bone turnover and clinical outcomes. In cohortsof elderly women, most of whom have early stages of CKD,
serum biochemical markers of bone turnover have been
associated with fractures.244246 The utility of these markers
S42

in individual patients is uncertain, and they are currently notrecommended in the routine evaluation of patients with
postmenopausal osteoporosis. These markers, however, may
be helpful in identifying those patients who respond toosteoporosis medications. In the fracture intervention trial ofalendronate, the change in b-ALP and CTX was significantly
related to the reduction in fracture incidence, and for hip
fractures, the changes in markers predicted fractures better
than did the BMD changes.247 Furthermore, in those women
who had postmenopausal osteoporosis with low baseline
PINP levels, alendronate did not reduce the risk offractures.248 With raloxifene, the osteocalcin change predicted fracture incidence better than did the BMD change.249
In patients with CKD stages 4–5, there are limited datathat relate serum markers to fractures. Urena et al.175 foundthat cross-laps (C-terminal peptide) and b-ALP were notdifferent between fracture and non-fracture cases in a surveyof 70 dialysis patients.
A recent study evaluated patients with CKD stages 1–5
without known CVD and found that reduced tartrateresistant acid phosphatase-5B and elevated b-ALP were both
associated with an increase in the RR of cardiovascularmortality.250 These somewhat paradoxical findings suggestthat much more work needs to be carried out to fully
understand the clinical utility of such biomarkers.
Bone markers and bone histology

In CKD patients, a few studies show significant correlations
between collagen cross-linking molecules and the boneformation rate (shown in Figure 14).
Bone volume was not related to these markers in two
studies. Coen et al.220 measured a panel of circulating
biomarkers (iPTH, osteocalcin, b-ALP, tartrate-resistant acidphosphatase, CTX, and deoxypyridinoline) in 41 patientswith CKD stage 5, and none of them correlated with the
BV/TV. Barreto et al.230 focused on factors that related toosteoporosis in 98 patients with CKD stage 5, half of whom had
a BV/TV less than one s.d. from the normal mean. They foundno relationship between the low BV/TV and serum iPTH,b-ALP, or deoxypyridinoline, but the tumor necrosis factor-aand the osteoprotegerin/receptor activator for nuclear factor kB
ligand ratio was higher in those with a low BV/TV. Thus, at thispoint in time, there is insufficient evidence for the use of thesemarkers. More research is clearly needed.
Bone markers and BMD
Predicting BMD at a single point in time.

In the general
population, observational studies of elderly people show thatcirculating bone turnover markers are not related to BMD at
one point in time.251 In clinical trials of osteoporosis
medications, the baseline biochemical markers do notconsistently predict the change in BMD. (As noted above,
however, the baseline biochemical measurements may
predict fractures in some cases, and this is more important
than predicting BMD results.) The data in patients with CKD
stages 4–5 are limited and inconsistent, as shown in Table 18.
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Predicting change in BMD. In studies on osteoporosis, thechanges in measurements of bone formation and resorption
may be related to the changes in BMD with sometreatments.247 On an individual level, it is not certain how
reliable these markers will be in predicting BMD change. At
present, there is no consensus with regard to the clinicalutility of markers in individual patients with osteoporosis,
but many ongoing studies are examining this issue, especiallyas anabolic drugs are being developed.
On a theoretical basis, bone markers should be able topredict the change in bone volume, which is determined bybone balance. Unfortunately, none of the current serum or
urine markers of bone turnover are sensitive enough to allow
the calculation of bone balance, and the interpretation of themeasurements depends on the clinical situation. For example,
the highest serum levels of turnover markers are found inpatients with metastatic cancer, Paget’s disease, and in healthyadolescent boys.
When interpreting bone turnover markers, it is importantto remember the distinction between bone volume, as
measured on bone biopsies, and BMD, as measured with aradiographic technique. Density depends on both the bonevolume and the mineralization of the bone. Newly formed
bone is not as dense as older bone, and patients with a highturnover have a greater proportion of newly formed bonewith a low BMD. When bone turnover is decreased, the bone
becomes ‘older’ and accumulates more minerals, increasing
the DXA value without necessarily increasing the bonevolume. In patients with CKD, the relationships are evenmore complicated because the mineralization is frequently
abnormally low, so that BMD can be low even when bonevolume is normal. Rapid increases in BMD can be observed
when osteomalacia is treated, even without any formation of
new bone, because the osteoid fills with mineral. The markers
of bone formation that depend on the secretion of new collagen
would not be able to detect this improved mineralization.

3.2.5

We recommend that infants with CKD stages 2–5D
should have their length measured at least quarterly, while children with CKD stages 2–5D should
be assessed for linear growth at least annually (1B).

In children with CKD stages 2–5D, abnormalities in statural
growth are commonly observed. Such abnormalities may
include a height below the 3rd percentile of the growth curvefor normal children of the same gender; a negative statural
growth curve against the genetic potential based on midparental height formulas even when on the normal growth
curve; or a negative growth velocity, based on gender-specificcurves of normal children. Growth should be assessed at least
monthly in infants, quarterly in children below 2 years of age,
and at least annually in older children and adolescents, andplotted accurately on the appropriate growth chart for either
height, velocity, or ideally, both. This allows for an optimalunderstanding of the defects in linear growth that may occur
with CKD in children. Growth velocity as rates and absolute
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changes in height is used as an end point in clinical trials of
growth-hormone therapy in children and adolescents with CKD.
Linear height deficit (short stature) is one of the cardinalfeatures of progressive CKD in pediatric patients. In normalchildren, the 50th percentile for height corresponds to a
Z-score of 0. The 3rd percentile is a Z-score of 1.88. In
children with CKD, over one-third of patients have Z-scores
lower than 1.88.252 Baseline kidney function, by heightZ-score, shows that there are patients with severe height
deficits, even though they have a moderate kidney function(425 ml/min per 1.73 m2). In patients with a calculated
clearance between 50 and 75 ml/min per 1.73 m2, 18.2%(379 of 1720) had a height Z-score worse than 1.88. The
mechanisms of linear growth failure include the presence ofchronic metabolic acidosis, renal osteodystrophy, nutrient
wasting, chronic inflammation, functional hypogonadism insome adolescents, and dysregulation of the growth hormone–insulin-like growth factor 1 endocrine axis. The latter has
led to the development and use of a recombinant human
growth hormone, which has been licensed by the Food andDrug Administration in the United States since 1988 for thetreatment of linear growth failure in children with CKD, one of
the measures of bone in CKD–MBD. However, using data fromthe North American Pediatric Renal Transplant Cooperative
Study 2006 data report,252 only 6.5% of all patients at entry
into the registry were using recombinant human growth
hormone. By 24 months of follow-up, 15.9% of patients being
followed up were receiving recombinant human growth
hormone. This low usage prompted an examination of thebenefit and harm of recombinant human growth hormone inchildren (see Chapter 4.3).
RESEARCH RECOMMENDATIONS

Additional research is called for:K A prospective study of BMD to determine fracture risk
thresholds in CKD stages 3–5, 5D, and 1–5T.
K A prospective study of circulating biochemical markers(PTH, b-ALP, PINP, PICP, NTX, CTX, tartrate-resistantacid phosphatase, and osteoprotegerin) to determine ifthey can predict fractures or other clinical outcomes in
CKD stages 3–5, 5D, and 1–5T.
K The development of an international standard for theassessment of renal osteodystrophy, particularly for
dynamic measurements.
SUPPLEMENTARY MATERIAL
Supplementary Table 4. Prevalence and incidence of fractures in patientswith CKD 5D.
Supplementary Table 5. Fractures in patients with CKD stages 3–4.
Supplementary Table 6. Overview table of selected studies of the natural
history of bone disorders.
Supplementary Table 7. Overview table of selected studies demonstrating
the risk relationship between bone measurements and mortality in CDKstage 5D.
Supplementary Table 8. Overview table of selected studies demonstrating
the risk relationship between hormonal parameter, PTH, and fractures in
CKD stage 5D.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki
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http://www.kidney-international.org& 2009 KDIGO

Chapter 3.3: Diagnosis of CKD–MBD: vascular calcification
Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

The diagnosis of CKD–MBD includes the detection of
extraosseous calcification, including arterial, valvular, andmyocardial calcification. It is generally well recognized thatthe prevalence of calcification increases with progressively
decreasing kidney function and is greater than that in thegeneral population. Cardiovascular calcification is associatedwith, and predictive of, adverse clinical outcomes, including
cardiovascular events and death. However, there are someuncertainties with regard to the sensitivity and specificity ofthe different imaging tests available for detecting cardiovascular calcification. Further, there is also uncertainty as towhether altering the progression of cardiovascular calcification will impact patient outcomes (cause–effect relationship)in different stages of CKD. Finally, there is no clear evidencebased protocol or algorithm for the diagnostic andtherapeutic strategies that need to be followed after yielding
a positive calcification test result.
RECOMMENDATIONS

3.3.1

3.3.2

In patients with CKD stages 3–5D, we suggest that alateral abdominal radiograph can be used to detect
the presence or absence of vascular calcification,
and an echocardiogram can be used to detect thepresence or absence of valvular calcification, as
reasonable alternatives to computed tomographybased imaging (2C).
We suggest that patients with CKD stages 3–5D withknown vascular/valvular calcification be consideredat highest cardiovascular risk (2A). It is reasonable
to use this information to guide the management of
CKD–MBD (not graded).

Summary of rationale for recommendations

In the normal population, the magnitude of CAC asimaged by either electron beam CT (EBCT) or multislice
CT (MSCT) is a strong predictor of cardiovascular
event risk.
K In the CKD population, coronary artery and generalized
vascular calcification is exceedingly more prevalent, moreK

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severe, and follows an accelerated course compared withthat in the normal population.
K The reference standard in the detection of cardiovascular
calcifications in CKD and in the general population is theCT-based CAC score, but other, more easily available
techniques—for example, lateral abdominal X-ray, pulse
wave velocity (PWV) measurements, and echocardiography (valvular calcification)—may yield comparable
information.
K The presence and the severity of cardiovascular calcification strongly predict cardiovascular morbidity andmortality in patients with CKD.
K However, there is limited evidence from RCTs in CKD thatthe reduction of arterial calcification progression impacts
mortality.
K A majority of Work Group members felt that inconsistencies remained among RCT reports aimed at showingthat intervention improved patient level outcomes, andhence, indiscriminate screening in every patient withCKD–MBD was not recommended.
K However, there was consensus that known vascular/
valvular calcification and its magnitude identify patients
at high cardiovascular risk. Therefore, the presence ofvascular/valvular calcification should be regarded as acomplementary component to be incorporated into thedecision making of how to individualize treatment of
CKD–MBD.

BACKGROUND

Tissue calcification is a complex and highly regulated process
in bone and teeth, and also at extraosseous sites. The mostthreatening localization of unwanted calcification is at
vascular sites, where it may manifest as both medial andintimal calcification of arteries. In the general population,
autopsy and imaging studies have identified calcification in
495% of atherosclerotic plaques. Calcification seems to be apart of the natural history of atherosclerotic plaques, withextensive calcification associated with late-stage (American
Heart Association Stage Va and VII) atherosclerosis. In the
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general population, atherosclerotic plaque calcification isassociated with cardiovascular events such as myocardial
infarction, symptomatic angina pectoris, and stroke.253255
Medial calcification causes arterial stiffness, resulting in anelevated pulse pressure and increased PWV, thereby contributing to left ventricular hypertrophy, dysfunction, andfailure. Furthermore, an advanced calcification of the heart
valves may lead to dysfunction contributing to heart failure
and an increased risk of endocarditis. Cardiovascular
calcifications are usually progressive, and their extent andseverity are highest in patients with CKD. Recent reportssuggest an increased prevalence of cardiovascular calcificationin patients at early stages of CKD. Thus, a considerable
percentage of CKD patients are at risk of cardiovascular
events from vascular calcification.
As mentioned above, two patterns of vascular calcification
have been described: predominantly intimal and predominantly medial calcification. There is, however, an ongoingdebate with regard to the differential role of intimal(atherosclerotic) vs medial (arteriosclerotic) calcification in
CVD in CKD patients.256,257 In the general population, anelevated coronary artery calcium score almost exclusively
reflects the atherosclerotic disease burden. In two small
autopsy studies, it became apparent that, in dialysis patients,
CAC is also predominantly localized in the coronary intima,
whereas the medial calcifications observed in a minority ofsuch patients seemed to be adjacent to plaque areas justbeneath the internal elastic lamina.258,259 Although thecoronary vascular bed may differ considerably from otherarteries with regard to the calcification process and its
manifestations, the same group observed a ‘pure’ medial
calcification in the coronary arteries during the early stages of
CKD.257 A ‘pure’ medial calcification, in the absence of
intimal disease, was also observed in epigastric arteries
obtained from dialysis patients at the time of renaltransplantation.260 An older study identified both intimaland medial calcifications in iliac arteries of such patients.261
Thus, there is neither definitive evidence to suggest thatisolated medial calcification is distinct from the calcificationthat occurs in the natural history of atherosclerosis nor isthere definite proof against it.
Arterial calcification assessed by all the available imaging
studies cannot accurately differentiate calcification that is
localized to the intima from calcification in the media
adjacent to the internal elastic lamina, or in the medial
layer. Experimental and ex vivo studies suggest that thevascular smooth muscle cell may be critical in the development of calcification by transforming into an osteoblast-likephenotype.262 In addition, the pericyte in the media andadventitia may have a role in the secretion of vascular
calcification-inducing factors. The stimulus for such atransformation may depend on the location of calcification
within the artery wall. For example, in intimal lesions,atherosclerosis may be the most important stimulus.
However, in patients with CKD and medial calcification,
there may be additional, or additive, factors potentially
Kidney International (2009) 76 (Suppl 113), S22–S49

explaining why medial calcification of the peripheral arteries
can be seen without intimal changes and is more common in
CKD than in the non-CKD population.260 Elevated phosphorus, elevated calcium, oxidized low-density lipoproteincholesterol, cytokines, and elevated glucose, among others,
stimulate this transformation of vascular smooth muscle cells
into osteoblast-like cells in vitro using cell-culture techniques.
These factors likely interact at the patient level to increase
and/or accelerate calcification in CKD. Given the potential
complexity of the pathogenesis and the inability ofradiological techniques to differentiate the location of
calcification, the approach to all patients with calcification
should be to minimize atherosclerotic risk factors and control
biochemical parameters of CKD–MBD. In vivo animal studies
have shown less arterial calcification with non-calcium-based
binders compared to that with calcium-based binders.263,264
Unfortunately, trials in dialysis patients evaluating suchstrategies to treat either atherosclerosis or CKD–MBD havenot conclusively shown that such an intervention positively
affects patient-level outcomes.265267 Despite this, given thehigh cardiovascular burden in CKD, the majority of theWork Group felt that the treatment approaches to limit thecalcium intake from phosphate binders in CKD
patients with known vascular/valvular calcification wereappropriate until definitive studies are conducted, as detailedin Chapter 4.1.
Extraosseous calcification in patients in advanced stages of
CKD has been observed since the early days of dialysis,268,269
but was originally thought to result predominantly from asupersaturation of serum with calcium and phosphate ions,that is, passive precipitation. However, in recent years, it
became evident that vascular calcification is also an active
cellular process. As already pointed out above, the presenceor upregulation of inducers of cellular osteogenic transformation and hydroxyapatite formation (among which highphosphate probably has a central role)262 causes thedifferentiation of vascular smooth muscle cells into an
osteoblast-like phenotype of vascular smooth muscle cells.
Newly discovered calcium-regulatory factors, including
fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates—all of which possess properties of systemic or local
calcification inhibitors—may have a key role in fine-tuning
protection against unwanted calcification, and some of thesefactors may be dysregulated in uremia.270 A seminal paper by
Murshed et al., however, showed that even complex
pathological mineralization disorders can be prevented bymodulating extracellular phosphate concentration.271 Therefore, it is biologically plausible that the calcification processdevelops from unique stimuli and progresses in an accelerated manner in CKD patients. As epidemiological studies
suggest a direct relationship between calcification andimpaired clinical outcomes, cardiovascular calcification isthus regarded as a relevant clinical end point by mostinvestigators mirroring cardiovascular event risk. However,it cannot yet be used as a reliable surrogate marker
for interventions, as the link between intervention andS45

chapter 3.3

patient-level outcomes when calcification is ameliorated has
not been shown conclusively.
Finally, a rare but very severe form of medial
calcification of small (cutaneous) arteries is calciphylaxis,
also called calcific uremic arteriolopathy. This complication isstrongly associated with CKD-related disturbances ofmineral metabolism, including secondary HPT, inapproximately one-third of cases. It is characterized byischemic, painful skin ulcerations followed by superinfections, and is associated with high mortality. Relationships with dysregulated calcification inhibitors (fetuin-A
and matrix Gla protein) have been implicated in thepathogenesis of calciphylaxis, but because of the relatively
low incidence of the disease, no conclusive data are
available to firmly comment on the nature of the disease
process or to allow generalizable treatment options to berecommended.
This topic represents a comprehensive review of theliterature of selected topics by the Work Group withassistance from the evidence review team to formulate arationale for clinical recommendations. Thus, this should not
be considered as a systematic review.
RATIONALE

3.3.1

In patients with CKD stages 3–5D, we suggest that alateral abdominal radiograph can be used to detect
the presence or absence of vascular calcification,
and an echocardiogram can be used to detect thepresence or absence of valvular calcification, as
reasonable alternatives to computed tomographybased imaging (2C).

Diagnostic tests

Most studies examining calcification in CKD reported on
the use of CT-based techniques (EBCT and MSCT) in thedetection of cardiovascular calcification in patients withCKD–MBD (Supplementary Table 9). EBCT and MSCT are
currently regarded as the most sensitive methods for thedetection and quantification of cardiovascular calcification.
One study explicitly evaluated the sensitivity and specificity
of several imaging tests and functional/hemodynamic
measures for detecting CAC compared with EBCT.272 This
analysis focused on pulse pressure measurements, valvular
calcification (by echocardiography), and abdominal aortic
calcification (by lateral abdominal X-ray), respectively,
according to the severity of CAC scores as assessed by EBCT
scores of 30–99, 100–399, 400–999, and X1000. No meaningful correlation was found between pulse pressure and CAC
scores. In contrast, a strong correlation was detected between
abdominal aortic calcification by plain radiograph and CAC
scores. Valvular calcification, detected by echocardiography,
was another good predictor of CAC.
We reviewed six additional studies which carried out
correlation analyses comparing CT-based imaging techniquesof assessing CAC with other measures of calcification. Theselatter measures included pulse pressure, abdominal aortic
S46

calcification by lateral X-ray, PWV, echocardiography(valvular calcifications), intimal-media thickness (IMT) of
the carotid arteries, and MSCT of the thoracic and abdominal
aorta.273278 PWV and abdominal aortic calcifications
seemed to be reasonably good predictors of CAC
scores, whereas the value of IMT, valvular calcification,and especially pulse pressure was limited. However, thesestudies were not designed to test sensitivity and specificity inthis regard. The majority of the reported data referred to the
CKD stage 5D population, whereas some studies included
patients in different CKD stages.273,275 Only one study
evaluated children (CKD stageX4).278 Thus, EBCT and
MSCT remain the gold standard. However, a plain X-ray
examination allows the detection of vascular calcification,and echocardiography allows the detection of valvular
calcification, with reasonable sensitivity, as compared withthe more expensive CT-based techniques. Thus, the WorkGroup felt that plain X-ray and echocardiography werereasonable alternatives to the gold standard of CT-based
imaging.
3.3.2

We suggest that patients with CKD stages 3–5D withknown vascular/valvular calcification be consideredat highest cardiovascular risk (2A). It is reasonable
to use this information to guide the management of
CKD–MBD (not graded).

To recommend widespread global screening for the diagnosisof vascular calcification in all patients with CKD, the WorkGroup felt that the following was needed: (i) There should bean accurate and reliable diagnostic test (see above); (ii)vascular calcification should be prevalent enough to warrant
screening; (iii) the tests should prompt a specific intervention; and (iv) the intervention should impact hard clinicalend points. The Work Group felt that the data to support (i)and (ii) were strong, the data to support (iii) were somewhat
inconsistent, and the data to support (iv) were limited. Thus,
the Work Group did not recommend indiscriminate screening in all patients with CKD at this time, although this was a
split decision. However, vascular calcification is an importantcomponent of CKD–MBD, and animal, epidemiological, andobservational studies support that vascular/valvular calcification is a likely cause of cardiovascular morbidity andmortality in patients with CKD–MBD; thus, an assessment
for vascular calcification is warranted in some patients. Thesemay include, but are not limited to, patients with significant
hyperphosphatemia requiring a differentiated high-dose
phosphate-binder therapy, patients on a transplant waiting
list, and any patient in whom the caring physician decides
that a knowledge of the presence of vascular calcification may
impact therapeutic decision making.
Prevalence

Twenty-five reports including information on the baseline
prevalence of vascular or valvular calcification were evaluated(Supplementary Table 10). The studies included a total of
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more than 4000 patients in different stages of CKD, themajority being in CKD stage 5D. In adult patients on dialysis,
CAC has been detected in 51–93% of the study populations;prevalent dialysis patients had a higher likelihood of having
detectable CAC scores than did incident ones. Valvular
calcification was present in 20–47% of patients in CKD stage
5D. The prevalence of calcifications was variable at othervascular sites and was dependent on the sensitivity of themethod used.
In CKD stages 3–5, published information related mostly to
CAC scores showed that 47–83% of patients had cardiovascular
calcification. In children with CKD stage 5D, the prevalence of apositive CAC was found to be 20% in one study.278 In young
adults receiving dialysis treatment (age ranges: 20–30 years in
one study, 19–39 years in a second study) with childhood-onset
CKD, CAC prevalence was 87.5 and 92%, respectively.279,280
Valvular (aortal or mitral) calcifications were present in 20–25%
of 653 patients with CKD stages 3–5 in the Multi-Ethnic Studyof Atherosclerosis,281 whereas the degree of renal dysfunction
was only modestly associated with valvular calcification. In
patients on dialysis, valvular calcification is more common, with
one series reporting the presence of valvular calcification in 32%
of patients.282
Eight studies investigating the natural history of calcification in a predefined prospective longitudinal approach in
CKD were examined (Supplementary Table 11). Follow-up
periods ranged from 1 to 3 years; detection methods were
MSCT, EBCT, X-ray of pelvis and calves, and in one study,
IMT. The major finding in this context is that once
calcification is established, it follows a progressive course.
In contrast, non-calcified patients with CKD have a highlikelihood of remaining free of cardiovascular calcification
over months to years. Compared with the non-CKD
population, the progression of cardiovascular calcification isenhanced in patients with CKD. Furthermore, there is astrong relationship between the magnitude and severity ofcalcification and pre-existing coronary artery disease.
Risk relationships

We reviewed 10 reports on the risk relationships between
cardiovascular calcification and mortality in patients withCKD (Supplementary Tables 12 and 13). Most of these studies
were again conducted in dialysis patients, including one inperitoneal dialysis patients, but there is also information on
renal transplant recipients and patients in CKD stages 4–5.
EBCT, MSCT, ultrasound, echocardiography, and several
X-ray techniques (pelvis, abdomen and hands) were usedas diagnostic tests. In all but one study, cardiovascular
calcification or progression of calcification were identified as
independent risk predictors for cardiovascular and all-cause
mortality. In only one study283 did valvular calcification
lose its significance in predicting death after a multivariate
adjustment.
In some of these studies (as well as in others that primarily
addressed the natural history of calcification), risk associations were reported between the development and progresKidney International (2009) 76 (Suppl 113), S22–S49

sion of calcification and epidemiological and biochemicalparameters. Age was the most consistent risk factor for severeor progressive calcification, whereas diabetes, time on
dialysis, male gender, high serum iPTH and/or ALP levels,
inflammation (C-reactive protein levels), calcium intake,hyperphosphatemia, and increased Ca  P were identified insome studies, but the latter relationships could not be
uniformly reproduced. No studies of adequate quality
reported on the relationship between cardiovascular calcification and bone outcomes in CKD patients.
Management of patients with vascular/valvular calcification

Cardiovascular calcification development and progression
can be influenced by treatment. Given that vascular
calcification is associated with increased cardiovascular risk,
and that the pathogenesis seems to be related to CKD–MBD(biochemical and bone) abnormalities and atherosclerosis, it
is appropriate to evaluate and modify both.
CKD–MBD. Longitudinal studies have also shown that the
progression of vascular calcification seems to be modifiableby the choice of phosphate binders. Five studies compared
the effects of different phosphate-binder therapies on the
progression of CAC scores in chronic HD patients284288 (seeChapter 4.1). The Treat-to-Goal study (n ¼ 200) comparedsevelamer-HCl to calcium-containing phosphate binders,
analyzing the progression of coronary artery and aortic
calcification (by EBCT) in prevalent HD patients over 1 year.
Although calcification scores progressed with calcium-containing phosphate binders, treatment with sevelamer-HCl
was associated with a lack of calcification progression. A
similar design was used, and the results showed morecalcification progression in patients treated with calciumbased binders compared with sevelamer-HCl in the Renagel
in New Dialysis Patients study (n ¼ 129), which studied
incident HD patients who were randomized within 90 days
after starting dialysis treatment. The Calcium Acetate Renagel
Evaluation-2 study (n ¼ 203) showed that the use of
sevelamer-HCl and calcium acetate was associated with equal
progression of CAC when statins were used to achieve asimilar control of the serum low-density lipoproteincholesterol in the two study arms.287 Interestingly, in Calcium
Acetate Renagel Evaluation-2, the combination of sevelamerHCl and atorvastatin was actually associated with a higher
progression rate of CAC than that in Treat-to-Goal,284
instead of showing an amelioration of CAC progression withthe combination of calcium acetate and statin. It is difficult
to reconcile these differences, although one potential
explanation is that the Calcium Acetate Renagel Evaluation2 study patient population had a higher number ofcardiovascular risk factors than did that of the Treat-to-Goalstudy.289 The Bone Relationship with Inflammation andCoronary Calcification study (n ¼ 101) investigated theeffects of calcium acetate vs sevelamer-HCl on CAC
progression and bone histomorphometry in HD patients.
Although CAC progression rates did not differ between both
phosphate-binder arms, this study was hampered by a much
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chapter 3.3

smaller sample size and several significant confounders:imperfect matching of baseline CAC scores between the twostudy arms; the use of high dialysate calcium concentrations(1.75 mmol/l (3.5 mEq/l)) in most patients, resulting in apositive calcium balance; and multiple interventions during
the course of the study aimed at improving adynamic bonedisease.288 It is possible that these confounders ‘neutralized’
any potential advantage of sevelamer-HCl being a calciumfree phosphate binder. Finally, Russo et al. examined CAC
score progression in patients with CKD stages 3–5 (n ¼ 90).
Patients were treated with either low-phosphate diet alone,
low-phosphate diet plus calcium carbonate, or low-phosphate diet plus sevelamer-HCl. Calcification progression waslowest in the sevelamer-HCl-treated group compared withthe calcium- and diet-only groups.290 These studies are
discussed in more detail in Chapter 4.1.
There were no studies investigating the effect of parathyroidectomy on calcification progression or regression that
met the inclusion criteria for review. There was one study
addressing the issue of vascular calcification progression inrenal transplant recipients (CKD stages 1–5T; n ¼ 55) bymeasurements of IMT by high-resolution B-mode ultrasoundat 3, 6, and 12 months after transplantation.291 Regression of
IMT was observed in association with a decline in serum
iPTH levels. One question regarding this study is whether
IMT indirectly reflects carotid artery calcification or othervascular remodeling processes induced by atherosclerosis or
hypertension.
To date, there are no prospective studies in humans thathave evaluated the impact of calcimimetics or calcitriol andvitamin D analogs on arterial calcification. However, a recent
observational study showed a U-curve type of relationshipbetween serum 1,25(OH)2D3 and arterial calcification inchildren and adolescents with CKD stage 5D.292 No such
association existed between serum 25(OH)D and arterial
calcification. In one study in adult patients with CKD stage 5,
no independent association of serum 25(OH)D or
1,25(OH)2D3 levels with arterial calcification was observed,293 although the authors of another report identified
an association between 25(OH)D deficiency and themagnitude of vascular calcification.294 It is noteworthy that,in the two latter studies, there was an association of arterial
calcification with arterial PWV. Experimental studies showed
differential effects of calcimimetics and calcitriol on extraosseous calcification, the former being neutral or protective,
the latter being a dose-dependent risk factor for
calcification.295297 The experimental data supporting lesstoxicity of vitamin D analogs compared with calcitriol are notcompletely consistent across studies, but, in general, support
the claim that there is reduced calcification with equivalent
PTH lowering with different vitamin D analogs.295,298300
Atherosclerosis. CAC is a strong predictor of atherosclerotic disease in the general population. An evidence-based
review of cardiovascular calcification in the general population was not carried out by the Work Group. However, it wasrecognized that most population studies measuring CAC did
S48

not necessarily exclude individuals on the basis of kidney
function and thus include variable numbers of CKD patients.
These studies have been summarized in the American College
of Cardiology/American Heart Association 2007 ClinicalExpert Consensus Document on Coronary Artery Calcium
Scoring by Computed Tomography.301
In general, this literature evaluating the general population supports the view that CAC is part of the developmentof atherosclerosis and occurs almost exclusively in atherosclerotic human arteries. Calcification occurs early in theatherosclerotic process; however, the amount of calcification
per lesion has a variable relationship with the associatedseverity of luminal stenosis. The relationship between the
degree of calcification in an individual lesion and theprobability of plaque rupture is unknown. In the general
population, the overall coronary calcium score can beconsidered as a measure of the overall burden of coronary
atherosclerosis. The American College of Cardiology/American Heart Association document indicates that the relationship between CAC and cardiovascular events in the CKD
population is less clear than that in the non-CKD population
because of a relative lack of informative studies and thepossibility that medial calcification may not be indicative ofatherosclerotic disease severity. In the non-CKD population,
high-risk patients were not considered appropriate for thisform of testing and so other approaches to clinical assessment
and risk-reducing therapies were suggested. This lattersuggestion may or may not be applicable to CKD patients,
as the standard approaches for clinical assessment (Framingham risk-factor ranking) may be inappropriate for the kindof vascular disease in CKD patients. The almost exclusive
relationship between magnitude of calcification and atherosclerosis burden is controversial in CKD patients,256,257 incontrast to the situation in the general population. For
example, whereas X50% of cardiovascular events are classicalmyocardial infarctions in the general population, this figure
is below 20% in the CKD population, despite a higher
absolute number of cardiovascular events.302
Antiatherosclerotic strategies using statin treatment havebeen shown to have a beneficial impact on the atherogenic
profile, atheroma progression, and cardiovascular events inpatients with no known CKD.303305 However, at the sametime, they do not seem to protect against the progression ofarterial calcification when studied in the general population.306,307 In CKD patients, there are no data on the effectsof statins on arterial calcification, as compared with those ofplacebo. Even worse, the 4D study failed to show a benefit of
atorvastatin treatment on the outcome of diabetic dialysis
patients. Studies in progress like SHARP (Study of Heart andRenal Protection) and AURORA (A Study to Evaluate theUse of Rosuvastatin in Subjects on Regular Hemodialysis:
An Assessment of Survival and Cardiovascular Events) may
help to gain a better understanding of the benefits of correcting atherosclerotic risk factors on cardiovascular eventsand mortality in patients with CKD stages 3–5 and 5D,
respectively.308,309 (Note added in proof: In AURORA,
Kidney International (2009) 76 (Suppl 113), S22–S49

chapter 3.3

rosuvastatin failed to show a significant effect on thecomposite primary end point of death from cardiovascularcauses, nonfatal myocardial infarction, or nonfatal stroke inchronic hemodialysis patients.) In the interim, we currently
extrapolate the approach to atherosclerosis-related cardiovascular calcification from the general population, but there
is some skepticism as to whether this approach may indeed
apply to the CKD population, especially in CKD stage 5D.
RESEARCH RECOMMENDATIONS

To determine the efficacy of different pharmacologicalagents for the prevention or delay of arterial calcificationin patients with hyperphosphatemia, a prospective,
randomized,
placebo-controlled
trial
evaluating
different phosphate-binder regimens in CKD stages
4–5D, should be conducted. The primary end pointshould be cardiovascular and all-cause mortality,with parallel assessments of cardiovascular and aortic
calcification.
K Studies are needed to determine the role of screening for
cardiovascular calcification and validate its usefulness forindividual prognosis, risk reduction, and therapeutic
decision making in patients with CKD. Such studies
should address the question of whether a knowledge ofvascular calcification may prospectively impact patient
outcomes, and whether a broad approach of routine
testing in patients with CKD should be considered forrecommendation in the future.
K Studies are needed that compare patient outcomes of
specified treatment strategies in response to the presenceor absence of vascular calcification.
K To determine the efficacy of different pharmacologicalagents in the prevention or delay of arterial calcification inpatients with secondary HPT, a prospective, randomized,
placebo-controlled trial comparing calcitriol, vitamin D
analogs, and calcimimetics in CKD stages 4–5D should be
conducted. The primary end point should be cardiovascular and all-cause mortality, with parallel assessments ofcardiovascular and aortic calcification.
K To determine the efficacy of different pharmacologicalagents for the prevention or delay of arterial calcificationin patients with vitamin D deficiency, a prospective,
randomized, placebo-controlled trial evaluating the administration of cholecalciferol or ergocalciferol in CKD
KKidney International (2009) 76 (Suppl 113), S22–S49

stages 4–5D should be conducted. The primary end pointshould be cardiovascular and all-cause mortality,with parallel assessments of cardiovascular and aortic
calcification.
K To determine the efficacy of calcification inhibitors in theprevention or delay of arterial calcification, a prospective,
randomized placebo-controlled trial evaluating the administration of vitamin K in CKD stages 4–5D should be
conducted. The primary end point should be cardiovascular and all-cause mortality, with parallel assessments ofcardiovascular and aortic calcification.
K To understand the pathophysiology of arterial calcification, additional case–control pathological studies should
be conducted to evaluate the histological presence of
intimal and medial calcification in the aorta and othernon-coronary arteries in CKD patients compared with
non-CKD patients.
K To
understand the pathophysiology of calciphylaxis,
epidemiological or registry studies should be conducted
on individuals with calciphylaxis, either based on theclinical assessments (painful livedo and/or ulcerations andexclusion of differential diagnoses such as diabetic ulcers,
vasculitis, or cholesterol emboli) or, preferably, based on
biopsy results. The study should evaluate exposure to
candidate risk factors (calcification inhibitor levels,
CKD–MBD treatment, dialysis mode, vitamin K status,and mineral parameters such as PTH, calcium, phosphorus, and ALP) and the natural history of the disease on
the basis of pathology and risk factors.
SUPPLEMENTARY MATERIAL
Supplementary Table 9. Overview table of selected studies ofdiagnostic tests: studies for vascular and valvular calcification
techniques in CKD.
Supplementary Table 10. Overview table of selected studies presenting data on calcification prevalence.
Supplementary Table 11. Overview table of selected studies demonstrating the natural history of vascular and valvular calcifications in
CKD.
Supplementary Table 12. Overview table of selected studies demonstrating the risk relationship between vascular calcification andmortality in CKD.
Supplementary Table 13. Overview table of selected studies demonstrating the risk relationship between valvular calcification andmortality in CKD stage 5D.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki

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chapter 4.1

http://www.kidney-international.org& 2009 KDIGO

Chapter 4.1: Treatment of CKD–MBD targeted atlowering high serum phosphorus and maintaining
serum calcium
Kidney International (2009) 76 (Suppl 113), S50–S99; doi:10.1038/ki.2009.192

Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

The overall phosphate balance is positive in patients withchronic kidney disease (CKD) stages 4–5D,310 and therapeuticstrategies are aimed at correcting this. Approaches include
reducing phosphate intake by dietary modifications,311
reducing intestinal absorption using phosphate-binding
agents,312 and in patients with CKD stage 5D, enhancing
dialytic clearance with more dialysis.313,314
RECOMMENDATIONS

4.1.1 In patients with CKD stages 3–5, we suggest
maintaining serum phosphorus in the normal range(2C). In patients with CKD stage 5D, we suggest
lowering elevated phosphorus levels toward thenormal range (2C).
4.1.2 In patients with CKD stages 3–5D, we suggest
maintaining serum calcium in the normal range(2D).
4.1.3 In patients with CKD stage 5D, we suggest using a
dialysate calcium concentration between 1.25 and1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).
4.1.4 In patients with CKD stages 3–5 (2D) and 5D (2B),
we suggest using phosphate-binding agents in thetreatment of hyperphosphatemia. It is reasonable
that the choice of phosphate binder takes into
account CKD stage, presence of other components
of CKD–MBD, concomitant therapies, and side-effectprofile (not graded).
4.1.5 In patients with CKD stages 3–5D and hyperphosphatemia, we recommend restricting the doseof calcium-based phosphate binders and/or the doseof calcitriol or vitamin D analog in the presenceof persistent or recurrent hypercalcemia (1B).
S50

In patients with CKD stages 3–5D and hyperphosphatemia, we suggest restricting the dose of calciumbased phosphate binders in the presence of arterial
calcification (2C) and/or adynamic bone disease (2C)
and/or if serum PTH levels are persistently low (2C).
4.1.6 In patients with CKD stages 3–5D, we recommend
avoiding the long-term use of aluminum-containing
phosphate binders and, in patients with CKD stage
5D, avoiding dialysate aluminum contamination toprevent aluminum intoxication (1C).
4.1.7 In patients with CKD stages 3–5D, we suggest
limiting dietary phosphate intake in the treatmentof hyperphosphatemia alone or in combination withother treatments (2D).
4.1.8 In patients with CKD stage 5D, we suggest increasing
dialytic phosphate removal in the treatment of
persistent hyperphosphatemia (2C).
Summary of rationale for recommendations

Hyperphosphatemia has been associated with pooroutcomes and mortality in CKD stage 5D, and highnormal serum phosphorus levels have been associatedwith mortality in non-CKD patients and in CKD stage 3
patients.
K Many patients with CKD stages 4–5D have a high serum
phosphorus level that is linked to the developmentof aspects of CKD–MBD, including secondary hyperparathyroidism (HPT), reduced serum calcitriol levels,
abnormal bone remodeling, and soft-tissue calcification.
K Laboratory-based experimental data suggest that hyperphosphatemia may directly cause or exacerbate otheraspects of CKD–MBD, specifically secondary HPT, a
reduction in calcitriol levels, bone disease, and arterial
calcification.
K

Kidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.1

There is no evidence that lowering serum phosphorus
to a specific target range leads to improved clinicaloutcomes in patients with CKD. Recommended goals oftherapy must therefore be based on observational data.
K Despite a lack of evidence from randomized controlled
trials (RCTs) demonstrating that lowering phosphorus
levels impact clinical outcomes, it is reasonable to lower
phosphorus in CKD patients with hyperphosphatemia
using phosphate binders. Additional options to lower
phosphorus include limiting dietary phosphate intake(while ensuring adequate protein intake) and/or increasing the frequency or duration of dialysis (in those who
require renal replacement therapy).
K There is insufficient evidence that any specific phosphatebinder significantly impacts patient-level outcomes.
Thus, the choice of phosphate binder should be
individualized, and the guidance offered in this recommendation is based on the effects of available agents on a
range of clinical parameters, rather than on phosphorus
lowering alone.
K

BACKGROUND

Hyperphosphatemia is an important and inevitable clinicalconsequence of the advanced stages of CKD. The rationale forcontrolling serum phosphorus is based on epidemiologicalevidence suggesting that hyperphosphatemia is an importantrisk factor, not only for secondary HPT but also for
cardiovascular disease (CVD).205,315 Long-standing hyperphosphatemia, together with an elevated serum Ca  P, is associatedwith an increased risk of vascular, valvular, and other softtissue calcification in patients with CKD.262 Large epidemiological studies have consistently shown the importance ofhyperphosphatemia as a predictor of mortality in CKD stage 5
patients receiving dialysis.205,316318 Taken together, theseobservational data suggest that there is a need to control
serum phosphorus in patients with CKD. Experimental datasuggest a direct causal relationship between phosphorus andseveral components of CKD–MBD, specifically secondary
HPT,319,320 bone abnormalities,321 calcitriol deficiency,322 andextraskeletal calcification,323 providing biological plausibility
to support these human observational studies.
The use of phosphate-restricted diets in combination withoral phosphate binders has become well established in the
management of patients with CKD stages 3–5 (including
CKD stage 5D), and this strategy has been endorsed byprevious guidelines, with appropriate education and counseling to ensure adequate protein intake.5 Aluminum hydroxide
is a potent phosphate binder, but concern about skeletal,
hematological, and neurological toxicity led to a preferential
use of calcium salts (carbonate and acetate) in the 1990s. The
use of large doses of calcium-containing phosphate binders
subsequently led to concerns about calcium overload becauseof a potential for generating a positive calcium balance.
Table 19 lists phosphate binders that are presently in use orthat have been used in the recent past. Unfortunately, the true
benefits of phosphate lowering with respect to hard clinical
Kidney International (2009) 76 (Suppl 113), S50–S99

end points have not been established, and most studies
evaluate surrogate end points. In addition, because of ethicalconcerns regarding a prolonged lack of treatment, moststudies evaluating these newer agents against placebo havebeen short term, with longer term studies using calcium salts
as the comparator.
The following tables are found at the end of this chapter:
Table 20 summarizes the RCTs of phosphate binders inchildren with CKD. For CKD stages 3 and 4, only one
sevelamer-HCl study met the inclusion criteria and is
described in Tables 21 and 22. The evidence matrix, a tablethat describes the methodologic quality of all of the included
studies for CKD stage 5D, and the evidence profile, a tablethat provides an overall assessment of the quality of theevidence and balance of potential benefits and harm are
Tables 23 and 24 for sevelamer-HCl compared to calcium
containing phosphate binders, and Tables 25 and 26 forlanthanum carbonate compared to other binders. A narrative
review of the literature on the topic of alternate hemodialysis
regimens can be found in Tables 27–29. These studies are
discussed in the rationale for each recommendation. Additional detailed information about the studies of phosphatebinders reviewed in this chapter are further described indetail in the Supplementary Tables 14–23.
RATIONALE

4.1.1 In patients with CKD stages 3–5, we suggest
maintaining serum phosphorus in the normal range(2C). In patients with CKD stage 5D, we suggest
lowering elevated phosphorus levels toward thenormal range (2C).
No prospective studies have specifically examined the benefitsof targeting different phosphorus levels to determine the effecton patient-level end points. Epidemiological data suggest that
serum phosphorus levels above the normal range are associatedwith increased morbidity and mortality (Supplementary
Table 14). Higher levels of serum phosphorus, even within
the normal range, have been associated with increased risk ofcardiovascular events and/or mortality (all-cause or cardiovascular mortality) in patients with a normal renal function who
were free of CVD,324 in patients with coronary artery disease
and normal renal function,325 and in patients with CKD stages
3–5.316 Not all studies find these relationships. A subanalysis of
the modification of diet in renal disease (MDRD) study failed
to identify phosphorus as an independent risk factor forincreased mortality in patients with CKD who were not on
dialysis.326
In patients on dialysis, multiple studies from different
parts of the world have shown that higher levels of serum
phosphorus have been associated with an increased relativerisk (RR) of mortality. In most of these studies, the observed
risk associations were robust and ‘dose dependent’, with
progressive increases in risk with higher levels of serum phosphorus. The inflection point or range at which phosphorus becomes significantly associated with increased
S51

Table 19. Phosphate-binding compounds
Binder source

Rx

Forms

Content (mineral/metal/element)

Potential advantages

Potential disadvantages

Aluminum hydroxide

No

Calcium acetate

Yes/
no

Liquid, tablet,
capsuleCapsule, tablet

Aluminum content varies from 100 to>200 mg (per tablet)
Contains 25% elemental Ca2+ (169 mg
elemental Ca2+ per 667 mg cap)

Potential for aluminum toxicity; altered bone mineralization,
dementia; GI side effects
Potential for hypercalcemia-associated risks including extraskeletal
calcification and PTH suppression; more costly than CaCO3; GI side
effects

Calcium carbonate

No

Contains 40% elemental Ca2+ (200 mg
elemental Ca2+ per 500 mg CaCO3)

Calcium citrate

No

Liquid, tablet,chewable,
capsule, gum
Tablet, liquid,
capsuleVery effective phosphate-binding capacity;
variety of forms
Effective phosphate-binding, potentially forenhanced phosphate-binding capability
over CaCO3 potentially less calcium
absorption
Effective, inexpensive, readily available
Not recommended in CKD

Enhancement of aluminum absorption; GI side effects

Calciumketoglutarate
Calcium gluconate
Ferric citrate
Magnesium/
calcium carbonate

Contains 22% elemental Ca2+

Tablet, powder
No

TabletApprox 28% Mg2+(85 mg) per total
MgCO3 and 25% elemental Ca2+(100 mg)
per total CaCO3

Magnesium
carbonate/calcium acetate
Sevelamer-HCl

Yes

TabletYes

TabletNone

Sevelamercarbonate

Yes

Tablet, powder

None

Effective; potential for lower calcium load
than pure calcium-based binders

Potential for hypercalcemia-associated risks including extraskeletal
calcification and PTH suppression; GI side effects

Similar to other calcium salts, costly, GI side effects, potentially lesshypercalcemic than calcium carbonate or acetate, not well studied
Similar to other calcium salts, not well studied
GI side effects, not well studied
GI side effects, potential for hypermagnesemia, not well studied
Lack of availability worldwide; assumed to have similar effects of its
components

Effective; no calcium/metal; not absorbed;
potential for reduced coronary/aortic
calcification when compared with calciumbased binders in some studies; reduces
plasma concentration of LDL-C
Effective; no calcium/metal; not absorbed;
assumed to have similar advantages as
sevelamer-HCl; potentially improved acidbase balance
Effective; no calcium; chewable

Lanthanum
Yes
Tablet,Contains 250, 500, 750, or 1000 mg
carbonatechewableelemental lanthanum per tablet
CKD, chronic kidney disease; GI, gastrointestinal; LDL-C, low-density lipoprotein cholesterol; PTH, parathyroid hormone.

Cost; potential for decreased bicarbonate levels; may require
calcium supplement in presence of hypocalcemia; GI side effects

Cost; may require calcium supplement in the presence of
hypocalcemia; GI side effects
Cost; potential for accumulation of lanthanum due to GI absorption,although long-term clinical consequences unknown; GI side effects

chapter 4.1

all-cause mortality varies among studies for the reasonscited above, 5.0–5.5 mg/dl (1.6–1.8 mmol/l),205 45.5 mg/dl(41.8 mmol/l),327 6.0–7.0 mg/dl (1.9–2.3 mmol/l),328 and46.5 mg/dl (42.1 mmol/l).33,329,330 A recent Dialysis Outcomes and Practice Pattern Study (DOPPS) analysis showsthat the relationship between elevations in serum phosphorus
and the RR of mortality is consistent across all countries
analyzed.33 The study by Noordzij et al.327 also found similar
relationships in peritoneal dialysis (PD) and hemodialysis(HD) patients. These observational data are consistent withanimal and other experimental data, providing biologicalplausibility to the association, and leading the WorkGroup to recommend interventions that lower phosphorus
toward the normal range. Hypophosphatemia may also be
problematic. In the DOPPS series, there is an increased riskof mortality for CKD stage 5D patients with a phosphorus
level less than 2.0 mg/dl (0.65 mmol/l). However, fewer
than 5% of patients are in this risk category. Analyses
of DOPPS data by a dialysis unit (which was randomly
selected) showed that if a facility had 10% more patientswith phosphorus levels between 6.1–7.0 and 47.0 mg/dl(1.97–2.26 and 42.26 mmol/l), the mortality risk was 5.3 and4.3% higher, respectively.33
In summary, although the benefits of lowering serum
phosphorus on patient-level clinical outcomes (for example,
hospitalization, bone fracture, cardiovascular events, andmortality) have not been studied, numerous epidemiological
data show a positive association, although not a causal link,
between higher serum phosphorus levels and RR of mortality,
independent of CKD stage. Experimental data support thebiological plausibility of a direct effect of phosphorus on
PTH secretion and parathyroid cell proliferation,320,331,332
and on vascular calcification.333 However, the use ofphosphate binders is associated with side effects, especiallygastrointestinal, and with a high pill burden. Thus, in somepatients, treatment to achieve a serum phosphorus levelwithin the normal range may not be possible or may lead to a
reduction in quality of life. Therefore, in the absence of aprospective RCT showing outcome benefits at any level ofphosphate control, it seems reasonable that therapy is
individualized. However, it is generally accepted andbiologically plausible that elevated serum phosphorus levels
should be lowered in patients with CKD stages 3–5D in aneffort to control complications of CKD–MBD. The lack ofdata showing that patient-centered outcomes are improved
by lowering serum phosphorus means that the strengthof this recommendation is level 2 or ‘weak’, as it is based on
observational and experimental data.
4.1.2 In patients with CKD stages 3–5D, we suggest maintaining serum calcium in the normal range (2D).
In patients with CKD stages 3–5, there are no data to support anincreased risk of mortality or fracture with an increasing serum
calcium concentration. The association in CKD stage 5D
patients is generally similar to that of serum phosphorus. The
Kidney International (2009) 76 (Suppl 113), S50–S99

inflection point or range at which calcium becomes significantly
associated with an increased RR of all-cause mortality
varies among studies for the reasons cited above, from being
49.5 mg/dl (42.38 mmol/l)205 to 410.1 mg/dl (42.53 mmol/l),33
410.4 mg/dl (42.60 mmol/l),330 410.5 mg/dl (42.63 mmol/l),328
and to 411.4 mg/dl (42.85 mmol/l).329 Globally, 50% of
CKD stage 5D patients have serum calcium levels above
9.4 mg/dl (42.35 mmol/l) and, of these, 25% have serum
calcium levels above 10.0 mg/dl (42.50 mmol/l).33 At the low
end, there is little evidence of an increase in RR until serum
levels fall below 8.4 mg/dl (o2.10 mmol/l).33 In anotherstudy from the United States, the increased RR of mortality
with a low serum calcium was reversed when adjusted forcovariates.205 It is therefore unclear at what level of low
serum calcium is there an increased risk. It is also importantto realize that none of these studies evaluated patients
receiving cinacalcet, which lowers calcium by its effects on
the calcium-sensing receptor (CaR) while also increasing thereceptor’s sensitivity to the cation. Treatment leads to an
expected decrease in the total serum calcium concentration.
Thus, we do not know whether patients with low serum
calcium levels due to cinacalcet have a similar risk as thosewith identical calcium levels who are not on the drug.
Overall, the interpretation of serum calcium, similar to otherbiochemical values, should be evaluated on the basis oftrends, which may be related to specific medications thatraise (calcium-based phosphate binders, vitamin D sterols)
or lower (cinacalcet) serum calcium values.
4.1.3 In patients with CKD stage 5D, we suggest using a
dialysate calcium concentration between 1.25 and1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).
There was a discussion among the Work Group members as
to whether the optimal dialysate calcium concentration should
be adapted to each patient’s individual needs, wheneverpossible. The final vote on this recommendation was 16 infavor and 1 vote against. The vote against was to argue that a
1.0 mmol/l (2.0 mEq/l) of calcium dialysate was also helpful insome patients to reduce their positive calcium balance.
Calcium balance during HD is important in determining
short-term cardiovascular function, as it influences thehemodynamic tolerability of dialysis. In the longer term,
calcium flux during HD is an important determinant of overall
calcium balance. The calcium concentration of the dialysate
therefore should be adjusted to optimize the total body calcium
load.334 Theoretically, this strategy should help to improve bonehealth by reducing calcium flux during dialysis in patients withadynamic bone disease and extraskeletal calcification, and by
inducing positive calcium flux during dialysis in patients withhypocalcemia. However, these possibilities have not been tested
prospectively. The percentage of total body calcium that is
dialyzable is very small, and studies that evaluate calcium
balance are limited. The total amount of calcium removed witheach dialysis treatment will depend not only on calcium
concentration but also on the patient’s serum-ionized calcium
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chapter 4.1

level, the intradialytic interval, and the rate of ultrafiltration.335
Studies that have measured spent dialysate for calcium todetermine net flux have found near-neutral calcium flux inpatients with a dialysis concentration of 1.25 mmol/l (2.5 mEq/l).336,337 A more recent study used more frequent assessments ofspent dialysate and found a mean calcium flux with each dialysis
session of 187±232 mg (46±58 mmol) on a 1.25 mmol/l(2.5 mEq/l) of calcium dialysate. However, six of the 52 patients
had positive calcium balance, supporting the fact that calcium
flux with dialysis is not uniform in all patients.338 Thus, theWork Group felt that, in general, a dialysate calcium concentration of 1.25 mmol/l (2.5 mEq/l) would be a near-neutral calcium
balance for most patients. However, it is important to point out
that a low dialysate calcium concentration may also predispose
to cardiac arrhythmias and hemodynamic instability during
dialysis sessions, with intradialytic hypotension.339,340 At present,
it is probably wise to maintain flexibility with dialysate calcium
concentrations, which should be individualized, wheneverpossible, to meet specific patient requirements.
Similar considerations apply to PD, in which dialysate
calcium concentration should be tailored to the individual
patient’s needs, if possible. Compared with patients receiving
HD, patients receiving PD are exposed to a given dialysate
calcium concentration for longer periods of time. Therefore,
peritoneal dialysate calcium concentrations as high as
3.5 mEq/l (1.75 mmol/l) are generally avoided to prevent
calcium overload and the induction of adynamic bonedisease. Concentrations between 1.25 and 1.50 mmol/l (2.5
and 3.0 mEq/l) are recommended.
4.1.4 In patients with CKD stages 3–5 (2D) and 5D (2B),
we suggest using phosphate-binding agents in thetreatment of hyperphosphatemia. It is reasonable
that the choice of phosphate binder takes into
account CKD stage, the presence of other components of CKD–MBD, concomitant therapies, andside-effect profile (not graded).
A systematic review of all RCTs examining phosphate binders
was undertaken and considered in the context of the review
of calcium-based binders published in the Kidney Disease
Outcomes Quality Initiative (KDOQI) guidelines.5 Thesestudies showed that all medications currently used as
phosphate binders (calcium salts, aluminum salts, magnesium salts, sevelamer-HCl, and lanthanum carbonate) are
effective in lowering serum phosphorus levels. The nonphosphorus-lowering effects are discussed in detail in theremainder of the chapter. The use of sevelamer, comparedwith the use of calcium-based salts, has been shown toattenuate progression of arterial calcification in one RCT
involving patients with CKD stages 3–5286 and two RCTs
involving patients with CKD stage 5D.284,285 However, twomore recent RCTs have not reproduced these results and havefound high and similar rates of progression of vascular
calcification in patients receiving sevelamer-HCl as comparedwith those receiving calcium acetate.287,288 The effect of otherS54

binders on progression of vascular calcification has notbeen systematically studied. Most importantly, it is notclear whether slowing vascular calcification translates into
improvements in clinical outcomes or whether other noncalcium-containing binders (for example, lanthanum carbonate) have similar effects. The use of lanthanum carbonate andsevelamer-HCl does not adversely affect bone histology inshort-term studies and, when compared with calcium-based
binders, may be less likely to lead to adynamic bone disease.
Comparative studies of phosphate binders have shown
differences in effects on the biochemical parameters of
CKD–MBD. For example, the use of calcium salts is generally
associated with higher serum calcium (and more frequentepisodes of hypercalcemia) and lower serum PTH levels whencompared with the use of sevelamer-HCl or lanthanum
carbonate. The effects of different binders on biochemicalend points, on surrogate markers of bone and vascular
calcification, or on mortality, are described in the rationale
following Recommendation 4.1.5. Overall, there is insufficientcomparative efficacy data on clinical outcomes to make a
recommendation for the use of a specific binder for all patients.
4.1.5 In patients with CKD stages 3–5D and hyperphosphatemia, we recommend restricting the dose of
calcium-based phosphate binders and/or the doseof calcitriol or vitamin D analog in the presence of
persistent or recurrent hypercalcemia (1B).
In patients with CKD stages 3–5D and hyperphosphatemia, we suggest restricting the dose of
calcium-based phosphate binders in the presence ofarterial calcification (2C) and/or adynamic bonedisease (2C) and/or if serum PTH levels are persistently low (2C).
The Work Group asked if there were differences between thevarious phosphate binders in terms of their effects onbiochemical indices of CKD–MBD, bone, vascular calcification, or clinical end points. The group felt that there wereinconclusive data to indicate that any one binder has
beneficial effects on mortality or other patient-centeredoutcomes when compared with any other binder, and thus
the strength of this recommendation is graded as level 2.
The specific recommendations regarding limiting calcium
intake from phosphate binders were extensively discussed. As
detailed below, there are consistent data regarding the risk of
inducing hypercalcemia and calcium overload in patients on
calcium-based phosphate binders, necessitating dose reduction. The Work Group also felt that the available bone biopsy
data suggested that patients receiving calcium-based binders
were more likely to develop adynamic bone disease. Therewas extensive discussion with respect to the role of calciumvs non-calcium-based binders in the pathogenesis of vascular
calcification. The Work Group acknowledged that the evidence was not conclusive and that more research is needed.
However, the majority of the Work Group felt that limiting
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chapter 4.1

calcium intake in the form of phosphate binders was justified
until further research is available on the basis of ourknowledge of calcium balance in CKD patients. It was notedthat at least some studies in humans showed a beneficial
effect of sevelamer-HCl compared with calcium-based
binders on progression of arterial calcification. The majorityof the Work Group (16 of 17 members) felt that, given
the high cardiovascular burden, recommending a limited
calcium intake was likely to be more beneficial than harmful.
A single member of the Work Group felt that thisrecommendation had the potential for too large an impact
with too little data to support it, bringing the final vote to
16 in favor and 1 vote against.
Results of evidence review

The KDOQI guidelines5 extensively reviewed trials evaluating
calcium carbonate and calcium acetate. No additional studies
fulfilling our screening criteria were identified, with the
exception of those comparing a calcium-containing phosphatebinder with sevelamer-HCl or lanthanum carbonate. The
KDOQI guidelines concluded that both calcium carbonate andcalcium acetate were effective in lowering serum phosphorus
when compared with placebo, but that both were associatedwith hypercalcemia and gastrointestinal side effects. A metaanalysis performed for the KDOQI guidelines indicated thatcalcium acetate is less hypercalcemic than is calcium
carbonate.5 None of these studies assessed bone histology,
vascular calcification, or hard clinical end points and thus will
not be further reviewed. The KDOQI guidelines also evaluatedaluminum hydroxide as a phosphate binder, but again no dataon vascular calcification or hard clinical end points wereidentified. However, studies have shown that aluminum may
induce osteomalacia, microcytic anemia, and central nervous
system toxicity.341,342 Thus, in the absence of a clear benefit
beyond phosphorus lowering, and because of known potential
toxicity, the Work Group felt that the use of aluminumhydroxide should be restricted.
The remaining studies identified by our systematic searchcompared sevelamer-HCl or lanthanum with calcium-based
binders, or lanthanum with a previously prescribed binder(a calcium salt or sevelamer). These studies are listed intables by treatment comparisons and are reviewed below
by end point.
a)Patient-centered end points: Studies of phosphatebinders comparing sevelamer-HCl and calcium-based
binders that have mortality as the primary end point
have been inconsistent.

The largest of these studies, the Dialysis Clinical Outcomes
Revisited (DCOR) study, randomized 2103 prevalent CKD
stage 5D patients to either sevelamer-HCl or a calcium-based
phosphate binder (70% calcium acetate or 30% calcium
carbonate), (Table 24; Supplementary Tables 15–18).266 Patientswere allowed to receive other medications according to current
standards of care and were followed up for a mean of
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approximately 20 months. The trial was designed to evaluate
all-cause mortality as the primary end point and had 80%
power to detect a 22% difference between the groups,
assuming a mortality rate of 20 per 100 patient-years in the
calcium-treated group and a two-sided alpha (a) of 0.05. The
study had a high early discontinuation rate and collected only
90 days of follow-up data on discontinued patients, providing
limited information on these individuals. The overall dropout
rate was 47% in the sevelamer-HCl arm and 51% in the
calcium-based binder arm. More patients discontinued
because of adverse events (AEs) in the sevelamer-HCl arm (8vs 5%), but types of events and event rates were notcomprehensively reported. The study was extended because
the mortality rate in the control group was lower than
expected. No details of interventions, treatment targets, ordose-titration protocols were provided, neither were baseline
biochemical parameters available. Only 1068 patients completed the study, and there were no differences in all-cause
or cause-specific mortality rates when comparing sevelamerHCl (mortality rate 15.0 per 100 patient-years) withcalcium-treated patients (16.1 per 100 patient-years), hazard
ratio (HR) 0.93, 95% confidence interval (CI) 0.79–1.10, log
rank P ¼ 0.40. There were also no differences in cardiovascularmortality and hospitalization on the basis of data fromcase-report forms. Much attention has been focused on theanalysis of subgroups, particularly patients over 65 years of age(a prespecified analysis) and those receiving treatment for
more than 2 years in whom benefits associated with allocation
to sevelamer-HCl therapy have been claimed. However, theWork Group took the view that, in light of the equivalence ofthe two therapies with respect to the primary end point in theoverall cohort, such analyses could be, at best, consideredhypothesis generating and should be interpreted with extreme
caution. The ERT graded the quality of this study as C (lowquality) with respect to all outcomes because of several factors,
including the lack of an intention-to-treat analysis andpossible bias resulting from the limited (90-day) follow-up
of discontinued patients, as well as a lack of documentation of
baseline biochemical parameters and AEs.
A secondary preplanned analysis of the DCOR study by
St Peter et al.267 using Medicare claims data (rather than datacollected at the study sites on case-report forms) showed noeffect of phosphate-binder allocation on overall mortality(primary outcome), cause-specific mortality, morbidity,
or first or cause-specific hospitalization (secondary outcomes).267 This study did show a beneficial effect ofsevelamer-HCl on the secondary outcomes of multiple allcause hospitalizations (1.7 vs 1.9 admissions per patient-year,
P ¼ 0.02) and hospital days (12.3 vs 13.9 days per patientyear, P ¼ 0.03).267 This study was graded as ‘B’ (that is,moderate quality) for mortality outcome. The study
ascertainment for mortality was complete and allowed a true
intention-to-treat analysis, having included many patients
lost to follow-up in the original publication; however, this
could not overcome the high dropout rate.266 The quality ofdata for hospitalization was graded as low (or ‘C’). The
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analysis by St Peter et al.267 using claims data described ahigher rate of hospitalization in a smaller group of patientswith a shorter duration of follow-up than that reported by
Suki et al.,266 as a result of the fact that the denominator for
hospitalization rates did not include days spent in thehospital. Thus, although both analyses showed a trend
toward lower hospitalization rates, the fact that the difference
between patients allocated to different binders was ofstatistical significance in the analysis by St Peter et al.267
was not considered to be robust. Furthermore, hospitalizations from CVD as ascertained from the administrative data
did not differ, lending no support to the study’s hypothesisthat sevelamer-HCl reduces CVD morbidity.
The second study examining clinical outcomes data,
RIND, randomized a smaller group of 148 incident HD
patients (patients new to dialysis) to either sevelamer-HCl or
calcium-based binder, but followed up these patients for alonger period. Only 127 patients received baseline electronbeam CT (EBCT) scans and the dropout rate was 26% in
the sevelamer-HCl arm and 27% in the calcium-based
phosphate-binder arm. At a median of 44 months, there
was a difference in the unadjusted mortality rate for patientsassigned to calcium-containing binders, which was 10.6 per
100 patient-years (CI 6.3–14.9), compared with 5.3 per 100
patient-years (CI 2.2–8.5) for patients assigned to sevelamerHCl, with the HR for mortality in the univariate analysis for
calcium vs sevelamer being 1.98 (P ¼ 0.06). However, in
multivariate analysis, which included 10 variables (felt to be alarge number considering that there had only been 34
deaths), the difference between the groups was significant(HR 3.1, P ¼ 0.016), suggesting an imbalance with respect tothe covariates entered into the model and raising thepossibility of an unsuccessful randomization. As a result of
this concern, the Work Group downgraded the methodological quality of this study to B or ‘moderate.’
No data on cardiovascular events other than death, fractures,or parathyroidectomy rates were available from either of thesestudies, making it impossible to draw conclusions on theimpact of using sevelamer-HCl instead of a calcium-based
phosphate binder on such outcomes. In addition, no studies
have examined the effects of lanthanum carbonate or indeed
any other phosphate binder (including calcium- and aluminum-based compounds) on patient-level outcomes.
b)

Vascular calcification: The use of sevelamer-HCl
attenuates the progression of arterial calcification inpatients with CKD stages 3–5 and stage 5D whencompared with the use of calcium-based salts in some,
but not all, studies. The effect of other binders on
progression of vascular calcification has not beensystematically studied. Most important, it is not clear
whether slowing vascular calcification translates into
improvements in clinical outcomes.

Three of the five randomized trials (Supplementary Tables
15, 16), as reported in multiple publications, comparing
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sevelamer-HCl with calcium-based binders284286,288,343,344
studied the impact of phosphate-binder therapy on arterial
calcification, assessed using computerized tomography imaging techniques. One examined the effect of these two oral
phosphate-binder approaches on valvular calcification,345
and one compared the effect of sevelamer-HCl with calciumbased binders, adding atorvastatin treatment to both arms as
required to reach a comparable low-density lipoproteincholesterol target.287 Only one of these trials involved
patients with CKD stages 3–4,286 whereas the remaining four
recruited patients with CKD stage 5D.284,285,287,288,343345
In their study involving 90 binder-naive Italian patientswith CKD stages 3–5 who were not receiving dialysis, Russo
et al.286 (Tables 21, 22) randomized patients (30 per group)
into either a low-phosphate diet alone group, a lowphosphate diet in combination with fixed doses of calcium
carbonate (2 g/d) group, or a low-phosphate diet incombination with sevelamer-HCl (1600 mg/d) group, andfollowed up these individuals for 2 years. The primary end
point of the study was progression of cornary artery
calcification (CAC), assessed as the total calcium score using
multislice computed tomography. Among the 84 patients
who completed the study, the final CAC scores were greaterthan the initial scores in those receiving diet alone (Po0.001)
or diet in combination with calcium carbonate (Po0.001),
whereas there was no progression of calcification in the dietplus-sevelamer-HCl-treated group. In patients with CKD
stage 5D, four studies have examined the effect of sevelamerHCl compared with that of calcium-containing phosphatebinders on the progression of CAC (Supplementary Tables
15, 16). One of the secondary aims of the ‘Treat to Goal’
study was to assess the progression of cardiovascular
calcification in 200 prevalent HD patients randomized toreceive either sevelamer-HCl or a calcium-based phosphatebinder (107 calcium acetate in the United States and 93
calcium carbonate in Europe) in an open-label design.284 The
study was conducted in the United States, Germany, andAustria, and was powered to achieve a serum Ca  P
difference of 10 mg2/dl2 (124 mmol2/l2). Patients wererandomized after a 2-week ‘washout’ period and investigators
were instructed to manage blood calcium, phosphorus,
and PTH levels to achieve prespecified targets for theremaining 50 weeks (hence, the ‘Treat to Goal’ study).
During this period, absolute calcium scores in the coronary
arteries and aorta increased in the calcium-treated patients,
but not in those receiving sevelamer-HCl. Many dropouts
were reported, with 37% of the sevelamer-treated patientsand 31% of the calcium-treated patients missing from theanalysis at week 52. These data were partially duplicated in a
publication that describes 93 patients from the European
cohort343 (with 21 additional patients whose origin is
unclear); in a third article that also reported valvular
calcification, its progression did not differ when the twogroups were compared at the start and end of a 52-week
study period.345 Another report suggested that patientsrandomized to receive calcium salts, compared with those
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randomized to sevelamer-HCl, experienced greater trabecular(but not cortical) bone loss on the basis of changes inthoracic bone mineral density (BMD) on EBCT scans in a
subset of 132 patients in whom the necessary imaging wasavailable.346 At the end of the 52-week study period, aEuropean subgroup of 72 patients out of the initial ‘Treat to
Goal’ cohort chose to remain under follow-up and attended
for subsequent EBCT scans approximately 2 years after
enrollment into the study (although no longer randomized todifferent phosphate binders beyond 52 weeks). This approachto subject retention may well have introduced biases. Data
from this extended follow-up, during which 53% of thepatients dropped out, were reported to endorse theobservation that assignment to a calcium-based binder
was associated with progressive arterial calcification anddecreased trabecular bone density when compared withassignment to sevelamer-HCl treatment.344 Changes in bonedensity and vascular calcification did not correlate. As
measurement of thoracic vertebral radiolucency by EBCT is
not a valid measure of BMD or mass, and bearing in mind
the high dropout rate, the Work Group was concerned withregard to the validity of these bone data and graded all thesesubstudies of ‘Treat to Goal’ as being of low quality.
Assessment of changes in CAC at 12 months was theprimary outcome of the RIND study285 (Supplementary Tables
15, 16). Of the 127 patients who underwent baseline EBCT,
26% did not receive follow-up EBCT scans. At 1 year, there wasno statistically significant difference in calcification. The meanannual rates of progression of calcification were 13.4 and25.3% for sevelamer-HCl and the calcium-based bindergroups, respectively, P ¼ 0.06. The median increase in the
calcification score at 18 months was 11-fold higher in the
calcium-treated group compared with the sevelamer-HCltreated group (an increase of 127 points from a baseline of
667±1248 vs 11 points from a baseline of 648±1499,
respectively, P ¼ 0.01). In a subgroup analysis, patients witha baseline CAC score of 430 Agatston units confirmed a trend
for higher absolute and percentage increases in calcium-treatedpatients. In the RIND trial, the amount of calcium consumed
in calcium-based binders was not associated with the rate ofprogression of calcification.
In the CARE 2 study, chronic HD patients from the UnitedStates were randomized to receive either calcium acetate orsevelamer-HCl.287 Patients in both groups received atorvastatin to achieve a low-density lipoprotein cholesterol goal of
70 mg/dl (1.81 mmol/l). The study was designed to assess noninferiority, evaluating CAC using EBCT at 6 and 12 months
after randomization. Before 1 year, 30% of the patients in the
selevamer arm and 43% in the calcium acetate arm dropped
out. Although achieving comparable levels of serum cholesterol, no difference in the progression of arterial calcification
was noted when comparing the two treatment arms (annual
progression of coronary calcification was 29 and 30% in the
calcium acetate and sevelamer-HCl groups, respectively,
P ¼ 0.90). Although the study had a high percentage of lossof follow-up, several sensitivity analyses (including some that
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imputed missing values under different assumptions) showed
the findings to be robust. Furthermore, this is the only study
that defined a metric for the primary calcification outcome up
front. However, the study was downgraded from ‘high’ to‘moderate’ quality, because the selection of the upper 95%
confidence limit for outcome was not explained and, in the
study design, it was not intuitive what the ‘upper bound forthe non-inferiority margin of 1.8’ means in terms of clinically
relevant differences in progression of calcification. It isnoteworthy that CARE 2 showed that the combination ofsevelamer-HCl and atorvastatin was associated with a muchhigher rate of progression of CAC than that in ‘Treat to
Goal’,284 instead of showing a delay in CAC progression withthe combination of calcium acetate and statin in accordancewith the initial study hypothesis. One of the possible
explanations for the equivalent progression of calcification in
the two treatment arms of CARE 2, as opposed to lesscalcification in the sevelamer-HCl compared with the calcium
arm in the ‘Treat to Goal’ study, is that the patient population
was exposed to a greater number of cardiovascular risk factors
in the CARE 2 study.289
The BRIC study investigated the effects of calcium acetate
vs sevelamer-HCl on CAC progression and bone histomorphometry in chronic HD patients from Brazil. The authors
randomized 49 patients to calcium acetate and 52 patients tosevelamer-HCl.288 The primary goal of the study was to test
the hypothesis that treatment with calcium-containing
phosphate binders has a negative impact on bone remodelingand this contributes to a more rapid progression of CAC
compared with sevelamer-HCl treatment. The annual rates ofprogression of coronary calcification scores were 27 and 26%
for sevelamer-HCl and calcium acetate, respectively, P ¼ NS.
The authors also found that neither CAC progression rates
nor indices of bone remodeling differed between the two
phosphate-binder arms. However, this study was hampered byseveral significant confounders, including small sample size,
differences in baseline CAC scores between the two study arms
(675±1267 for calcium acetate and 507±814 for sevelamer,
P ¼ 0.38), the use of high dialysate calcium concentrations(1.75 mmol/l (3.5 mEq/l)) in most patients, resulting in apositive calcium balance, and multiple interventions during
the course of the study based on bone biopsy results.
The inconsistencies between the results of the recent BRIC
and CARE 2 studies on the one hand and those of theprevious studies on the other hand cast some doubt on
the hypothesis of a major role of calcium loading in the
progression of arterial calcification, with the CARE 2 andBRIC study results not duplicating the beneficial effects
observed with sevelamer-HCl in the other three trials. Taken
together, the data on vascular calcification overall are onlyof low quality, bearing in mind that changes in the rate of
calcium deposition have not been validated as a predictor of
benefit in terms of clinical outcomes in CKD patients. Given
the present uncertainty in this field, further trials comparing
phosphate binders and examining hard clinical end points
are needed.
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c)Bone histology: Clinical trials comparing calcium
carbonate with lanthanum carbonate or sevelamerHCl do not show major differences among treatments.
The changes in bone turnover with both calciumand non-calcium-based binders are heterogeneous,with some patients showing worsening and others
showing improvement. The results are also influenced
by baseline turnover rates.

Sevelamer-HCl. Two clinical trials compared sevelamer-HCl
with calcium carbonate, yielding a moderately high quality
for this outcome, and a smaller study compared these
therapies in children (Supplementary Table 17).
In the first adult study comparing the effects of sevelamerHCl and calcium carbonate on bone histology, Ferreira
et al.104 enrolled 119 HD patients in a 54-week randomized,
open-label study. Of them, 100 patients underwent baseline
and 68 underwent follow-up bone biopsies after 1 year.
Serum calcium was lower and serum intact PTH (iPTH) was
higher in those patients assigned to sevelamer-HCl. Neither
overall bone volume nor mineralization changed after 1 year
in an intention-to-treat analysis when compared with that at
baseline in either of the two groups, but turnover increased in
the sevelamer group compared with that in calcium-treatedpatients (P ¼ 0.02). The turnover worsened by becoming
higher in 12% of sevelamer-HCl and 3% of calcium groups;
on the other hand, it worsened by becoming lower (development of adynamic disease) in 17% of calcium patients and
9% of sevelamer-HCl patients. Turnover improved in 26% of
calcium and 15% of sevelamer-HCl patients. Change in bonevolume was almost the same in both groups (the volume
increased by 0.9% in the calcium vs sevelamer-HCl group).
The second adult study, the BRIC study, also compared
the effects of sevelamer-HCl and calcium acetate on bone
histology.288 Among the 101 HD patients randomized, 27 in
the calcium acetate arm and 37 in the sevelamer-HCl arm
had an interpretable repeat bone biopsy after a 12-monthtreatment period. Overall, there were no significant changes
in the main bone parameters. Turnover: The resulting 12month bone-formation rates were not statistically different
between groups. The mean bone-formation rate increased by
76% with calcium treatment, which was not statisticallysignificant for the before and after within-arm comparison,and by 93% with sevelamer-HCl treatment, which wassignificant (Po0.05) for the before and after within-groupcomparison. The authors then separately analyzed those who
initially had a high or low bone turnover. In those with a low
bone turnover, there was a similar improvement with both
treatments. In those with a high bone turnover, there was nomean change in bone formation with either treatment.
Mineralization: There was no significant change in themineralization lag time (MLT) with either treatment. In the
low-turnover group, there was improvement with both
treatments. It is noteworthy that bone aluminum surface
was 21.1±28.7% in the calcium-treated group and
27.6±27.4% in the sevelamer-treated group, although the
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number of patients who had positive aluminum staining was
not provided. Volume: There was a significant (Po0.05) but
slight improvement with calcium treatment and no changewith sevelamer-HCl treatment.
A third study in children did not show differences between
calcium and sevelamer-HCl for turnover or mineralization,and the same number developed adynamic disease.17
In all three of the studies, bone volume was slightly
improved with calcium treatment compared with sevelamerHCl treatment, but the results were not significant.
Lanthanum carbonate. Three studies compared the effectsof lanthanum carbonate with those of calcium carbonate
on bone histomorphometry (Supplementary Table 22). The
larger studies13,103 were of moderate quality, with someinconsistencies in data reporting, and the third study98 waslimited by a small sample size.
In the first study by D’Haese et al.,12 98 HD patients
underwent baseline bone biopsy, and paired iliac crest bonebiopsies were measured after 1 year from 63 patients, 33
of whom received lanthanum carbonate and 30 of whom
received calcium carbonate. These biopsy results werereported in three publications.12,13,21 The first reportpresented data in a categorical form. The second reportpresented changes in activation frequency (a marker of boneturnover), which were considered to have improved if they
became closer to normal.13 Data were extracted from a figurethat presented individual changes in the bone-formation rate
per bone surface. The third report presented changes in
activation frequency, and defined improvement in terms of
1 s.d.21 When all three reports of the same biopsy study weretaken together, an improvement in turnover was seen in
36–45% of patients receiving lanthanum and in 20–23% of
those receiving calcium. The turnover worsened in 30% withcalcium treatment (20% developed adynamic disease) and in
12% with lanthanum treatment (6% developed adynamic
disease). Mineralization changes were similar in both
treatment groups. Volume was not reported. Overall, theresults favored lanthanum carbonate treatment.
The second study by Malluche et al.103 evaluated 2 yearsof treatment. Paired bone biopsy samples for histomorphometric analysis were available at baseline and at 1 year in
32 lanthanum carbonate-treated HD patients and in 33 HD
patients receiving standard care, and at baseline and 2 years
in 32 lanthanum carbonate-treated patients and in 24
patients receiving standard care. The majority of patients inthe standard-care group (480%) received calcium-containing phosphate binders.103 Turnover: At 1 year, turnoverworsened in 45% of the calcium group and in 42% of thelanthanum group, and improved in 3% of the calcium groupand in 12% of the lanthanum group. At 2 years, the turnover
had worsened in 72% of the calcium group (29% decreasing
toward adynamic lesions) and in 40% of the lanthanumgroup (23% decreasing), with improvement being similar inboth groups. Therefore, at 2 years, the results showed a better
turnover with lanthanum carbonate treatment. Mineralization worsened in two patients receiving lanthanum carbonate
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and in none receiving standard-care treatment. Volume wasslightly better in the lanthanum carbonate group at 2 years.
The third study by Spasovski et al.98 included 20 new HD
patients randomly treated with lanthanum carbonate or
calcium carbonate for 1 year, thereafter with calcium
carbonate for an additional 2 years. Bone biopsies were
performed at baseline, 1, and 3 years. Turnover: None of thepatients in the lanthanum carbonate group developed low
bone turnover at the 1-year biopsy in contrast to threepatients developing adynamic bone disease in the calcium
carbonate group. The bone-formation rate showed a nonsignificant increase in the first year and a return to baselinein year 3 in the lanthanum carbonate group, whereas it
decreased slightly in the calcium group. Mineralization andvolume were not reported.
In summary, there are only minor overall changes
observed in response to non-calcium-containing phosphatebinders, compared with calcium-containing phosphatebinders, when patients are considered as a group. Thechanges in bone turnover are heterogeneous and influenced
by initial bone turnover. None of the studies had enoughpower to provide adequate evidence for a change in volume.
The studies did not identify consistent beneficial or adverse
effects on bone with the administration of any of thephosphate binders in the doses used.
The Work Group felt it was important to acknowledge
that existing adynamic bone or the development of a lowturnover disease may be related to the development of arterial
calcification as described earlier. A cross-sectional study
found that arterial calcification is higher in patients whosebone formation was below the median value. The meancalcium intake was higher in those with adynamic bone andin those with aortic calcification. Furthermore, in those withadynamic bone disease, calcium intake was directly related tothe degree of aortic calcification.117 In the study by Barreto
et al.,119 the relationship between bone histology andprogression of arterial calcification was evaluated. In patients
who began the 1-year study with a low-turnover disease,those who had coronary calcification progression were more
likely to have a persistent low-turnover disease at the
12-month biopsy (58 vs 17%; P ¼ 0.01). Logistic regression
analysis showed the diagnosis of a low-turnover bone state at the
12-month bone biopsy as being the only independent predictor
for coronary artery progression (P ¼ 0.04; b-coefficient ¼ 4.5;
95% CI 1.04–19.39). The mechanism for this effect may be thatadynamic bone is an ineffective reservoir for excess calcium
intake. A study showed that HD patients with biopsy-provenadynamic bone disease had minimal radio-labeled calcium
influx into bone, whereas those with a high-turnover bonedisease had a marked influx of calcium into the bone.347 The
RCTs detailed above show that some patients develop adynamic
bone disease with calcium-containing phosphate binders more
often than do those with non-calcium-based binders in
some,12,104 but not all, studies.103,118 This raises a concern withrespect to excessive calcium intake and the risk of vascular
calcification, but the amount of calcium intake that is safe
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remains to be determined and is likely to not be a uniform
amount across all patients. Despite these limitations, the WorkGroup recommended limiting calcium intake in the presence of
low-turnover bone disease or adynamic bone disease, but
acknowledged that this is a low-quality evidence and thus
graded it as 2C. Formal balance research studies are needed.
d)Biochemical end points: Comparative studies ofphosphate binders have shown differences in thebiochemical parameters of CKD–MBD. For example,
the use of calcium salts is generally associated withhigher serum calcium (and more frequent episodes ofhypercalcemia) and lower serum PTH levels whencompared with sevelamer-HCl or lanthanum carbonate.

Sevelamer-HCl. All eight RCTs reported biochemical parameters reflecting a mineral-bone disorder (blood levelsof calcium, phosphorus, and PTH) with broadly consistent
results.104,266,267,284288 In the context of these studies,sevelamer-HCl and calcium salts were equally effective asphosphate binders. In the population with CKD stages 3–5
studied by Russo et al.286 (Tables 21, 22), there were nodifferences in serum calcium, phosphorus, or PTH whencomparing diet, diet plus calcium, or diet-plus-sevelamerHCl-treated patients at the end of the 2-year study period.
Compared with baseline, urinary phosphate excretion
increased in the diet-only-treated patients but decreased inthose receiving phosphate binders. Among-group comparisons of serum calcium, phosphorus, and PTH were notreported. Concerns with regard to this study included theimbalance between baseline levels of biochemical parameters,
the lack of blinding, a high dropout rate (10% in thesevelamer-HCl arm), and the lack of a power analysis.
The DCOR investigators reported time-weighted biochemical parameters (but not baseline values). Patients
receiving sevelamer-HCl had a lower serum calcium, buthigher phosphorus and higher PTH serum levels than thosereceiving calcium-based binders. Serum calcium levels werealso lower in the sevelamer-HCl-treated patients in the ‘Treat
to Goal’ study284 and overt hypercalcemia was less common
in such patients.284 These findings were broadly reflected in
the RIND study results reported after 18 months oftreatment,285 and in the CARE 2 study after 12 months.287
Ferreira et al.104 reported similar results after 13.5 months offollow-up, although biochemical data were only included for
those patients undergoing a second bone biopsy, potentiallybiasing the results. In BRIC, those patients randomized tosevelamer-HCl had both higher PTH and alkaline phosphatase (ALP) levels after 12 months of treatment, although
there were no differences in serum calcium or in thefrequency of hypercalcemic episodes.288 Thus, in all of theseeight comparative studies, a randomization to sevelamer-HCl
was associated with higher serum iPTH levels, and in all but
one study (BRIC), with a lower serum calcium concentration.
The Work Group considered these biochemical data to
be of high quality, although the importance of laboratory
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outcomes was considered to be low, the increase in PTH may
or may not reflect a desirable change depending on the end
point, and most importantly, the true relationship ofbiochemical measures with clinical end points has not been
established.
Lanthanum carbonate. Of the three randomized studies
comparing lanthanum carbonate with other binders(Supplementary Tables 20–22), only the study by Hutchison
et al.348 reported biochemical parameters reflecting mineralbone disorder (serum phosphorus, calcium, Ca  P, andPTH) as the primary end point. However, this study
compared the ability of the binders to maintain phosphorus
control only in those patients who achieved serum phosphorus levels p5.58 mg/dl (1.8 mmol/l) within the initial
dose-titration phase. The ERT therefore considered these data
to be of limited applicability and was concerned with regard
to potential bias introduced by the exclusion of study
participants after randomization. The results of the other two
studies were broadly consistent in that lanthanum carbonate
was as effective as calcium carbonate in controlling serum
phosphorus, but neither of these studies were primarily
designed to compare efficacy in phosphorus lowering or
to examine other biochemical end points.13,349
In a longer term study,349 46% of patients in the lanthanum
carbonate group (maximum daily dose of 3000 mg elemental
lanthanum) achieved control of serum phosphorus levels to
o1.9 mmol/l (5.9 mg/dl) compared with 49% in the standardtherapy group (P ¼ 0.5) after 2 years of treatment. However,there was a higher frequency of hypercalcemia reported as
an AE in the calcium carbonate group (20.2%) comparedwith that in those receiving lanthanum carbonate therapy(0.4%). Serum PTH levels attained the range recommended
by the KDOQI guidelines for patients with CKD stage 5(150–300 pg/ml (15.9–31.8 pmol/l)) during titration in thelanthanum carbonate group, but remained below this range
throughout the study period in the standard-therapy group.
The Work Group considered these data on biochemicalmarkers to be of low quality. First, the study was designed
for safety analysis and not for efficacy. In addition, there wasno option to switch treatments in the event of inefficacy in thelanthanum group. Patients in the lanthanum group wererequired to withdraw if they experienced AEs or if theinvestigator decided that additional therapy was required.
However, patients randomized to the standard-therapy groupwere permitted to change to other phosphate binders or toreceive additional binders. Furthermore, the lanthanum groupwas subjected to a dose-titration phase, whereas the standardtherapy group was placed on previously known and likely
efficacious doses of phosphate binders. Overall, 38% of
patients dropped out of the study. Dropouts due to AEs werehigher in the lanthanum arm (14%) than in the ‘other binder’arm (4%). The Work Group considered that these issues could
bias efficacy results in favor of the standard-therapy group,
who were more likely to complete the study.
In the smallest study involving 98 patients,13 serum
calcium, phosphorus, Ca  P, and calcitriol values were similar
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in both groups and did not change from baseline throughout
the study. The mean serum PTH also remained constantthroughout treatment in the lanthanum carbonate group, but
a reduction in levels was observed in calcium carbonate-treatedpatients. Overall, the Work Group considered these data on
biochemical markers to be of moderate quality. However, inboth studies,13,349 there was concern with regard to thedirectness of PTH data for the same reasons expressed above.
4.1.6 In patients with CKD stages 3–5D, we recommend
avoiding the long-term use of aluminum-containing
phosphate binders and, in patients with CKD stage
5D, avoiding dialysate aluminum contamination toprevent aluminum intoxication (1C).
The use of aluminum-containing phosphate binders has been
extensively evaluated in the KDOQI Bone and Mineral
Metabolism Guidelines.5 The major toxicities are neurotoxicity and impairment of bone mineralization, both of which
can be prevented by minimizing aluminum exposure.
However, the Work Group acknowledged that the literature,
as detailed in the KDOQI guidelines,5 supports that the most
severe cases of aluminum toxicity occurred in patients whose
dialysate was contaminated with aluminum, and thataluminum-based binders only played a secondary role. The
quantity of aluminum-based phosphate binders that is safe isunknown. Moreover, several conditions may favor intestinalaluminum absorption, such as diabetes mellitus, secondary
HPT, vitamin D status, and a high citrate intake.350 Therefore, the Work Group felt that as numerous alternative
phosphate binders have become available, and there is no
ability to predict a safe aluminum dose, the long-term useof aluminum-based phosphate binders should be avoided.
This was a unanimous vote.
4.1.7 In patients with CKD stages 3–5D, we suggest
limiting dietary phosphate intake in the treatmentof hyperphosphatemia alone or in combination withother treatments (2D).
Only one RCT, by Russo et al.,286 (Tables 21, 22) has
specifically assessed the effect of dietary phosphate restriction
on CAC. However, it was not designed to show a superiority
or an equivalence of dietary phosphate modification whencompared with oral phosphate binders. The investigators
recruited 90 phosphate-binder-naive patients with CKD
stages 3–5 who were not on dialysis. Of these patients, 30
were randomized to a low-phosphate diet alone, with theremaining 60 patients receiving the diet in combination with
fixed doses of calcium carbonate (2 g/d) or sevelamer-HCl(1600 mg/d) over a 2-year follow-up period. Final CAC scores
were increased in the group receiving phosphate-restricteddiet alone and in the group receiving diet in combination
with calcium carbonate. There was no progression of
calcification in the diet-plus-sevelamer-HCl-treated group(as discussed under Rationale 4.1.5). It is noteworthy that the
Kidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.1

prescription of phosphate restriction alone did not lead to adecrease in urinary phosphate excretion. Thus, a lowphosphate diet alone did not prevent CKD-associatedprogression of CAC in patients not receiving dialysis.
In the absence of other RCTs, the Work Group thensearched for studies that compared diet with an active orplacebo control including more than 25 patients in each arm(or less for bone biopsy studies) with a follow-up of morethan 6 months. The only two studies351,352 that met these
extended criteria evaluated biochemical data, although
one also assessed bone parameters and vascular calcification.352 Zeller et al.351 showed that the restriction of dietary
protein and phosphate intake was feasible with the maintenance of nutritional parameters in a study of 35 type I
diabetes patients with nephropathy. In relation to thebiochemical markers of CKD–MBD, they found a significant
reduction in urinary phosphate excretion in the groupassigned a protein/phosphate restriction as compared withpatients receiving a control diet. They did not examine
markers of bone turnover. Using bone biopsy in 16 patientswith CKD stages 4–5, Lafage-Proust et al.353 reported thatafter 5 years of a very-low-protein, low-phosphorus diet(supplemented with essential amino acids and their
ketoanalogs), the bone-formation rate was normal or highin 10 patients, and low in the remaining six. They did
not observe any low-protein-associated malnutrition in thesepatients.
Thus, there are insufficient data at present to strongly
endorse dietary phosphate restriction as the primaryintervention for the management of CKD–MBD, especiallystage 5D. It is biologically plausible that such diets are helpfulin early CKD and as an adjunct to phosphate binders anddialytic removal in dialysis patients. The limited safety datasuggest that dietary phosphate restriction does not compromise nutrition in a monitored setting.
4.1.8 In patients with CKD stage 5D, we suggest increasing
dialytic phosphate removal in the treatment of
persistent hyperphosphatemia (2C).
A narrative review of the literature addressing this issue wascarried out. Although research in this area is becoming moreabundant, studies are typically small in sample size and lack
the rigor required to direct practice. One prospective RCT
has reported the impact of alternative dialysis therapies
using biochemical markers of CKD–MBD as a secondary
end point.314 In this study, Culleton et al.314 (Tables 27–29)
compared the effect of a nocturnal prolonged-duration HD
six times weekly (26 patients) with that of standard HD given
thrice weekly for 4 h each session (25 patients) in a parallel
design, reporting serum calcium, phosphorus, Ca  P, and
iPTH. The authors found significant decreases in serum
phosphorus and iPTH in patients allocated to frequent
nocturnal HD, as compared with those on standard HD
treatment. Serum calcium was comparable in the two groups.
The amount of oral phosphate binder needed to control
Kidney International (2009) 76 (Suppl 113), S50–S99

hyperphosphatemia was also reduced. These data suggest thatfrequent nocturnal HD can lead to an improvement in mineralmetabolism (see Tables 27–29). Thus, in efforts to control
hyperphosphatemia, dialysis regimens that allow an increase inphosphate removal may be an alternative in patients who
cannot tolerate phosphate binders or are not willing to takesufficient amounts of them.
SPECIAL CONSIDERATIONS IN CHILDRENOf all the available binders, only sevelamer-HCl and calcium
carbonate have been examined in children, with a total of
47 children studied in two RCTs to date (see Table 20). In
one study, 29 children on maintenance dialysis were assigned
to either sevelamer-HCl or calcium carbonate, as well as toeither calcitriol or doxercalciferol in a factorial design.17
During sevelamer-HCl treatment, levels of serum phosphorus
control were similar when compared with those with calcium
treatment during the 8 months of study. Serum PTH waslower in the calcium arm compared with that in thesevelamer-HCl arm. There were more episodes of hypercalcemia in the calcium arms compared with that in thesevelamer-HCl arms. There was a 31% dropout rate in thisstudy, but among those who attended for a second biopsy at
the end of the study, bone histomorphometric data did not
differ between the two groups. In the other study, which hada cross-over design and involved 18 children with CKD stages
3–5 not on dialysis, there was equivalent serum phosphorus
control between the groups.354 Given the small number ofchildren studied, the only conclusion that can be derived
from these studies is that an avoidance of hypercalcemia may
be easier to achieve with the use of sevelamer-HCl. There
have been no studies on the use of lanthanum carbonate inchildren.
ADVERSE EVENTS
Sevelamer-HCl. (Supplementary Table 18) Compared withcalcium-based phosphate binders, sevelamer-HCl seems to bewell tolerated. Although European patients participating inthe ‘Treat to Goal’ study reported more gastrointestinal side
effects with sevelamer-HCl,343 this difference was not seenin the study cohort as a whole.284 As mentioned above,
hypercalcemia was more commonly seen in patients treatedwith calcium-based binders participating in ‘Treat to Goal’
study,284 and accounted for several of the withdrawals in the
calcium-treated arm of the DCOR study.266 In the twostudies that reported total serious AEs,266,284 there was nodifference between calcium-based phosphate binder andsevelamer-HCl treatment. This observation is consistent withthe conclusion reached by Tonelli et al.355 in a recently
published systematic review of the clinical efficacy and safetyof sevelamer-HCl in dialysis patients.
Lanthanum carbonate. (Supplementary Table 23) Lanthanum
carbonate was shown to be generally well tolerated. The mostnotable difference between lanthanum carbonate and calcium
carbonate was the frequency of clinically significant hypercalcemia with the use of calcium carbonate reported as an AE, asS61

chapter 4.1

discussed earlier. The incidence of other AEs showed noclinically important differences between lanthanum carbonate
and calcium carbonate groups.13,348,349
Cognitive function was assessed in the substudy by
Altmann et al.356 using the Cognitive Drug Research
computerized assessment system. This showed that the useof lanthanum carbonate did not adversely affect cognitive
function in HD patients compared with those undergoingstandard therapy. Both groups showed a similar decline incognitive function over a 2-year time period.
The plasma and bone lanthanum levels were assessed andcompared as a primary end point in the study by Spasovski
et al.98 Plasma lanthanum levels reached a steady stateof around 0.6 ng/ml after 36 weeks of treatment. Six weeks
after the cessation of 1 year of lanthanum treatment, plasma
lanthanum levels had declined to a value of 0.17±0.12 ng/ml(Po0.05) and after 2 years to 0.09±0.03 ng/ml. The meanbone lanthanum concentration in patients receiving lanthanum carbonate increased from 0.05±0.03 to 2.3±1.6 mg/g
(Po0.05) after 1 year and slightly decreased at the end of
the study to 1.9±1.6 mg/g (Po0.05). The mean bonelanthanum concentration in the calcium carbonate group
was 0.1±0.04 mg/g at the 1-year biopsy and 0.15±0.06 mg/g
at the end of 3 years. These data, together with thebone histomorphometry findings, suggested that bonelanthanum deposition was not associated with aluminumlike toxicity.
RESEARCH RECOMMENDATIONSAdvancing the evidence base for phosphorus-lowering
therapies

The Work Group considered that robust studies of a large
sample size addressing the following issues should be given
priority.
K Does lowering serum phosphorus with any phosphatebinder improve clinical outcomes, including mortality,
cardiovascular events, bone pain, or fracture in patientswith CKD stages 3–5 and 5D?
K Doesthe use of lanthanum carbonate improve
cardiovascular calcification compared with the use of
calcium-based phosphate binders in patients with CKD
stage 5D?
K Is slower progression of arterial calcification (as observedin association with the use of non-calcium-based

S62

phosphate binders, such as sevelamer, in comparison
with calcium-containing phosphate binders) associatedwith better survival?
K Can aluminum hydroxide be used safely, at least in the
short term, in selected CKD stage 5D patients, provided
dialysis water is free of this metal?
K Do improvements in the biochemical parameters that havebeen associated with alternative dialysis regimens translate
into an improvement in clinical outcomes of CKD–MBD?
K Studies are needed to evaluate the clinical benefits
associated with the use of dietary intervention in patientswith CKD stages 3–5D and stages 1–5T.
K Studies are needed to identify the presence and degree ofphosphate additives in foods and their impact on
phosphate metabolism.
K More studies in children with CKD–MBD are needed,
especially to evaluate cardiovascular end points.
SUPPLEMENTARY MATERIAL

Supplementary Table 14. Overview table of selected studies demonstrating the risk relationships between biochemical parameters of Ca,
P, Ca  P, and mortality in CKD stages 3–5 and 5D.
Supplementary Table 15. Summary table of RCTs examining thetreatment of CKD–MBD with sevelamer-HCl vs calcium-containing
phosphate binders in CKD stage 5D—description of population atbaseline.
Supplementary Table 16. Summary table of RCTs examining thetreatment of CKD–MBD with sevelamer-HCl vs calcium-containing
phosphate binders in CKD stage 5D—intervention and results.
Supplementary Table 17. Summary table of RCTs examining thetreatment of CKD–MBD with sevelamer-HCl vs calcium-containing
phosphate binders in CKD stage 5D—bone biopsy results.
Supplementary Table 18. Adverse events of sevelamer-HCl vs calciumcontaining phosphate binders in CKD stages 3–5 and 5D.
Supplementary Table 19. Ongoing RCTs examining the effect ofphosphate binders on CKD–MBD.
Supplementary Table 20. Summary table of the treatment of
CKD–MBD with lanthanum carbonate vs other phosphate binders in
CKD stage 5D—description of population at baseline.
Supplementary Table 21. Summary table of the treatment of
CKD–MBD with lanthanum carbonate vs other phosphate binders in
CKD stage 5D—intervention and results.
Supplementary Table 22. Summary table of the treatment of
CKD–MBD with lanthanum carbonate vs other phosphate binders in
CKD stage 5D—bone biopsy results.
Supplementary Table 23. Adverse events of lanthanum carbonate vsother phosphate binders in CKD stage 5D.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki

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chapter 4.1

Table 20 | RCTs of phosphate binders in children with CKD
Author (year)

N

Population

F/U

Study design

Arm 1

Arm 2

Outcomes

Salusky (2005)1729

PD

8 months

RCT

Sevelamer

Ca carbonate

Pieper (2006)354

18

HD, PD, CKD
stages 3–4

8 weeks

RCT, cross-overSevelamer

Ca acetate

Bone Bx, P, Ca, Ca  P, PTH,
hypercalcemic episodes
P, Ca, iPTH, lipids

Bx, biopsy; Ca  P, calcium–phosphorus product; CKD, chronic kidney disease; HD, hemodialysis, iPTH, intact parathyroid hormone; PD, peritoneal dialysis; PTH, parathyroid
hormone; RCT, randomized controlled trial.

Table 21 | Summary table of RCTs examining the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing phosphatebinders in CKD stages 3–5—description of population at baseline

Author (year)

N

Agea

Countryof study% Malea90

54 (55) [54]286% RaceItaly

89 (82) [86]

CKD
stage

% Prior Al
exposurea
0%

ND

Russo (2007)

% DMa

3–4
0%

Baseline MBD Labsa

Vascular/valvular calcification
by EBCTa

Ca 2.30 (2.25) [2.30] mmol/l
P 1.45 (1.49) [1.26) mmol/l
CAC by MSCT (TCS) 415 (340)
PTH 14.5 (18.2) [14.9] pmol/l [369]
ALP 134.2 (148) [113.7] mg/dl % with no CAC: 19% (18%) [17%]Bioactive intact-PTH(Diagnostic Products) [ref: ND]

ALP, alkaline phosphatase; CAC, coronary artery calcification; CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; DM, diabetes
mellitus; EBCT, electron-beam CT; MBD, mineral bone disease; MSCT, multislice computed tomography; N, number of subjects; ND, not documented; PTH, parathyroid
hormone, TCS, total calcium score.
No study reported DXA or bone histology at baseline.
a
Arm 1 (Arm 2) [Arm 3].

Table 22 | Summary table of RCTs examining the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing phosphatebinders in CKD stages 3–5—intervention and results
N

Arm 1

Results

Follow-up Arm 2
Author (year)

CKD stage [Arm 3]

90

Russo
(2007)286

Cointerventions

Sevelamer
1600 mg/d

Mean 24monthsCa carbonate:2000 mg/d
Elemental Ca:
800 mg/d

3–4[Control]

Low P diet
No vitamin D or statins

Outcomes

Arm 1 vs Arm 2 vs Arm 3(P-value)

Quality

Vascular calcificationa
Mean CAC at 12 mo
D Mean CAC

453 vs 473 vs 547 (NS)b
38 vs 133 vs 178c

B
B

2.25 vs 2.27 vs 2.32 (ND)
1.55 vs 1.52 vs 1.26 (ND)
3.48 vs 3.25 vs 2.91 (ND)
14.3 vs 18.7 vs 15.6 (ND)
103.4 vs 143.0 vs 85.1 (ND)
4.69 vs 4.76 vs 4.88 (ND)

B
B
B
B
B
B

2.77 vs 2.61 vs 3.05 (ND)
1.3 vs 1.2 vs 1.3 (ND)
1.49 vs 1.57 vs 1.49 (ND)
24.1 vs 25.9 vs 33.6 (ND)

B
B
B
B

Laboratory
Mean Ca (mmol/l)Mean P (mmol/l)Mean Ca  P (mmol2/l2)
Mean PTH (pmol/l)Mean ALP (mg/dl)
Mean total cholesterol(mmol/l)Mean LDL-C (mmol/l)Mean HDL-C (mmol/l)Mean triglycerides (mmol/l)
CrCl (ml/min)

ALP, alkaline phosphatase; CAC, coronary artery calcification; Ca  P, calcium–phosphorus product; CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineraland bone disorder; CrCl, creatinine clearance; D, change; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; N, number of subjects;
ND, not documented; NS, not significant; PTH, parathyroid hormone; RCT, randomized controlled trial.
aPrimary outcome.
b
No two-arm statistical comparisons provided. Within-arm changes in CAC were NS for sevelamer-HCl arm and Po0.001 for Ca carbonate and control arms.
cCalculated from pre- and post-mean values.

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S64

Table 23 | Evidence matrix for sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D
Methodological quality
A
OutcomeMortality

Author—B

N (on agent)
—

F/U
—

AuthorBlock (2007)265
St Peter(2008)267 aC

N (on agent) F/U
44 months
median2102 (1051) 28 months
127 (60)

AuthorAdverse event reporting

N (on agent)

F/U—

Braun (2004)

—

—

—

—

—

—

—

—

—

Suki (2007)266 c

2103 (1053)

20 months

QoL
Fractures
PTx

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

Bone density

—

—

—

—

—

—

—
—
—
Raggi (2005)346
Asmus (2005)344———
111 (51)+ p21 (+ p11b)———
12 months
21 months

91 (44)13.5 months

Bone histology

Ferreira(2008)104
Barreto(2008)288

101 (41)

12 months——

Vascular/valvular
calcification—

Lab: Ca, P, PTH

—

—

—

Lab: ALP, b-ALP

—

—

—

Lab: Bicarbonate

—

—

—

Kidney International (2009) 76 (Suppl 113), S50–S99

Adverse events

—

—

—

—

8 months

Qunibi (2008)287
Chertow (2002)284
Block (2005)285
Qunibi (2008)287
Chertow (2002)284
Block (2005)285
Ferreira (2008)104
Qunibi (2008)287
Ferreira (2008)104
Qunibi (2008)287
Chertow (2002)284
Ferreira (2008)104

203 (103)132 (62)148 (73)203 (103)
200 (99)
148 (73)
91 (44)203 (103)
91 (44)203 (103)
200 (99)
91 (44)

12 months
12 months
18 months
12 months
12 months
18 months
13.5 months
12 months
13.5 months
12 months
12 months
13.5 months

—

—

—

—

—

Asmus (2005)

—

—

344

284

F/U

200 (99)

12 months—

Hospitalization

29 (15)N (on agent)

Chertow (2002)—

Clinical CVD

Salusky (2005)17

Author—343—
Chertow (2002)284
Braun (2004)343———+p21 (+ p11 ) 12 monthsb—
200 (99)+ p21 (+ p11b)————
12 months
12 months
—
—
—

—

—

—

—

—

—

—

—

—

—

—

—

b

+ p21 (+ p11 ) 21 months

Barreto (2008)288
Suki (2007)266
Asmus (2005)344
Barreto (2008)288

101 (41)2103 (1053)+ p21 (+ p11b)
101 (41)

12 months
20 months
24 months
12 months

Raggi (2005)346
Barreto (2008)288

111 (51)
101 (41)

12 months
12 months

—

—

—

—

—

—

—

—

—

—

—

—

Suki (2007)266
Qunibi (2008)287
Chertow (2002,
2003)284,357
Braun (2004)343
Block (2005)285
Ferreira (2008)104

2103 (1053)
203 (103)
200 (99)

20 months
12 months
12 months+ p21 (+ p11b) 12 months
148 (73)
18 months
91 (44)13.5 months

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; N, number of subjects; PTH, parathyroid hormone; PTx, parathyroidectomy;
QOL, quality of life.
Number randomized may be higher than number analyzed; this evidence profile does not include studies of sevelamer-HCl vs calcium-containing phosphate binders in CKD stages 3–5 (refer to summary table entry for Russo(2007)286) or studies in pediatric population (refer to summary table entry for Salusky (2005)17).
a
See also report by Suki (2007)266b
Unclear reporting regarding the number of individuals who received study drug.
c
See also report by St Peter (2008).267

Kidney International (2009) 76 (Suppl 113), S50–S99

Table 24 | Evidence profilea for the treatment of CKD–MBD with sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D
Summary of findings

OutcomeMortality-

Clinical CVD
and CeVD
All-cause
hospitalization
Quality of life
Fractures
PTx
X-ray boneassessment
Bone histology-

No. of studies
and study
designTotal N
(N on study
drug)

2 RCTs2230 (1126)

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Methodologicalquality of studies

Consistency
across studies

Seriouslimitations (1)c

Important
inconsistenciesd (1)

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Directness of theevidence (generalizability/ applicability)

Other
considerationsb

Direct

—

-

-

-

-

-

-

-

-

-

-

-

-

-

-

AE from 1+ RCTse

221 (99+?)

Very serious
limitations (2)

—

—

—

—

—

—

—

—

—

1 RCT

2103 (1053)

Very serious
limitations (2)f

NA

Direct

—

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

AE from 1+ RCTse

221 (99+?)———
1+ RCTse———111+? (51+?)

2 RCTs192 (85)

Very serious
limitations (2)———
Very serious
limitation (2)g
No limitations

673 (316 +?)Vascular/valvular 4+ RCTse
calcification

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Quality ofevidence foroutcomeLow

Phosphorus
Ca  P

6+ RCTsePTH
ALP, b-ALP

4 RCTsBicarbonate

3 RCTsAdverse events

6+ RCTse

Importance ofoutcomeNo difference in one moderatequality study in prevalent HD patients.
CriticalBorderline statistically significant
benefit for sevelamer-HCl in one
moderate quality study in incident
HD patients——

Critical

Low

Trend to lower all-cause hospitalization in one low-quality study

High

—

—

—

—
—
—
NA

—
—
—
Major uncertainty (2)h———Sparse (1)———Very Low———
Unable to assess

High
High
High
Moderate

NA

DirectSparse (1)Moderate

Moderate

Serious limitations Important(1)iinconsistenciesj (1)

Direct—Low

Overall not much difference
between groups
Trend toward less progression
with sevelamer, but inconsistency
regarding statistical significanceand size of difference assessedwith different metrics at different
time points and at different sites

No important
inconsistencies
No important
inconsistencies
No important
inconsistencies
No important
inconsistencies
NA

Direct—Moderate

Higher with calcium

Direct—Moderate

No consistent difference—

Moderate

No consistent difference—

Moderate

Lower with calcium

DirectSparse (1)

Low

Unable to assess

NA

DirectSparse (1)

Low

Lower with sevelamer

Laboratory measurements
Calcium

Qualitative and quantitativedescription of effectSerious limitations(1)kSerious limitations
k2867 (1413+?) (1)
Serious limitations(1)kSerious limitations(1)k595 (287)
Serious limitations(1)m494 (246)
Serious limitations(1)mDirectDirectl

2867 (1413+?)

Quality of overall evidence:
Moderate for biochemical outcomes
Low to very low for other surrogate outcomes
Low for patient-centered outcomes

Moderate

Depends on
outcome

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chapter 4.1

Balance of potential benefits and harm:
Sevelamer-HCl is as effective as calcium-based binders in terms of target-driven attainment of biochemical values. There is a trend towards
slower progression of vascular calcification (sevelamer-HCl vs calcium-containing phosphate binders); there is no robust statisticallysignificant difference for mortality or hospitalizations

Inconsistent trend in GI and CVD
events when using sevelamer-HCl
vs Ca-containing P binders. Morehypercalcemia with Ca-containing
P bindersModerateAE, adverse event, ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineraland bone disorder; CVD, cardiovascular disease; GI, gastrointestinal, HD, hemodialysis; N, number of subjects; NA, not applicable; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial.
? Unclear number of patients studied for outcome.
aThis evidence profile does not include studies of sevelamer-HCl vs calcium-containing phosphate binders in CKD stages 3–5 (refer to summary table entry for Russo (2007)286) or studies in pediatric population (refer to summary tableentry for Salusky (2005)17).
b
Other considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), and all plausible
confounders would have reduced the effect (+1).
c
2 grade B.
dOne study showed a trend toward benefit in terms of all-cause mortality, whereas the other showed not statistically significant difference.
eBraun (2004)343 and Asmus (2005)344 have considerable patient overlap (N=93 out of 114) with Chertow (2002)284 and Raggi (2005)346 respectively.
f
One grade C, inconsistency for statistical significance for all-cause hospitalization between reports for same study (Suki (2007)266, St Peter (2008)267).
g
One plus grade C.
hNonvalidated method.
i
Three grade B, one grade C.
j
Heterogeneity in the study designs.
kFour grade B, two grade C.
lHowever, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
m
Two grade B, two grade C.

chapter 4.1

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Table 24 | Continued

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Kidney International (2009) 76 (Suppl 113), S50–S99

Table 25 | Evidence matrix for lanthanum carbonate vs other phosphate binders in CKD stage 5D
Methodological quality
A
OutcomeB

Author N (on agent) F/U

AuthorC

N (on agent)

Mortality

—

—

—

—

—

Clinical CVD and CeVD
All-cause hospitalization
QoL
Fractures
PTx
Bone density
Bone histology

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

Vascular/valvular calcification
Lab: Ca, P, PTH

—
—

—
—

—
—

Lab: ALP, b-ALP
Lab: Bicarbonate
Adverse events

—
—

—
—

—
—

—
—
—
—
—
—
Malluche (2008)103
Freemont (2005)13
Spasovski (2006)98—
Freemont (2005)13
Malluche (2008)103
Malluche (2008)103
—

—
—
—
—
—
—
211 (51)
63 (30)24 (12)—98 (49)211 (51)
211 (51)—

F/U—

Author
—

—
—
—
—
—
—
—
—
—
—
—
—
24 months—
12 months
12 months——
12 months Finn (2006)349
24 months
24 months Finn (2006)349—
Finn (2006)349

N (on agent)

Adverse events (no grade)
F/U

Author

—

—

349

—
—
—
—
—
—
—

—
—
—
—
—
—
—

Finn (2006)
Malluche (2008)103
Spasovski (2006)98
—
—
—
—
—
—
—

—
1359 (682)—
24 months——

1359 (682)1359 (682)

24 months
24 months

N

F/U

1359 (682) 24 months
211 (51) 24 months
24 (12) 12 months
—
—
—
—
—
—
—
—
—
—
—
—
—
—

—
—

—
—

—
—
—
—
—
—
1359 (682) 24 months
Finn (2006)349
Hutchison (2005)348 800 (533) 6 months
211 (51) 24 months
Malluche (2008)103
98 (49) 12 months
Freemont (2005)13
24 (12) 12 months
Spasovski (2006)98

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
N analyzed may be less than N randomized.

chapter 4.1

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Summary of findings
No. of studies
and study
designOutcomeMortality-

Total N (N on Methodologicalstudy drug) quality of studies

Consistency
across studies

Directness of theevidence generalizability/ applicability

Other
considerationsa

—
—
—
—
—
—
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AE from 2 RCTs 1383 (694)

Quality ofevidence foroutcomeQualitative and quantitativedescription of effectImportance ofoutcomeVery low

Unable to assess

Critical

—
—
—
—
—
—
Lanthanum biopsies showed overall
better turnover with no differencesin mineralization, and possible
higher volume—

Critical
High
High
High
High
Moderate
Moderate

Very serious
limitations (2)
—
—
—
—
—
—
Serious limitations
(1)b

—

—

—

—
—
—
—
—
—
No majorinconsistencies

—
—
—
—
—
—
Direct

—
—
—
—
—
—
—

—
—
—
—
—
—
Moderate

Clinical CVD and CeVD
All-cause hospitalization
Quality of life
Fractures
PTx
Bone density
Bone histology

—
—
—
—
—
—
3 RCTs——————333 (63)

Vascular/valvular calcification

—

—

—

—

—

—

—

Calcium

3 RCTs1668 (782)—Low

3 RCTs1668 (782)

Direct—Low

Tendency toward lower Ca and lower
rates for hypercalemic episodes
Similar P control

Ca  P

1 RCT

98 (49)No majorinconsistencies
No majorinconsistencies
NA

DirectPhosphorus

DirectSparseVery low

Tendency toward higher Ca  P

PTH

3 RCTs1668 (782)—Low

Tendency toward higher PTH

2 RCT

1570 (733)

No majorinconsistencies
NA

Directe

ALP, b-ALP

Direct—Low

Tendency toward higher b-ALP

Bicarbonate

1 RCT1359 (682)

Very serious
limitations (2)cVery serious
limitations (2)cVery serious
limitations (2)dVery serious
limitations (2)cVery serious
limitations (2)f
Very serious
limitations (2)gNA

Direct—Low

No difference in bicarbonate

Adverse events

5 RCTs2492 (1327)

Moderate

Laboratory measurements

Kidney International (2009) 76 (Suppl 113), S50–S99

Balance of potential benefits and harm:
No evidence of benefit or harm on clinical and calcification outcomes. Uncertain effect on bone laboratory outcomes. Bone histology was
improved more often in lanthanum group but formal statistical comparisons were not done.

One study showed no worse decline
in cognitive function with lanthanum.
Bone and plasma lanthanum levels
were higher in lanthanum groups

Moderate

Depends on
outcomeQuality of overall evidence:
Low for biochemical outcomes
Moderate for other surrogate outcomes
Very Low for patient-centered outcomes

AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; N, numberof subjects; NA, not applicable; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial.
aOther considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
bThree grade B.
c
Two grade B and one grade C in studies not designed for comparative efficacy.
dOne grade B in study not designed for comparative efficacy.
eHowever, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
f
One grade B and one grade C.
g
One grade C.

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Table 26 | Evidence profile of lanthanum carbonate vs other phosphate binders in CKD stages 5D

chapter 4.1

Table 27 | Summary table of RCT examining alternate HD regimens in CKD stage 5D—description of population at baseline
Author(year)

Culleton(2007)314

N

Agea

Countryof study% Malea52

55 (53)

Canada69 (56)% Racea

White:
88 (84)

Dialysis vintagea% DMa

Dialysatecalciuma% HDmodalitya

66 (58)months38 (44)

Vascular/valvularBonecalcification
evaluation imagingaBaseline MBD Labs

Adjusted between In-center:1.00 and69 (52)1.75 mmol/l
Home: 23 (28)
Self-care: 8 (20)

Ca 2.37 mmol/l (2.27)
P 1.78 mmol/l (1.58)
Ca  P 4.18 mmol2/l2 (3.62) NonePTH 26.4 pmol/l (14.8)
Assay ND
b-ALP ND

None

b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CKD, chronic kidney disease; DM, diabetes mellitus ; HD, hemodialysis; MBD, mineral bonedisease; N, number of subjects; ND, not documented; PTH, parathyroid hormone; RCT, randomized controlled trial.
aOverall or Arm 1 (Arm 2).

Table 28 | Summary table of RCT examining alternate HD regimens in CKD stage 5D—intervention and results
N
Author (year)

Follow-up

Arm 1

Modality

Arm 2

Cointerventions

OutcomesaNocturnal
HD 6  /week

52
Culleton (2007)314

6 months
HD

Conventional
HD 3  /week

Dialysate calcium was adjusted
between 1.00 and 1.75 mmol/ldepending on serum Ca level

DLV mass
HRQOL
DiPTH
DCa
DP
DCa  P
% Reduction or
D/C of phosphatebinders

Results Arm 1 vs
Arm 2 (P-value)

Quality

Not in the realm of theguideline8.9 vs +1.6 (0.05)
0.02 vs 0.05 (NS)
0.36 vs +0.13 (o0.05)
0.9 vs +0.19 (o0.05)
73% vs 12% (o0.001)

—
B
A
A
A
B

Ca  P, calcium–phosphorus product; CKD, chronic kidney disease; D, change; D/C, discontinued; HD, hemodialysis; HRQOL, health-related quality of life; iPTH, intact
parathyroid hormone; LV, left ventricular; N, number of subjects; NS, not significant; RCT, randomized controlled trial.
aPrimary outcome.

Table 29 | Adverse events of alternate HD regimens in CKD stage 5D
Arm 1

Author (year)
Follow-up

N

Arm 2

Culleton (2007)314
6 months

26
25

Nocturnal
Conventional

Hospitalizations
Mean no. per Pt
0.62
0.84

D/C

Vascular accesscomplicationsa
% Pts

0%
0%

38
32

D/C

Other reported
AE
% Pts

D/C

Total D/C
due to AE

DeathsModalitychange

0%
0%

None
None

—
—

0%
0%

4%
0%

8%
0%

AE, adverse event; CKD, chronic kidney disease; D/C, discontinued; HD, hemodialysis; N, number of subjects; pts, patients.
’—’ indicates data not documented.
a
Vascular access complications include bacteremia, insertion or replacement of tunneled dialysis catheter, vascular access angiogram, and vascular access surgicalintervention (including percutaneous angioplasty or arterial or venous stenosis).

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chapter 4.2

http://www.kidney-international.org& 2009 KDIGO

Chapter 4.2: Treatment of abnormal PTH levels in
CKD–MBD
Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

Patients with CKD and HPT may develop abnormalities of allcomponents of CKD–MBD. Bone effects include an increasedbone turnover that may be associated with marrow fibrosis
and abnormal mineralization, described as osteitis fibrosaand mixed uremic osteodystrophy. Patient-level consequences may include increased bone and muscle pain,
weakness, postural instability, and fracture, whereas marrow
fibrosis may exacerbate the anemia of CKD. Severe HPT
may lead to pruritus, worsening of residual kidney function
caused by hypercalcemia, calciphylaxis, CVD, neuromuscular disturbances, and death. Over the years, approaches
to the management of secondary HPT have included using
oral calcium salts and increasing dialysate calcium levels toraise serum calcium levels, the prescription of vitamin D,
calcitriol or its analogs, parathyroidectomy, and—more
recently—the use of calcimimetics, alone or in combination
with other drugs. However, some patients with CKD have
PTH levels that are inappropriately suppressed, leading to a
low bone turnover or adynamic bone disease, conditions that
may be exacerbated by the measures listed above.
RECOMMENDATIONS

4.2.1 In patients with CKD stages 3–5 not on dialysis, theoptimal PTH level is not known. However, we suggestthat patients with levels of intact PTH (iPTH) above
the upper normal limit of the assay are first evaluatedfor hyperphosphatemia, hypocalcemia, and vitamin
D deficiency (2C).
It is reasonable to correct these abnormalities withany or all of the following: reducing dietary phosphateintake and administering phosphate binders, calcium
supplements, and/or native vitamin D (not graded).
4.2.2 In patients with CKD stages 3–5 not on dialysis, inwhom serum PTH is progressively rising andremains persistently above the upper limit of normal
S70

for the assay despite correction of modifiable factors,
we suggest treatment with calcitriol or vitamin D
analogs (2C).
4.2.3 In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two tonine times the upper normal limit for the assay (2C).
We suggest that marked changes in PTH levels ineither direction within this range prompt an initiation or change in therapy to avoid progression tolevels outside of this range (2C).
4.2.4 In patients with CKD stage 5D and elevated or rising
PTH, we suggest calcitriol, or vitamin D analogs, or
calcimimetics, or a combination of calcimimetics
and calcitriol or vitamin D analogs be used to lower
PTH (2B).
K It is reasonable that the initial drug selection for
the treatment of elevated PTH be based on serum
calcium and phosphorus levels and other aspects of
CKD–MBD (not graded).
K It is reasonable that calcium or non-calcium-based
phosphate binder dosage be adjusted so thattreatments to control PTH do not compromiselevels of phosphorus and calcium (not graded).
K We recommend that, in patients with hypercalcemia, calcitriol or another vitamin D sterol be
reduced or stopped (1B).
K We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol be
reduced or stopped (2D).
K We suggest that, in patients with hypocalcemia,
calcimimetics be reduced or stopped depending on
severity, concomitant medications, and clinicalsigns and symptoms (2D).
K We suggest that, if the intact PTH levels fall below
two times the upper limit of normal for the assay,
calcitriol, vitamin D analogs, and/or calcimimetics
be reduced or stopped (2C).
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chapter 4.2

4.2.5 In patients with CKD stages 3–5D with severe
hyperparathyroidism (HPT) who fail to respond to
medical/pharmacological therapy, we suggest parathyroidectomy (2B).

Summary of rationale for recommendations

CKD may lead to a rise in the circulating PTH level,
which is a component of CKD–MBD. Lowering serum
PTH has been a primary focus of therapy for over
30 years.
K Severe HPT is associated with morbidity and mortality
in patients with CKD stages 3–5D. Observational studies
consistently report an increased RR of death in CKD
stage 5D patients who have PTH values at the extremes(less than two or greater than nine times the uppernormal limit of the assay).
K Once developed, severe HPT may be resistant to medical/
pharmacological therapy and may persist after transplantation. Thus, progressive increases of PTH should
be avoided.
K However, there is difficulty in establishing narrow target
ranges for serum iPTH because of the following reasons:
J
Cross-sectional studies in the CKD population showthat the median iPTH increases and the range
widens with progressive CKD.
JThere are methodological problems with regard to
the measurement of PTH, because assays differ intheir measurement of accumulating PTH fragments
and there is interassay variability (see Chapter 3.1).
J
With a progressive deterioration of kidney function,bone becomes increasingly resistant to the actionsof PTH.
J
The predictive value of PTH for underlying bone
histology is poor when PTH values are between
approximately two and nine times the uppernormal laboratory range.
K In RCTs of patients with CKD stages 3–4, calcitriol andvitamin D analogs each lower levels of serum PTH
compared with placebo.
K In RCTs of patients with CKD stage 5D, calcitriol,
vitamin D analogs, and calcimimetics each lower levels of
serum PTH compared with placebo.
K In CKD stages 3–5D, calcitriol and vitamin D analogs
may increase serum calcium and phosphorus levels
compared with placebo.
K Laboratory-based experimental data show differences inthe efficacy and adverse effects of calcitriol and vitamin D
analogs, but an analysis of the limited comparative
studies in humans fails to show consistent differences.
K In studies of patients with CKD stage 5D, calcimimetics
may lower serum calcium and phosphorus levels
compared with placebo.
K There are no comparative RCTs that evaluate the use of
calcitriol or vitamin D analogs compared with calcimimetics alone.

There is a lack of RCT data in patients with CKD stages
3–5D that directly shows that the change in PTH withvitamin D (cholecalciferol and ergocalciferol), calcidiol,calcitriol, vitamin D analogs, or cinacalcet leads toimproved clinical outcomes or adequately describes
potential harm.
K Therefore, these recommendations remain weak.
K

K

Kidney International (2009) 76 (Suppl 113), S50–S99

BACKGROUND

Secondary HPT is a common complication of CKD that,
before currently available medical and surgical therapies,
resulted in considerable morbidity and mortality, including
crippling bone disease. Recently, many observational studies
have reported associations between levels of serum PTH,
calcium and/or phosphorus and the RR of cardiovascular andall-cause mortality. Experimental and clinical data support
the hypothesis that abnormalities of mineral metabolism
constitute important ‘nontraditional’ cardiovascular risk
factors. Over the past few years, recommended target ranges
have been promoted for serum calcium, phosphorus, andPTH, and an increasing number of therapies are available
that assist in achieving these targets. Traditionally, thesehave included calcium salts, calcitriol, and alfacalcidol. Morerecently, active vitamin D analogs, cinacalcet hydrochloride,and non-calcium- or aluminum-based phosphate binders
have become available. Surgical parathyroidectomy remains
a definitive therapy.
Vitamin D

The nomenclature for vitamin D has become unnecessarily
complicated over the last several years, although the terms arewell defined in chemical and endocrinology literature. The
term vitamin D represents both vitamin D2 (ergocalciferol)and vitamin D3 (cholecalciferol). Ergocalciferol is synthesizedin plants and yeasts after an ultraviolet radiation-catalyzed
conversion of its precursor, ergosterol, and, together withsome cholecalciferol from oily fish, is a dietary sourceof vitamin D in humans. However, over 90% of humanvitamin D requirements come from exposure of the skin toultraviolet-B solar radiation. Sunlight converts 7-dehydrocholesterol to previtamin D3, which undergoes a rapid,
temperature-dependent isomerization to vitamin D3 orcholecalciferol. Both vitamin D2 and D3 are hydroxylated in
the liver to metabolites specified as 25-hydroxyergocalciferol(ercalcidiol), 25-hydroxycholecalciferol (calcidiol), or commonly without specificity as 25-hydroxyvitamin D(25(OH)D). Further, 1-a-hydroxylation occurs mainly inthe kidney and also at extrarenal sites. The most active,
naturally occurring vitamin D derivative in man is calcitriol(1,25-dihydroxycholecalciferol; commonly abbreviated as
1,25(OH)2D3).
The therapeutic forms of vitamin D sterols available foruse in patients with CKD include naturally occurring
ergocalciferol, cholecalciferol, 25(OH)D, and calcitriol.
Synthetic vitamin D2 analogs include paricalcitol andS71

chapter 4.2

doxercalciferol, and synthetic vitamin D3 analogs include
alfacalcidol, falecalcitriol, and 22-oxacalcitriol (maxacalcitol).
Doxercalciferol and alfacalcidol, which are 1-a vitamin D
derivatives, require 25-hydroxylation by the liver for activity
and are commonly referred to as ‘prodrugs.’
VITAMIN D NOMENCLATURE: For the purposes of common
nomenclature, the KDIGO Work Group recommended utilization of
the following terms and abbreviations in this Guideline (see also
Chapter 3.1):
Vitamin D to represent cholecalciferol and/or ergocalciferol.
25-Hydroxyvitamin D to represent the 25-hydroxylated metabolites ofvitamin D, also known as ercalcidiol or calcidiol; abbreviated as 25(OH)D.
Calcitriol to represent 1,25-dihydroxycholecalciferol; abbreviated as
1,25(OH)2D3.
Vitamin D analogs to represent derivatives of vitamin D2 and vitamin
D3, of which the clinically investigated synthetic derivatives include
doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol(maxacalcitol).

Vitamin D has an established role in mineral homeostasis
and musculoskeletal function and is recognized to havepleiotropic extraskeletal effects, including modulation ofendothelial and immune function, inflammatory responses,
and cell cycle regulation. The rate of calcitriol production andinactivation is tightly regulated. In the setting of normal
kidney function, a reduction in the levels of calcitriol issensed by parathyroid gland vitamin D receptors, with aconsequent increase in the production and release of PTH.
Increased PTH levels increase the activity of renal 1-ahydroxylase and the conversion of 25(OH)D to calcitriol,
which suppresses PTH to its former level. In addition to atransient rise in levels of PTH, this feedback loop may resultin a reduction in the levels of serum 25(OH)D. In thepresence of CKD, most patients have reduced circulatinglevels of calcitriol. Initially, this is related to reduced
phosphate excretion and a rise in the levels of serum
phosphate and fibroblast growth factor-23, both of which
suppress renal 1-a-hydroxylase activity. Lower calcitriol levels(and reduced intestinal calcium uptake) facilitate a rise in
PTH production, and for a time, this restores levels of serum
calcitriol, increases renal phosphate excretion, and improves
renal calcium conservation. However, despite increasing
circulating levels of PTH, these homeostatic mechanisms
inevitably fail if CKD progresses and the number offunctioning nephrons decline.
Vitamin D, calcitriol, and vitamin D analogs are used in
CKD stages 3–5 and CKD stage 5D to improve abnormal
mineral homeostasis and to reduce the risk of secondary
HPT developing and progressing. An evaluation of thistherapy has generally focused on maintaining levels of serum
PTH and calcium within predetermined ‘target’ ranges, orgauged by bone histomorphometry. A number of preclinical(animal) studies have shown differences in PTH suppression,
gastrointestinal calcium absorption, incidence of hypercalcemia and hyperphosphatemia, vascular calcification, and bone
histology between calcitriol and some synthetic vitamin D
S72

analogs.299,358362 However, the evaluation of these drugs inpatients with CKD has only rarely shown similar clear-cut
differences. It is well known that, in humans, such ademonstration is inherently difficult, particularly whendrugs such as calcium-based phosphate binders are usedconcomitantly.
The use of cholecalciferol and ergocalciferol has received
relatively little attention because of an earlier, widely heldview that the kidneys were the only sites of 1-a-hydroxylationof calcidiol and that, in the presence of kidney failure, serum
25(OH)D levels were of less significance. On the other hand,recent data suggest a potential role for 25(OH)D in a numberof tissues, independent of renal conversion.363366 In patientswith CKD, levels of serum 25(OH)D are commonly
insufficient or deficient.48,180 Thus, consideration may need
to be given to both the management of endocrine (PTH
lowering and calcium increasing) and autocrine (local
inflammation and cell cycle regulation) effects of vitamin D
and calcitriol and its analogs.
Calcimimetics

Physiological studies in animals and humans in the 1980s
showed that there was a rapid release of PTH in response
to small reductions in serum-ionized calcium,367 lending
support to the existence of a calcium sensor in parathyroid
glands. This CaR was cloned in 1993,368 leading to arevolutionary understanding of the mechanisms by whichcells adjust to changes in extracellular calcium. It is now
known that the CaR is expressed in many organs controlling
calcium homeostasis, including parathyroids, thyroid C cells,
intestine, kidneys, and other tissues. In parathyroids, anactivation of CaR stimulates cell-signaling pathways tomobilize intracellular calcium and decreases PTH secretion,
whereas an inactivation reduces intracellular calcium andincreases PTH secretion.
Calcimimetics are a group of drugs that are allostericmodulators of CaR, augmenting the signal caused by thebinding of extracellular ionized calcium to CaR to increase
intracellular calcium and decrease PTH release.369 Thus, thesedrugs ‘mimic’ an increase in levels of extracellular calcium.
Cinacalcet, the only clinically available calcimimetic agent,
does not enhance intestinal calcium and phosphorus
absorption, and this action differentiates it from vitamin D
sterols and their analogs in that it can lower PTH without anincrease in circulating levels of calcium and phosphate.
The following tables are found at the end of this chapter:
Table 30 summarizes the RCTs of calcitriol or vitamin D
analogs in children with CKD. The evidence matrix, a tablethat describes the methodologic quality of the included
studies, and the evidence profile, a table that provides anoverall assessment of the quality of the evidence and balanceof potential benefits and harm are Tables 31, 32 (CKD stages
3–5) for calcitriol or vitamin D analogs compared toplacebos; Tables 33, 34 (CKD stage 5D) for calcitriol
compared to vitamin D analogs; and Tables 35, 36 (CKD
stage 5D) for calcimimetics. Additional detailed information
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chapter 4.2

about the studies of vitamin D, calcitriol and its analogs
reviewed in this chapter are further described in detail in the
Supplementary Tables 24–38.
RATIONALE

4.2.1 In patients with CKD stages 3–5 not on dialysis, theoptimal PTH level is not known. However, we suggestthat patients with levels of intact PTH (iPTH) above
the upper normal limit of the assay are first evaluatedfor hyperphosphatemia, hypocalcemia, and vitamin
D deficiency (2C).
It is reasonable to correct these abnormalities
with any or all of the following: reducing dietaryphosphate intake and administering phosphatebinders, calcium supplements, and/or native vitamin
D (not graded).
In patients with CKD stages 3–5, the optimal level of PTH is
unknown. There are no strong associative data sets to linkelevated PTH to patient-centered outcomes and, unfortunately, at this time, no RCTs have assessed the balance
between therapeutic risk and benefit when modest PTH rises
are suppressed in patients with CKD stages 3–5. Furthermore,in earlier stages of CKD, secondary HPT with modest
increases in levels of PTH represents an appropriate adaptive
response to declining kidney function that maintains
phosphate, calcitriol, and calcium homeostasis. It is not yet
clear how to differentiate an appropriate response from amaladaptive response, but it is likely that future studies
evaluating urinary phosphate excretion or fibroblast growth
factor-23 levels early in the course of CKD will clarify thisissue. In addition, it is possible that a patient whose PTH
level is always low is quite different from a patient who has ahistory of a sustained elevation in PTH and has the level
lowered to the same value. Thus, prevention and treatment
may not require similar approaches. When patients have very
high PTH levels, it is more difficult to lower those levels
because of marked parathyroid gland hyperplasia andpossible clonal parathyroid cell proliferation, with a reducedor absent ability of the gland to involute.370
Given this lack of data, yet a desire for guidance in the
management of patients with CKD stages 3–5, the Work Groupfelt that continuous increases in PTH over time likely represent
a maladaptive response, and it is the persistent rise that should
prompt therapy more than an absolute value. In addition,
because modest increases in PTH may represent adaptations toa number of underlying factors in patients with CKD stages
3–5, it is appropriate to consider all modifiable factors that may
have led to secondary HPT, in addition to the loss of GFR.
Calcium

Both historical use and experimental data support theefficacy of calcium supplementation in lowering PTH,
but these findings are not supported by RCTs in patientswith CKD stages 3–5 that fulfill our criteria for inclusion
Kidney International (2009) 76 (Suppl 113), S50–S99

into evidence tables. In the absence of such RCTs, it isunknown if benefits outweigh the possible harm associatedwith calcium overload and AEs of hypercalcemia. In asecondary analysis of one RCT designed to assess the effect of
calcium supplementation or placebo on bone density andfracture in postmenopausal women without CKD, a trend
was reported toward an increased risk for myocardial infarction and a composite end point of myocardial infarction,
stroke, or sudden death in the calcium-treated group.371
However, this finding is controversial; investigators in themuch larger Women’s Health Initiative did not detect anassociation between supplementation with calcium/vitamin
D and myocardial infarction, coronary heart disease, or
stroke.372 Russo et al.286 examined the effects of calcium
supplementation on serum iPTH in patients with CKD stages
3–5. The administered daily dose was 2 g of calcium carbonate over a time period of 2 years. Serum iPTH levels did notchange in response to this treatment (172 vs 176 pg/ml or
18.2 vs 18.7 pmol/l), whereas the GFR remained remarkably
stable over the same time period. However, there was anincrease in coronary calcification scores (see Chapter 4.1).
Thus, although historically calcium is efficacious in lowering
PTH in patients with CKD stages 3–5, it is important to realizethat the potential harm has not been adequately evaluated.
Hyperphosphatemia

There are no RCTs in patients with CKD stages 3–5 thatspecifically evaluate the effect of phosphate binders andlowering of serum phosphorus on PTH that fulfilled our
inclusion criteria. However, a recent 8-week RCT in patientswith CKD stages 3–4 with hyperphosphatemia found a
decrease in PTH in lanthanum-treated patients comparedwith those with placebo.373 In addition, secondary HPT is
known to be a compensatory response to phosphate
retention, hence this approach has theoretical efficacy.
Low serum 25(OH)D levels

Vitamin D insufficiency and deficiency occur commonlyin the general population and in patients with CKD. A recent
post hoc analysis of the Vitamin D, Calcium, Lyon Study II
was conducted by Kooienga et al.374 (Supplementary Tables
25–26). This study assessed the impact of treatment withcholecalciferol 800 IU plus calcium 1200 mg daily vs placebo
on biochemical parameters in 610 elderly French women, ofwhom 322 had estimated glomerular filtration rate (eGFR)values o60 ml/min per 1.73 m2, using the MDRD formula.
Similar improvements in the proportion of individuals achieving 25(OH)D levels 430 ng/ml (75 nmol/l) at 6 months
were seen in all kidney function groups. The proportion ofindividuals with a X30% reduction in iPTH at 6 months was
50% in all eGFR groups receiving treatment with cholecalciferol plus calcium compared with 6–9% for those on placebo(Po0.001 for all). However, this study was unable to distinguish between the effects of calcium and vitamin D, because
the treatments were given in combination and the results may
not be applicable to other demographic groups. In patients
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chapter 4.2

with CKD stages 3 and 4 with 25(OH)D levelso30 ng/ml(75 nmol/l) and elevated levels of PTH, an observational
treatment study using ergocalciferol reported a normalizationof the mean 25(OH)D levels in both CKD stages.375 A
significant reduction in the median levels of PTH was seen inpatients with CKD stage 3, with a trend toward reduced
median PTH levels in CKD stage 4.375
4.2.2 In patients with CKD stages 3–5 not on dialysis, inwhom serum PTH is progressively rising andremains persistently above the upper limit of normal
for the assay despite correction of modifiable factors,
we suggest treatment with calcitriol or vitamin D
analogs (2C).
Calcitriol or its analogs

Four RCTs were identified that assessed patients with CKD
stages 3–5 and met inclusion criteria (Tables 31, 32;
Supplementary Tables 25–26). These trials compared the useof doxercalciferol, paricalcitol, alfacalcidol, or calcitriol withplacebo. The study evaluating doxercalciferol included
55 patients376 and the study evaluating paricalcitol included
220 patients.377 Both assessed laboratory biochemical end
points. African–Americans contributed toward one-quarter to
one-half of study participants, with the remainder predominantly Caucasians. The study using alfacalcidol included
176 patients97 and the study using calcitriol included 30
patients.102 Both assessed laboratory values and bone histomorphometry. These latter studies were from 1995 and 1998,
respectively, which creates problems of interpretation becauseof changing patient demographics and altered clinicalpractices. Many patients in these studies were treated withaluminum-based phosphate binders, and the racial distribution of participants in the European studies was not provided.
These studies will be discussed with respect to their end points.
a)Patient-centered end points: For CKD stages 3–5, dataon mortality were available from safety analyses of
two studies,97,377 on clinical CVD and cerebrovasculardisease from one study,376 and on other clinicaloutcomes from three studies97,102,376 (see Evidence
Profile for stages CKD 3–5, Table 32). However,
because these data were based on safety and toxicity
rather than on end points identified a priori, theinformation suffered from serious methodologicallimitations such that treatment effects could not
be assessed for these outcomes. Data were absent for
hospitalization, fracture, parathyroidectomy, qualityof-life measures, and for changes in BMD.

b)

Vascular calcification: No study has evaluated the roleof calcitriol or its analogs or of cinacalcet on vascular
calcification in CKD stages 3–5.

c)Bone histomorphometry: Three studies evaluated theeffect of calcitriol or its analogs on bone histology

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in CKD stages 3–5: (Tables 31, 32 and Supplementary
Table 27)
Nordal and Dahl102: In this study published in 1988,

30 patients had bone biopsies at baseline and 28 patients
had bone biopsies after 8 months of treatment with calcitriolor placebo. Turnover: The mean bone-formation rate
decreased significantly in the calcitriol group and increasedin the placebo group, with a significant difference between
treatment groups. Approximately 25% of the calcitrioltreated patients had low bone formation (adynamic bonedisease) at the end of the study. The eroded surfaces showed asimilar pattern, so that calcitriol treatment decreased boneturnover. Fibrosis disappeared in all but four of the biopsies
in the calcitriol group, but in none of those taking placebo.
Mineralization: Median mineralization, assessed by MLT, wassimilar and normal in both groups and did not change witheither therapy. Volume: Median bone volume was normal inboth groups and there was no significant change with either
therapy. Overall, calcitriol treatment was effective in treating
osteitis fibrosa. The report was limited because adynamic
bone disease was not discussed. Approximately 25% of
calcitriol-treated patients developed low bone formation after
therapy, but none of them had osteomalacia. However, theexact number was not reported.
Hamdy et al.97: In this study published in 1995, bonebiopsies were performed in 176 patients at baseline and in 134
patients after treatment with alfacalcidol or placebo. The
biopsies were initially placed into diagnostic categories, butlater some of the abnormalities were felt to be unimportant.
The criteria for ‘important’ abnormalities were not specified.
The measurements were analyzed separately in those patientswith unimportant abnormalities at baseline; this was therefore apost hoc subgroup analysis. The paper did not report thechanges in measurements according to the entire group ofplacebo vs the entire group of alfacalcidol-treated patients.
There was also an apparent error in the mineralization lag-time
calculation in the placebo group. Although detailed measurements were made in a large number of biopsies, the presentation does not allow a critical evaluation of the results. Turnover:
The following percentages were deduced from the results
section: for patients treated with alfacalcidol, biopsies improvedin 32% (improved osteitis fibrosa) and worsened (developed
adynamic disease) in 11%. Placebo biopsies improved in 3%
and worsened in 13% (6% developed adynamic disease and therest developed worsened osteitis fibrosis). Mineralization: MLT
and osteoid width improved in the alfacalcidol group. There
was an increase (worsening) in the osteoid width in some of theplacebo-treated patients. Volume: The mean bone volume did
not change significantly in any of the groups. Overall, thealfacalcidol treatment resulted in bone histological improvement (related to improvement in osteitis fibrosa andmineralization) more often than did the placebo treatment.
However, adynamic bone disease developed more frequently.
Birkenhäger-Frenkel et al.378: This study examined the effectof 24,25(OH)2D in subjects who were already taking
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chapter 4.2

alfacalcidol. The study met our inclusion criteria, but
24,25(OH)2D is not commercially available so we havenot included this in our evidence tables. Interpretationof the biopsy data was limited because the final biopsies
were taken close to the site of a biopsy performed 9 months
earlier, which alters the results. Also, the treatment group
had a significantly different prior response to alfacalcidolso the groups were not comparable at the beginning of
the study.
d)Biochemical end points: For patients with CKD stages
3–5, studies using doxercalciferol,376 paricalcitol,377
and alfacalcidol97 (as compared with placebo) assessedlaboratory biochemical outcomes. The doxercalciferol
study was a 24-week-duration, double-blind, intention-to-treat analysis with a o20% loss to follow-up.
In the paricalcitol and alfacalcidol studies, premature
patient withdrawal averaged 20–22%. Alfacalcidol
doses were adjusted to maintain calcium levels at theupper limit of the laboratory reference range. Compared with placebo, PTH levels fell significantly withthese active treatments. Only one study of patientswith CKD stages 3–5 was included that comparedcalcitriol with placebo.102 Over 8 months, the levels of
PTH fell significantly in the calcitriol arm comparedwith the baseline values and the end-of-study placebo
values. However, this study enrolled only 15 individuals in each arm and, although it was included in thisguideline because of the bone biopsy data, it did notachieve entry criteria for biochemical outcomes.

In studies of patients with CKD stages 3–4, calcium levels
trended upward for paricalcitol and doxercalciferol,376,377
whereas calcium levels increased significantly for alfacalcidol.97 Phosphate levels and the calcium phosphorus productsignificantly increased for doxercalciferol, with an upward
trend for paricalcitol and alfacalcidol.
In CKD stages 3–4, levels of bone-specific ALP (b-ALP)
were assessed in two studies,376,377 and fell significantlywith doxercalciferol compared with placebo (28% for
doxercalciferol with no outcome value provided for theplacebo arm; Po0.05) and with paricalcitol vs placebo(Po0.001). Total ALP levels were assessed in the alfacalcidol
study97 and fell significantly in the active treatment arm(Po0.001).
ADVERSE EVENTS (Supplementary Table 28)

For paricalcitol vs placebo, the percentage of patients
reported with hypercalcemia (42.62 mmol/l) over two
consecutive measurements was 2 vs 0%, respectively, andthe incidence of hyperphosphatemia was reported to be
similar between groups.377 Twelve percent of paricalcitoltreated patients and 6% of placebo-treated patients had twoconsecutive measurements of Ca  P44.44 mmol2/l2. For
doxercalciferol vs placebo, neither hypercalcemia (defined
as 42.67 mmol/l and reported in 4% of both active- andKidney International (2009) 76 (Suppl 113), S50–S99

placebo-treated groups) nor hyperphosphatemia differedsignificantly between active and placebo arms.376 For doxercalciferol, serum phosphorus levels45.0 mg/dl (1.61 mmol/l)and 46.0 mg/dl (1.94 mmol/l) occurred in 8.5 and 2.6%of patients, respectively, vs 6.5 and 0.5%, respectively, forthose in the placebo-treated group, this difference
being nonsignificant. Nevertheless, at 24 weeks, serum
phosphorus levels were higher in the doxercalciferol group,
as were levels of Ca  P. Levels of serum calcium were notsignificantly different. One patient in the doxercalciferol
arm had treatment suspended twice because of hypercalcemia; one had a suppression of serum iPTH too150 pg/ml (15.9 pmol/l) at week 24; and doxercalciferol
treatment was reduced in three patients because of low levelsof iPTH. In the alfacalcidol vs placebo study from 1995,
hypercalcemia (410.5 mg/dl or 2.62 mmol/l) occurred in
14% of alfacalcidol-treated patients vs 3% of placebo-treatedpatients (0.05oPo0.01 between groups),97 and in the
calcitriol vs placebo study from 1998, eight calcitriol-treatedpatients developed hypercalcemia (undefined) vs zeroplacebo-treated patients.102 Study discontinuation due to
AEs ranged from 0 to 12%, with no patient reported to havediscontinued treatment because of abnormal laboratory
results. When reported, the incidence of other AEs washigh for both active treatment and placebo arms.
Calcimimetics

Only one RCT which assessed the effect of the calcimimetic
cinacalcet treatment in patients with CKD not receiving
dialysis met our inclusion criteria.379 This study assessedbiochemical outcomes and AEs. It was not designed to assess
effects on vascular calcification, bone histomorphometry, orother clinical outcomes. Patients meeting entry criteria withCKD stage 3 were enrolled, if iPTH levels were X100 pg/ml(10.6 pmol/l) and patients with CKD stage 4 were enrolled if
iPTH levels were X160 pg/ml (16.8 pmol/l). The study,
conducted over 32 weeks with a 16-week dose titration anda 16-week drug efficacy phase, allowed the concomitant useof vitamin D sterols and/or calcium supplementation.
Compared with placebo, cinacalcet reduced plasma iPTH
(43 vs 1%), but at the price of frequent, generally asymptomatic decreases in serum calcium (two consecutive values
o8.4 mg/dl (2.1 mmol/l) in 62% of participants taking
cinacalcet) and increases in levels of serum phosphorus and24-h urinary calcium excretion. More patients taking
cinacalcet than placebo received vitamin D sterols (46 vs25%). The proportion of participants receiving phosphatebinders/calcium supplements increased from 19 to 58% for
those taking cinacalcet and from 18 to 20% for those taking
placebo. In CKD stages 3 and 4, the effect on bone turnoverof this reduction in PTH is unknown, as is the change inurinary calcium. The long-term impact of increased levels of
serum phosphorus combined with increased calcium supplementation is of concern, and thus the Work Group felt moredata were needed before suggesting that calcimimetics could
be used in CKD stages 3–5.
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chapter 4.2

4.2.3 In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately
two to nine times the upper normal limit for theassay (2C).
We suggest that marked changes in PTH levels ineither direction within this range prompt an initiation or change in therapy to avoid progression tolevels outside of this range (2C).
The target PTH in the KDOQI guidelines for CKD stage 5D
was based on the predictive ability of PTH, using a Nichols
iPTH assay, to predict low- and high-turnover bone disease.5
Unfortunately, that assay is no longer available, and recent
studies have shown that iPTH levels within a range of150–300 pg/ml (15.9–31.8 pmol/l) are not predictive ofunderlying bone histology (see Chapter 3.2)229 or fractures(Figure 15).
Thus, additional evidence in the form of observational
data determining associations between PTH and patient-levelend points (mortality, cardiovascular death, and fractures)
was evaluated by the Work Group (Supplementary Table 24).
However, an important caveat is that conclusions based onthese reports are limited, because of residual confounding
and artificial constraints induced by statistical modeling.
Some studies find a ‘U’-shaped association with increased
risk at both ends,328 although more current international
analyses (DOPPS) often find only an increased RR of
all-cause but not cardiovascular mortality when the PTH
is 4600 pg/ml (63.6 pmol/l).33 The inflection point or
range at which PTH becomes significantly associated with

30
25

n

20
15
10
5
0
iPTH
(pg/ml)<150(n =35)LT

150–300(n =22)NL>300(n =40)HT

Figure 15 | Comparison of PTH levels to underlying bone
histology in chronic hemodialysis patients. Intact PTH levels
o150 pg/ml presented a 50% sensitivity, an 85% specificity, andan 83% positive predictive value for the diagnosis of low boneturnover (LT). In contrast, iPTH levels4300 pg/ml presented a 69%
sensitivity, a 75% specificity, and a 62% positive predictive value
for the diagnosis of high bone turnover (HT). iPTH, intact
parathyroid hormone; n, number of patients; NL, normal boneturnover. Reprinted with permission from Barreto et al.229
S76

increased all-cause mortality varies among studies forthe reasons cited above, and ranges from 4400 pg/ml(42.4 pmol/l)328 to 4480 pg/ml (50.9 pmol/l),329 4500 pg/ml(53 pmol/l),330 4511 pg/ml (54.2 pmol/l),317 and 4600 pg/ml(463.6 pmol/l).205 All PTH analyses have been complicatedby problems with assay methods and poor precision, as
detailed in Chapter 3.1. Unfortunately, most of these analyses
either do not indicate the assay type, or the data come from
PTH measured with multiple assays. Another confounding
factor for these analyses is that many studies featuresingle-baseline PTH values or infrequent (quarterly or less)measurements. One report has suggested that the 1–84 PTH‘bio-intact’ or ‘whole’ assay is a better predictor of mortality
than so-called iPTH assays.30 However, this finding needs
to be confirmed. Therefore, the Work Group does notrecommend the routine use of 1–84 (‘bio-intact’ or ‘whole’)
PTH assays at present. On the basis of these observational data, the Work Group considered that levels of
iPTH less than two or greater than nine times the upper
limit of normal for the PTH assay used represent extreme
ranges of risk.
It is important to recognize that there are no RCTs
showing that treatment to achieve a specific PTH level resultsin improved outcomes. In addition, there are no interventional RCTs that establish a ‘cause and effect’ relationshipbetween the observed outcomes and the measured biochemical variables; the observational data cannot fully evaluate
benefits and harm and are inherently biased. The analysis ofsuch relationships is further complicated by the clinical‘reality’ that these laboratory parameters do not move inisolation from one another, but rather change in often
unpredictable ways depending on the levels of otherparameters. This is best demonstrated by the work of Stevens
et al.,380 which assessed various biochemical combinations inconcert with dialysis vintage and found that specific risks
varied significantly according to three-pronged constellations. Thus, the RR for mortality was greatest whenlevels of serum calcium and phosphorus were elevated inconjunction with low levels of iPTH, and was lowest withnormal levels of serum calcium and phosphorus in
combination with high levels of iPTH. In addition, durationof dialysis significantly affected the results. A DOPPS
study also evaluated combinations of serum parameters ofmineral metabolism and reached slightly different conclusions.33 For example, in the setting of an elevated serum
PTH (4300 pg/ml (31.8 pmol/l)), hypercalcemia (410 mg/dl(2.5 mmol/l)) was associated with increased mortality riskeven with normal serum phosphorus levels (Figure 16).
Thus, future studies aimed at risk-stratifying patients withCKD should look at combinations of various biochemical
abnormalities, rather than isolated parameters. At present,
the Work Group felt that clinicians should avoid extreme
ranges of PTH, and interpret changes in PTH together withcalcium and phosphorus levels to guide therapy. Serum PTH,
calcium, and phosphorus are all expected to change with
PTH-altering treatments. As extreme values of these
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chapter 4.2

Ca≤8.5

8.5<Ca≤ 10.0

2.5

Ca >10.0
PTH > 300

PTH≤300

HR

2
1.5
1

>7
.0

≤3
.5
3.
65.
0
5.
16.
0
6.
17.
0

≤3
.5
3.
65.
0
5.
16.
0
6.
17.
0
>7
.0

0.5

Phosphorus (mg/dl)

Figure 16 | Risk of all-cause mortality associated withcombinations of baseline serum phosphorus and calcium
categories by PTH level. HR, hazard ratio; PTH, parathyroid
hormone. Reprinted with permission from Tentori et al.33

biochemical parameters have been linked to adverse patient
outcomes in large observational studies, it is important tomonitor serum levels of calcium and phosphorus during
PTH-altering treatments more frequently.
4.2.4 In patients with CKD stage 5D and elevated or rising
PTH, we suggest calcitriol, or vitamin D analogs, or
calcimimetics, or a combination of calcimimetics
and calcitriol or vitamin D analogs be used to lower
PTH (2B).
K It is reasonable that the initial drug selection for
the treatment of elevated PTH be based on serum
calcium and phosphorus levels and other aspects of
CKD–MBD (not graded).
K It is reasonable that calcium or non-calcium-based
phosphate binder dosage be adjusted so thattreatments to control PTH do not compromiselevels of phosphorus and calcium (not graded).
K We recommend that, in patients with hypercalcemia, calcitriol or another vitamin D sterol
be reduced or stopped (1B).
K We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol
be reduced or stopped (2D).
K We suggest that, in patients with hypocalcemia,
calcimimetics be reduced or stopped depending on
severity, concomitant medications, and clinicalsigns and symptoms (2D).
K We suggest that, if the intact PTH levels fall
below two times the upper limit of normal forthe assay, calcitriol, vitamin D analogs, and/or
calcimimetics be reduced or stopped (2C).
The Work Group asked if there were differences between thevarious therapies used to lower PTH in their effects onbiochemical indices of CKD–MBD, bone, vascular calcification, or clinical end points. A systematic search wasundertaken to evaluate RCTs of vitamin D, calcitriol, or
any vitamin D analog vs each other or with placebo in
individuals with CKD stage 5D. The a priori criteria chosen
Kidney International (2009) 76 (Suppl 113), S50–S99

by the Work Group for inclusion of an RCT were duration ofat least 6 months and a sample size of at least 50, except forbone biopsy studies and studies evaluating children, whichwere included with a sample size of 10. Importantly, ourrecommendations parallel recent Cochrane reviews, whichwere inclusive of all studies and found similar results for
calcitriol and its analogs8 and for calcimimetics.381 Studies
evaluated with the KDIGO systematic review are reviewed
below by end point (see Tables 33–36).
a)Patient-centered end points: No RCTs of patientswith CKD have specifically evaluated the effect ofvitamin D, calcitriol, or vitamin D analogs onpatient-level outcomes (mortality, fracture, qualityof life, hospital admission, and cardiovascular outcomes), and observational data are inconclusive.
There are no studies of either moderate or highquality that show a beneficial or harmful effect of
calcimimetics on mortality, CVD, hospitalization,
fractures, or quality of life.

Vitamin D, calcitriol, or its analogs. (Tables 34, 35) Patientswith all stages of CKD, particularly those on dialysis, havegreatly increased mortality and morbidity compared with thegeneral population. Patient-level outcomes of vitamin Dtherapy that were considered to be of critical or highimportance included mortality, cardiovascular events, rates of
hospital admission, parathyroidectomy, fracture, musculoskeletal pain, and quality of life. No RCT evaluated mortality,
cardiovascular events, hospitalizations, quality of life, or
fracture as a primary or secondary end point.
Although the effects of vitamin D therapy on mortality
have not been studied in prospective RCTs, recent retrospective observational studies have suggested that survival on
dialysis may be improved by vitamin D therapy.45,328,382,383
Furthermore, in the large historical cohort study thatcompared treatment with the vitamin D2 derivative,
paricalcitol, with calcitriol, treatment with the former was
reported to provide a survival advantage over the latter.384
However, this finding was not confirmed (after adjustment
for laboratory values and clinical standardized mortality) inanother report that also assessed the vitamin D2 derivative,
doxercalciferol,383 or in a more recent DOPPS analysis.385 In
addition, in the latter analysis, no relationship was detected
between the use of vitamin D and outcome using an
instrumental-variable approach. However, using a patientlevel approach, there was an apparent survival benefit forvitamin D usage, as previously reported, suggesting asignificant degree of residual confounding. Therefore,
evidence from these observational studies could not be usedin the development of this guideline when applying theGrades of Recommendation Assessment, Development, andEvaluation approach (GRADE), which requires consistentevidence of an association with an RR42 (or an HRo0.5)
from two or more observational studies, with no plausible
S77chapter 4.2

confounders. None of these studies achieved an RR42 (or an
HRo0.5). Furthermore, authors of these studies pointed to anumber of potential confounders and, importantly, there isinconsistency in findings among the published studies. Thus,
RCTs are needed to confirm these findings.
Calcimimetics. All-cause hospitalization, quality of life,
fractures, and parathyroidectomy were defined as outcomes ofhigh importance and were evaluated in a secondary analysis386
of prospective RCTs387,388 that evaluated cinacalcet vs placebo(with the majority of both groups receiving calcitriol or ananalog). This analysis reported no statistically significant
differences in mortality or all-cause hospitalizations, but areduction in cardiovascular hospitalization. No differences inquality of life were detected using the Cognitive Functioning
scale from the Kidney Disease Quality of Life instrument, but
improvements were seen in some domains using the Medical
Outcomes Study Short Form 36 (SF-36). The number offractures and parathyroidectomies in cinacalcet-treated patientswas significantly reduced compared with that in those receiving
placebo. However, data were sparse for fracture and, although
the RR for parathyroidectomy was 0.07 (95% CI 0.01–0.55),
there was no description of the indications or protocol forparathyroidectomy, hence the overall quality for both theseoutcomes was classified as very low.
For all of these clinical outcomes, there were serious
methodological limitations, because they were not predefinedas either primary or secondary outcomes for RCTs andwere taken from the safety data of prospective trials, creatinga probable reporting bias. Furthermore, the length of thefollow-up varied among patients and, at most, 266 had a
1-year follow-up from the total of 1184, with some having
only a 6-month follow-up. More of the control patientsagreed to follow-up (138 placebo vs 128 cinacalcet), althougha much higher number were randomized to cinacalcet. In
addition, quality of life was measured at variable points
during the study, but the results were evaluated together, andonly 876 out of 1184 individuals had their quality of life data
evaluated. In both the Block et al.387 and Lindberg et al.388
studies, the percentage of dropouts was high, and it was
not clear whether those who dropped out when their PTH
was o250 pg/ml (26.5 pmol/l) were counted as successes
or failures. The overall quality of evidence for mortality,
hospitalization, and quality of life was thus deemed low.
b)

Vascular calcification: There are no conclusions as tothe effect of calcitriol or vitamin D analogs or
calcimimetics on cardiovascular calcification, as these
relationships have not been adequately evaluated inhumans.

Only one RCT of calcitriol that met our inclusion criteria
evaluated any measure of cardiovascular calcification.101 In
that study of calcitriol vs placebo, plain X-rays of the hands,
chest, pelvis, and feet were assessed. No differences werereported for the development or progression of CAC or forthe calcification of the vessels of the hands, feet, or pelvis.
S78

However, vascular calcification was only evaluated in patients
without radiological evidence of bone disease, and thisnumber was not provided, creating a potential bias. Furthermore, aluminum hydroxide was used for phosphate control,
the dialysate calcium level was 1.65 mmol/l (3.3 mEq/l), andhypercalcemia was common. There are no studies evaluating
the effect of cinacalcet on vascular calcification in humans.
Thus, the Work Group felt these data were insufficient toreach any conclusions.
c)Bone histology: On the basis of bone biopsy studies, theuse of calcitriol or vitamin D analogs is associated with
an improvement of osteitis fibrosa and mineralization,
and a reduction of bone turnover. The latter may
increase the risk of developing adynamic bone disease.
There are insufficient data to determine the effect of
cinacalcet on bone histomorphometry.

Calcitriol and its analogs. (Supplementary Table 32) Twostudies evaluated patients with CKD stage 5D, one in adults
and one in children.
Baker et al.101: Bone biopsies were taken from 54 patientsat baseline and from 20 patients after 12–57 months of followup; the results were published in 1986. The bone biopsies wereseparated into categories of normal, osteomalacia, osteitis
fibrosa, and mixed osteodystrophy on the basis of a visualassessment by the investigator. No tetracycline labels were
given; therefore, some of the patients who were designated as
normal could have had adynamic bone disease. The majorityof the patients had positive aluminum staining. Turnover:None of the follow-up biopsies showed an improvement inturnover as indicated by a change to the normal category.
Bone turnover became too high (normal to osteitis fibrosa or
mixed) in 50% of patients taking placebo and in 10% of thosetaking calcitriol, and too low (normal to osteomalacia) in 30%of the calcitriol group. Thus, turnover worsened in 50% of theplacebo and in 40% of the calcitriol-treated individuals.
Mineralization: It worsened (normal to osteomalacia or mixed)
in 40% of placebo-treated patients and in 30% of calcitrioltreated patients. Volume: No data were provided. Overall,
calcitriol may have retarded the development of osteitis
fibrosa, but it may have contributed to low bone turnover.
Salusky et al.18: This clinical trial included 46 children
undergoing PD. They were randomly assigned to oral or
intraperitoneal calcitriol for 12 months. The group receiving
intraperitoneal dosing had lower PTH values, but the bonebiopsy data were not significantly different between groups.
Turnover: Improvement was seen in 23% of oral and in 36%
of intraperitoneal treatment groups (all from improved
osteitis fibrosa), but a worsening of turnover was seen in
41% of those receiving oral treatment and in 44% of thosegiven intraperitoneal treatment (mostly development ofadynamic bone disease). Mineralization: This parameter
improved in 6% of the oral treatment group. Volume: Nochanges were reported. Overall, there were no significantly
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chapter 4.2

different bone biopsy findings between these two different
routes of administration.
Calcimimetics. (Supplementary Table 36) There is only one
RCT on the effect of cinacalcet vs standard treatment on bone
histomorphometry in patients with CKD stage 5D, using repeatbone biopsies at time zero and 12 months.389 Patients receiving
HD who had HPT, defined by serum iPTH4300 pg/ml(31.8 pmol/l), were randomly given cinacalcet or placebo for ayear. Tetracyline-labeled bone biopsies were performed before
and after therapy in 13 placebo and in 19 cinacalcet patients.
Although all had a high serum PTH, five patients did not havean increased bone turnover at baseline. Turnover: In placebo
biopsies, 45% showed an improved turnover (one patient
increased from adynamic to normal and the rest decreased
toward normal) and 23% showed an increased (worsened)
turnover. In cinacalcet biopsies, 26% showed a decreasing(improved) turnover and 26% showed a worsened turnover(three patients developed adynamic bone disease and, in twopatients, an abnormally high turnover became higher). Mineralization: None of the patients had overt osteomalacia, and thechange in median MLT was the same in placebo and cinacalcet
groups. Some of the biopsies had an abnormally high MLT, but
details were not presented. Bone volume: It increased slightly but
not significantly in the cinacalcet group, and did not change inthe placebo group. Overall, there were no significant differences
between groups on the basis of histomorphometry. The study
was limited by a small sample size.
d)Biochemical end points: The use of calcitriol orvitamin D analogs is effective in decreasing serum
PTH levels and ALP levels, but may increase calcium
and phosphorus levels.
The use of cinacalcet lowers serum PTH, calcium,
phosphorus, the calcium phosphorus product, andb-ALP in patients with CKD stage 5D.

Vitamin D. Despite potential theoretical benefits, data arelacking in CKD stage 5D patients to support treatment
to increase levels of 25(OH)D in patients on dialysis. No
RCTs of treatment with cholecalciferol or ergocalciferol wereidentified, but one uncontrolled study reported biochemical
responses to 6 months of treatment with oral 25(OH)D3
given to patients on HD.390 In that study, levels of b-ALP
improved toward the normal range over 6 months andlevels of PTH, calcium, and phosphorus improved toward
the KDOQI target ranges in some patients. AEs, such as
hyperphosphatemia, were infrequent.
Calcitriol and its analogs
PTH suppression: (Tables 34 and 35) In patients with CKD

stage 5D, PTH levels were effectively suppressed by calcitriol
compared with placebo in a study by Baker et al.101 conducted from 1977 to 1982.101 The placebo arm of that study
had a higher median PTH level at baseline. (Supplementary
Tables 30, 31) Levels of calcium increased for calcitriol
Kidney International (2009) 76 (Suppl 113), S50–S99

compared with placebo. In another study of calcitriol
compared with maxacalcitol (available in Japan), within-arm
PTH levels fell significantly in both groups.391 In that study,
doses of calcitriol and maxacalcitol were reduced or ceased if
levels of calcium were 42.87 mmol/l or levels of iPTH wereo15.9 pmol/l. Within-arm calcium levels rose significantly andthere was a trend toward increased phosphate levels, which did
not differ between the arms. An average of 20% of patients
withdrew from this study, which was not powered adequately
to show differences between the treatment groups. Sprague
et al.392 studied CKD stage 5D patients randomized in
1995–1996 to calcitriol and paricalcitol, using a 1:4 dosing
ratio of calcitriol to paricalcitol. Doses were titrated at 4-weekintervals to achieve a 50% or more reduction in levels of PTH,
with doses modified when calcium levels exceeded 2.87 mmol/l,Ca  P exceeded 6.05 mmol2/l2 for 2 weeks, or levels of PTH
were o10.6 pmol/l. PTH levels fell significantly in both arms,
and approximately 60% of patients in both groups achieved a
X50% reduction in levels of PTH at the end of the study
period. Hypercalcemia occurred at least once in 68% of
calcitriol-treated patients and in 83% of paricalcitol-treatedpatients (a nonsignificant difference), and hyperphosphatemic
episodes were reported to be comparable. In a secondary
analysis of this study, patients treated with paricalcitol
showed more rapid reductions of PTH with fewer sustained
episodes of hypercalcemia and/or an elevation of Ca  P(18 vs 38%, P ¼ 0.008). This composite outcome was defined
as two consecutive measurements of corrected total calcium
411.5 mg/dl (2.87 mmol/l) and/or Ca  P475 mg2/dl2(6.05 mmol2/l2) for at least one period of four consecutive
blood draws. The authors point out that lower doses ofparicalcitol (using a 1:3 ratio) may have increased the time
taken by paricalcitol to lower levels of PTH but decreased
the incidence of hypercalcemia and hyperphosphatemia inparicalcitol-treated subjects.
Calcium: Support for the use of newer vitamin D
analogs (22-oxacalcitriol, doxercalciferol, paricalcitol, andfalecalcitriol) is based on experimental studies showing
a similar or superior dose-equivalent suppression of PTH
with less calcemic and/or phosphatemic activity.393 Therefore, the included RCTs were assessed for these end points.
For calcitriol vs 22-oxacalcitriol (maxacalcitol),391 there wereno significant between-arm differences in any laboratory
biochemical parameter, although initially, calcium levels rose
more rapidly in response to therapy with maxacalcitol.
Outcomes of the earlier (1995–1996) study of calcitriol vsparicalcitol have been described above.392
Alkaline phosphatases: For CKD stage 5D, median total
ALP values were lower for calcitriol than for placebo,101 andb-ALP values did not differ between treatments withcalcitriol and maxacalcitol.391 Similar findings were reported
in a recent meta-analysis that assessed responses to vitamin D
compounds in CKD using more liberal inclusion criteria.8
This review also found no differences in levels of total ALP
for intravenous (i.v.) vs oral vitamin D therapy (four studies)or for intermittent vs daily therapy (two studies).
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chapter 4.2

Route of administration: Another question is the relative

efficacy of the administration of i.v. compared withoral calcitriol or its analogs. Owing to a lack of comparative
data in the included studies, no conclusions could bereached for preferred routes of administration or for dosing
frequency. A meta-analysis of vitamin D therapy that included
additional studies has reported that i.v. administration ofvitamin D was superior to oral administration in reducing endof-treatment PTH levels.8 However, there was significant
heterogeneity in this analysis, and when one study that usedhigher i.v. doses of vitamin D was removed,394 there were nodifferences in the levels of PTH. Levels of serum phosphorus
were marginally but significantly lower for the i.v. route(weighted mean difference –0.10 mmol; CI 0.19 to 0.01)
with no differences in episodes of hypercalcemia or in levels of
ALP. No differences were observed for daily compared with
less-frequent intermittent administration.
Calcimimetics. A change in PTH was deemed as amoderately important outcome at the outset of the review(Tables 35, 36 and Supplementary Tables 34, 35). The primary
outcome in the RCTs conducted by Block et al.387 and Lindberg
et al.388 was the percentage of patients with iPTHp26.5 pmol/l.
In both studies, significantly more patients achieved thisoutcome with cinacalcet (43% in Block’s study and 39% in
Lindberg’s). The percentage of patients with a X30% reductionin iPTH was also significantly higher for cinacalcet. The
methodological quality of these studies was graded B because of
the relatively short duration of follow-up (26 weeks), therelatively high percentage of patients who dropped out before
the evaluation time point (26–32% in cinacalcet-treated subjects
vs 22–24% in the control arm), and because of concerns withregard to the generalizability of the studies to patient carebecause the assay for PTH (the primary measured end point)
suffers from methodological problems, including reproducibility (see Chapter 3.1). In addition, one study395 was notanalyzed on an intention-to-treat basis, the outcome definitions
were shifted compared with the parent protocol, and one of thethree studies differed with respect to the inclusion criteria
governing the percentage of individuals with very high baseline
levels of PTH. Both Block’s and Lindberg’s studies387,388 showedthat cinacalcet significantly reduced the mean percentage ofserum calcium, phosphorus, and Ca  P, which were secondary
outcomes of both, with no major inconsistencies. The study by
Moe et al.395 showed that significantly more patients achieved
the KDOQI targets when given cinacalcet than when they
underwent the optimal standard treatment. The methodologicalquality for these end points was graded B because of thedropout rate and the other outcomes reported in the paragraphon PTH above. The quality of evidence for these moderately
important outcomes was moderate overall. The study by Blocket al.387 reported a lowering of the circulating levels of b-ALP(a bone turnover marker) toward normal in the cinacalcet
compared with the control arms. No ALP data (total or bone
specific) were provided in other studies.
The ACHIEVE study assessed the use of cinacalcet plus
paricalcitol/doxercalciferol vs flexible vitamin D analog
S80

therapy,396 although this study did not fulfill our inclusion
criteria in terms of duration. The proportion of patientsreaching the KDOQI targets for PTH and Ca  P was higher
with the combined therapy (21 vs 14%), although this did
not reach significance. Of those using cinacalcet plus vitamin
D analogs, 19% had iPTH levels o150 pg/ml and only
8% achieved all KDOQI targets for calcium, phosphorus,
PTH, and Ca  P compared with 0% using flexible vitamin D
analog treatment. No other RCTs comparing calcitriol orvitamin D analogs with calcimimetics, nor comparing
different combinations of therapy, are available. Thus, theWork Group could not recommend one therapy, or
combination therapy, over another.
Integrating therapies that alter PTH and phosphorus levels.

Therapeutic interventions to suppress PTH, but which may
compromise levels of calcium and phosphorus, may not bebeneficial. Therefore, the use of phosphate binders is an
important component of any integrated approach to PTH
control, because a dose modification of binders can ameliorate
unwanted changes in levels of calcium and phosphorus caused
by calcitriol, vitamin D analogs, and calcimimetics. In addition, phosphate binders affect levels of iPTH independently.
Calcium-based binders increase serum calcium, which suppresses PTH through the CaR, whereas a reduction in serum
phosphorus by calcium- or non-calcium-based binders
reduces PTH production at the posttranscriptional level.
SPECIAL CONSIDERATIONS IN CHILDREN

Calcitriol has been studied in RCTs in 102 children withCKD stage 5D and in some children with earlier stages of
CKD (Table 30). Only one study was placebo controlled(Greenbaum, n ¼ 42),397 whereas the others compared varying
dosages (daily vs twice weekly; oral vs i.v.). In 46 patientson PD studied for 1 year, equivalent calcitriol doses were
given either i.v. or orally thrice weekly. The groups showed asimilar improvement in histomorphometric changes ofsecondary HPT at follow-up bone biopsy and adynamic
bone disease developed in both groups. Intravenously
administered calcitriol reduced iPTH levels significantly andraised calcium levels, whereas orally administered calcitriol did
not lead to a reduction in the levels of iPTH (values remaining
above KDOQI suggested target levels), but increased serum
phosphorus. In a 12-week study, calcitriol therapy led toa 430% decrease in iPTH when compared with placebo,and in 24 patients studied for 1 year, daily calcitriol wassuperior to twice weekly calcitriol for the control of secondary
HPT. Another study of paricalcitol compared with placeboin 29 children on maintenance HD showed a 430% reduction in iPTH over a 12-week period. There are insufficient
data to recommend one vitamin D sterol over another. In
addition, there are no studies evaluating calcimimetics
in children.
ADVERSE EVENTS
Calcitriol and its analogs.

(Supplementary Table 28) For the
study comparing calcitriol and placebo, 16% of patients
Kidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.2

treated with calcitriol and 5% treated with placebo discontinued treatment because of hypercalcemia.101 Parathyroidectomy rates were 13% for calcitriol (five patients withparathyroid hyperplasia) and 5% for placebo (one patientwith a parathyroid adenoma and one with hyperplasia).
For maxacalcitol vs calcitriol, calcium levels411.5 mg/dl(2.87 mmol/l) occurred in 5 vs 2%, respectively (twomeasurements in two patients vs two measurements in one
patient), and phosphorus levels 46.1 mg/dl (1.94 mmol/l)
occurred in 68 vs 64%,391 but no patient discontinued treatment because of adverse effects of therapy. For paricalcitol vscalcitriol, calcium levels 411.5 mg/dl (2.87 mmol/l) and/or aCa  P46.05 mmol2/l2 occurred in 68% of paricalcitol- and
64% of calcitriol-treated patients.392
Calcimimetics. (Supplementary Table 37) Nausea andvomiting are the most frequently reported AEs in studies
by Block et al.,387 Lindberg et al.,388 and Moe et al.395 In the
cinacalcet-treated group, nausea occurred consistently,
approximately one-and-a-half times more frequently, andvomiting occurred about twice as often. Serious AEs that may
or may not have been treatment related occurred in about aquarter of patients in both the treatment and placebo groups
in Lindberg’s study. Approximately twice as many patients inthe cinacalcet group, in both Block’s (15%) and Lindberg’s(9%) studies, discontinued treatment because of side effects,
principally nausea, vomiting, and other gastrointestinal events.
In both Block’s and Lindberg’s studies, 5% of patients in the
cinacalcet groups and less than 1% of those in the control
groups had serum calcium values that fell below 7.5 mg/dl(1.9 mmol/l). Hypocalcemic episodes were transient and rarely
associated with symptoms. In a safety and efficacy 26- to
52-week extension study reported by Sterrett et al.,15 treatment
with cinacalcet was considered to be safe and effective. AEs(principally nausea and vomiting) caused the discontinuationof therapy in 10% of those treated with cinacalcet and in 0% of
controls, whereas 3% of controls withdrew for parathyroidectomy but none treated with cinacalcet. At 12 months, there
was no difference in the use of vitamin D (64 vs 63%:
cinacalcet vs placebo) or phosphate binders (92 vs 96%), andelemental calcium ingested per meal did not differ between
the groups (930±641 vs 940±625 mg).
4.2.5 In patients with CKD stages 3–5D with severe
hyperparathyroidism (HPT) who fail to respondto medical/pharmacological therapy, we suggest
parathyroidectomy (2B).
There are no studies evaluating parathyroidectomy of either
moderate or high quality that show a beneficial or harmful
effect of this treatment on mortality, CVD, hospitalization,
fractures, or quality of life; on bone and cardiovascular outcome; or on biochemical outcomes. However,parathyroidectomy performed by an expert surgeon generally
results in a marked, sustained reduction in levels of serum
PTH, calcium, and phosphorus. Subtotal parathyroidectomy
or total parathyroidectomy with autotransplantation effecKidney International (2009) 76 (Suppl 113), S50–S99

tively reduces elevated levels of iPTH, calcium, phosphorus,
and ALP. An improvement in these biochemical parameters isreported to be maintained at 1, 2, and up to 5 years
postoperatively, despite a relatively high incidence of recurrent
HPT or persisting hypoparathyroidism in some studies.401404
There is no evidence that total parathyroidectomy withimmediate ectopic parathyroid tissue reimplantation issuperior or inferior to subtotal parathyroidectomy. Total
parathyroidectomy without immediate parathyroid tissue
reimplantation may be contraindicated in patients with CKD
stage 5D on a waiting list for kidney transplantation.
Most patients who undergo parathyroidectomy exhibit an
improvement in biochemical parameters, but comparisons
between medical and surgical therapy for outcomes ofmorbidity and mortality are difficult to assess. In the absenceof RCTs, the available observational studies that compare
surgically and medically managed patients are open toimportant patient selection biases that limit the validity of
their findings. Individuals considered for parathyroidectomy
differ from those who enrolled in cinacalcet studies. The
study with the largest sample size is that of Kestenbaum
et al.,405 showing lower long-term mortality in patients who
underwent parathyroidectomy compared with a matchedcohort. However, this is a retrospective, observational study.
Short-term, postoperative mortality was high at 3.1% and thebetter long-term outcome after parathyroidectomy may be
due to selection bias, as in the study by Trombetti et al.406 In
that study, patients undergoing parathyroidectomy wereyounger and had fewer comorbidities. However, when theauthors proceeded toward a case–control analysis, thisdifference was no longer significant.
Owing to a lack of RCTs of medical vs surgical therapy of
HPT, these management strategies are difficult to compare.
For patients unsuitable for surgery or awaiting elective
surgery, a case can be made for the availability of medical
therapies, including cinacalcet. For patients able to undergo
surgery, parathyroidectomy is generally considered when
HPT is severe and refractory to medical management, usually
after a therapeutic trial of calcitriol, a vitamin D analog, or
cinacalcet as suggested above.
Parathyroidectomy could also be considered when medical
management to reduce levels of iPTH results in unacceptablerises in levels of serum calcium and/or phosphorus (as occurs
frequently using calcitriol or vitamin D analogs), or when
medical management is not tolerated because of AEs.
Determining what constitutes ‘refractory HPT’ may bedifficult. Clearly, the higher the PTH, the less likely the
gland is to involute in response to medical therapy. Whensevere HPT is present, with levels of PTH4800 pg/ml(85 pmol/l) using a second-generation PTH assay, 22% of
patients are reported to achieve levels of iPTHo300 pg/ml(32 pmol/l) with cinacalcet therapy. On the other hand,
81% with mild HPT (iPTH 300–500 pg/ml (32–53 pmol/l))
and 60% with moderate HPT (iPTH 500–800 pg/ml(53–85 pmol/l)) are reported to achieve reductions in serum
iPTH to o300 pg/ml (32 pmol/l).395
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chapter 4.2

RESEARCH RECOMMENDATIONS

Well-designed RCTs on the use of vitamin D, calcitriol, andvitamin D analogs in CKD stages 3–5 and stage 5D are
required to address a number of issues of clinical importance.
These trials should include reporting of allocation concealment, blinding of participants, investigators and outcome
assessments, patients lost to follow-up, and AEs:
K In a prospective RCT, does the use of vitamin D, calcitriol,
or a vitamin D analog influence patient-level outcomes,
including cardiovascular events, rates of hospital admission, parathyroidectomy, fracture, musculoskeletal pain,
quality of life or, in CKD stages 3–5, the risk of progression
or of requiring renal replacement therapy?
K In a prospective RCT, do any of the newer vitamin D
analogs provide a survival advantage over the use ofalfacalcidol or calcitriol?
K In a prospective RCT to assess the current dialysis
population, do laboratory outcomes differ for newer
vitamin D analogs vs doses of calcitriol or alfacalcidol,
which are equipotent for PTH lowering?
K In
a prospective RCT, what is the influence ofcholecalciferol or ergocalciferol on patient-level outcomes, surrogate biochemical outcomes, and AEs in
CKD stages 3–5 and stage 5D?
K In a prospective RCT, what is the effect of vitamin D,
calcitriol, or vitamin D analogs vs placebo or control onbone outcomes, particularly on the normalization ofbone histomorphometry?
K In the management of secondary HPT, particularly
in relation to patient-level and bone outcomes,
how do vitamin D, calcitriol, or vitamin D analogs
compare in terms of efficacy and AEs with calcimimetic
cinacalcet?
K When using vitamin D, calcitriol, or vitamin D analogs,
does the route of administration or the dosing schedule
influence efficacy or AEs?
K RCTs with a sufficient length of follow-up are required todetermine whether clinical outcomes—including all-cause
mortality, cardiovascular and cerebrovascular morbidity,
fractures, bone pain, hospitalization, parathyroidectomy
rate, and quality of life—are improved by cinacalcet
administration in patients with HPT associated with CKD.
There is an ongoing study, EVOLVE (NCT00345839,
www.clinicaltrials.com), which is evaluating a primary end
point of all-cause mortality, nonfatal cardiovascular events,
time to mortality, and time to cardiovascular events after a

4-year follow-up. EVOLVE is due to report in 2012. AEs
should be recorded to provide a balanced view of benefit vsharm.
K Further RCTs are required to directly compare treatmentof HPT with cinacalcet vs calcitriol/vitamin D analogs, andto establish the optimal use of cinacalcet in combination
with phosphate binders and vitamin D sterols.

Supplementary Table 24. Overview table of selected studies demonstrating the risk relationships between hormonal parameters of PTH, vitaminD, and mortality in CKD stages 3–5 and 5D.

Supplementary Table 25. Summary table of the treatment of
CKD–MBD with calcitriol or vitamin D analogs vs placebo in CKD
stages 3–5—description of population at baseline.
Supplementary Table 26. Summary table of the treatment of
CKD–MBD with calcitriol or vitamin D analogs vs placebo in CKD
stages 3–5—intervention and results.
Supplementary Table 27. Summary table of the treatment of
CKD–MBD with calcitriol or vitamin D analogs vs placebo in CKD
stages 3–5—bone biopsy results.
Supplementary Table 28. Adverse events of calcitriol or vitamin D
analogs in CKD stages 3–5D.
Supplementary Table 29. Ongoing RCTs examining the effect ofvitamin D, calcitriol, or vitamin D analogs on CKD–MBD in CKD
stages 3–5.
Supplementary Table 30. Summary table of the treatment of
CKD–MBD with calcitriol vs placebo or vitamin D analogs in CKD
stage 5D—description of population at baseline.
Supplementary Table 31. Summary table of the treatment of
CKD–MBD with calcitriol vs placebo or vitamin D analogs in CKD
stage 5D—intervention and results.
Supplementary Table 32. Summary table of the treatment of
CKD–MBD with calcitriol vs placebo or vitamin D analogs in CKD
stage 5D—bone biopsy results.
Supplementary Table 33. Ongoing RCTs examining the effect ofvitamin D, calcitriol, or vitamin D analogs on CKD–MBD in CKD
stage 5D.
Supplementary Table 34. Summary table of RCTs examining thetreatment of CKD–MBD with calcimimetics in CKD stage 5D—
description of population at baseline.
Supplementary Table 35. Summary table of RCTs examining thetreatment of CKD–MBD with calcimimetics in CKD stage 5D—intervention and results.
Supplementary Table 36. Summary table of RCTs examining thetreatment of CKD–MBD with calcimimetics in CKD stage 5D—bonebiopsy results.
Supplementary Table 37. Adverse events of calcimimetics vs placebo
in CKD stage 5D.
Supplementary Table 38. Ongoing RCTs examining the effect of
calcimimetics on CKD–MBD.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/kiTable 30 | RCTs of calcitriol or other vitamin D analogs in children with CKD
Author (year)
18

Salusky (1998)
Kuizon (1998)398
Schmitt (2003)399
Greenbaum (2005)397
Greenbaum (2007)400

N

Population

F/U

Study design

Arm 1

Arm 2

Outcomes46

PD

12 months

RCT

Oral calcitriol

Intraperitoneal calcitriol

Bone Bx, Ca, P, PTH, calcitriol

24
42
29

CKD 3–5HDHD

12 months
12 weeks
12 weeks

RCT
RCT
RCT

Daily calcitriol
Calcitriol
Paricalcitol

Twice weekly calcitriol
Placebo
Placebo

iPTH, growth, Ca  P
PTH, Ca, Ca  P,
Ca, P, Ca  P, PTH

Bx, biopsy; Ca  P, calcium–phosphorus product; CKD, chronic kidney disease; F/U, follow-up; HD, hemodialysis; iPTH, intact parathyroid hormone; N, number of subjects;
PD, peritoneal dialysis; PTH, parathyroid hormone; RCT, randomized controlled trial.

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Kidney International (2009) 76 (Suppl 113), S50–S99

Table 31 | Evidence matrix of calcitriol or vitamin D analogs vs placebo in CKD stages 3–5
Methodological quality
A
Outcome

AuthorB

N (on agent)

F/U

AuthorC

N (on agent)

F/U

AuthorAdverse event reporting

N (on agent)

F/U

AuthorN (on agent)

F/U

Coyne (2006)
Hamdy (1995)97
Coburn (2004)376
Coburn (2004)376—
Hamdy (1995)97
Coburn (2004)376
Nordal (1988)102
—
—
—
—
—

220 (107)
176 (89)
55 (27)55 (27)—176 (89)
55 (27)30 (15)—————6 months
24 months
6 months
6 months—
24 months
6 months
8 months
—
—
—
—
—

—
—

—
—

—
—

—

—

—

377

Mortality

—

—

—

—

—

—

—

—

—

Clinical CVD
Hospitalization
CKD clinical outcomes

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

QoL
Fractures
PTx
Bone density
Bone histology

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

Vascular/valvular calcification
GFR loss

—
—

—
—

—
—

—
—

—
—

—
—

Coyne (2006)377
Coburn (2004)376
Coyne (2006)377

220 (107)55 (27)220 (107)

6 months
6 months
6 months

Hamdy (1995)97
Kooienga (2009)374
Hamdy (1995)97
Coburn (2004)376

176 (89)322 (214)176 (89)
55 (27)24 months
24 months
24 months
6 months————
Hamdy (1995)97
Nordal (1988)102—
Coyne (2006)377
Hamdy (1995)97
Coburn (2004)376
—

—
—
—
—
134 (72)30 (15)—220 (107)
176 (89)
55 (27)—————24 months
8 months—
6 months
24 months
6 months—

322 (214)

24 months

—

—

—

—

—

—

—

—

—
Coyne (2006)377
Hamdy (1995)97
Coburn (2004)376
Nordal (1988)102—
220 (107)
176 (89)
55 (27)30 (15)—6 months
24 months
6 months
8 months

Lab: Ca, P, PTH
Lab: ALP, b-ALP
Lab: Bicarbonate
Adverse events

Kooienga (2009)—

374

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; GFR, glomerular filtration rate; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.

chapter 4.2

S83

Summary of findings

OutcomeMortality

Clinical CVD and CeVDb
All-cause hospitalization
CKD clinical outcomes
Quality of life
Fractures
PTx
Bone density
Bone histology

Vascular/valvular
Calcification
GFR Loss

No. of studies
and study
designTotal N (N onstudy drug)

Methodologicalquality of studies

Consistency
across studies

Directness of theevidence generalizability/ applicability

Other considerationsa—- - - - - - - - —————- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AE from 3 RCTs 451 (223)
Very serious———
limitations (2)
—
—
—
—
—
—
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AE from
Very serious———
55 (27)
1 RCT
limitations (2)
—
—
—
—
—
—
—
—
—
—
—
—
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AE from
Very serious
—
—
—
261
(131)
3 RCTslimitations (2)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
2 RCTs164 (87)
Very serious
No important
Some uncertainty—
limitations (2)inconsistencies
about directness
c
(1)
-

Quality ofevidence foroutcomeQualitative and quantitativedescription of effectImportance ofoutcomeVery low

Unable to assess

CriticalVery low

Unable to assess

Critical

—

—

High

Very low

Unable to assess

High

—
—
—
—
Low

High
High
High
Moderate
Moderate

Moderate

—

—

—

—

—

—

—

—
—
—
—
Osteitis fibrosa (high turnover) but
also more cases of adynamic bone(low turnover). Mineralization
improves with calcitriol. Volume
is not different from placebo—

3 RCTs451 (223)

Very serious
limitations (2)d

No important
inconsistencies

Direct—Low

No difference

Moderate

No limitationseNo important
inconsistenciesf

Direct—High

No limitationseNo important
inconsistenciesf
No important
inconsistenciesf
No important
inconsistenciesf
No important
inconsistencies—

Direct

—

High

—

High

Trend to or statistically significantly
higher calcium with active vitamin D
sterols
Trend to elevated phosphorus withactive vitamin D sterols
Active vitamin D sterols lower PTH

Moderate

Direct—High

Direct—Moderate———

Laboratory measurements
Calcium

Phosphorus

4 RCTs773 (437)

PTH

No limitationseg

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Ca  P

2 RCTs275 (134)

No limitations

ALP, b-ALP

3 RCTs451 (223)

Bicarbonate
Adverse Events—
4 RCTs—481 (238)

Serious limitations(1)i—

DirecthBalance of potential benefits and harm:
No evidence regarding benefit for clinical outcomes
Vitamin D sterols lower PTH. Trends toward higher serum phosphorus, calcium, and Ca  P and lower ALP and b-ALP
Uncertainty regarding harm

Trend to higher Ca  P with active
vitamin D sterols
Statistically significantly lower ALP
or b-ALP with active vitamin D sterol—
Depends on
One study of alfacalcidol vs placeboshows trend toward greater proportion outcomeof patients with episodes ofhypercalcemia. No consistent reportingof GI and cardiac AEs

Quality of overall evidence:High for biochemical outcomes
Low for other surrogate outcomes
Absent for patient-centered outcomeschapter 4.2

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Table 32 | Evidence profile of treatment of CKD–MBD with calcitriol or vitamin D analogs vs placebo in CKD stages 3–5

Kidney International (2009) 76 (Suppl 113), S50–S99

Table 32 | Continued
AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CKD–MBD, chronic kidneydisease–mineral and bone disorder; CVD, cardiovascular disease; GFR, glomerular filtration rate; GI, gastrointestinal; N, number of subjects; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial.
aOther considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
bClinical cardiovascular and cerebrovascular disease.
c
The use of aluminum-containing phosphate binders at baseline limits generalizability.
dThree grade C.
e
Two grade A, one grade B.
f
Direction of effect is consistent across studies.
g
Two grade A.
hHowever, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
i
One grade A, two grade B.

Table 33 | Evidence matrix for calcitriol vs vitamin D analogs in CKD stage 5D
Methodological quality
A
Outcome

AuthorN (on calcitriol)

B
F/U

AuthorC

N (on calcitriol)

F/U

—
—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—
—
Sprague (2003)392

—
—
—
—
—
—
—
—
—
266 (133)

—
—
—
—
—
—
—
—
—
3–8 months

Lab: ALP, b-ALP

—

—

—

—

—

—

Lab: Bicarbonate
Adverse events

—

—

—

—

—

—

—
—
—
—
—
—
—
—
—
Hayashi(2004)391
Hayashi(2004)391—

N (on calcitriol)

F/U

Author391

N (on calcitriol)

F/U

82 (47)
—
—
—
—
—
—
—
—
—

12 months
—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—
—
91 (47)

—
—
—
—
—
—
—
—
—
12 months

Hayashi (2004)
—
—
—
—
—
—
—
—
—

91 (47)

12 months

—

—

—

—

—

—
Sprague (2003)392
Hayashi (2004)391—
266 (133)
91 (47)—
3–8 months
12 months

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ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
N randomized may be more than N analyzed; this evidence matrix does not include studies of calcitriol vs placebo in CKD stage 5D (refer to summary table entry for Baker (1986)101) or studies in pediatric patients (refer tosummary table entry for Salusky (1998)18).

chapter 4.2

Mortality
Clinical CVD and CeVD
All-cause hospitalization
QoL
Fractures
PTx
Bone density
Bone histology
Vascular/valvular calcification
Lab: Ca, P, PTH

AuthorAdverse event reportingSummary of findings

OutcomeMortality
Clinical CVD andCeVDAll-cause
hospitalization
Quality of life
Fractures
PTx
Bone density
Bone histology
Vascular/valvular
Calcification

Total N(Calcitriolarm)

No. of studies
and study
design-

Methodologicalquality ofstudies

Consistency
across studies

Directness of theevidence generalizability/applicability

Other considerationsb

—
—
—
—
—
—
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AE from91 (47)
Very serious
—
—
—
1 RCT
limitations (2)
—
—
—
—
—
—

Quality ofevidencefor outcome

Qualitative and quantitative descriptionof effect

Importanceof outcome

Very low

Unable to assess

Critical——Critical

—

—

—

—

—

—

—

—

High

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

—
—
—
—
—
—

High
High
High
Moderate
Moderate
Moderate

Serious limitations(1)cVery serious
limitations (2)eSerious limitations(1)c

No important
inconsistencies
No important
inconsistencies
No important
inconsistenciesf

Direct—Moderate

No differenced

—

Low

—

Moderate

No difference in mean phosphorus
or % with high phosphorus
No difference between calcitriol
compared with maxacalcitol andparicalcitol in number of individuals
achieving lower PTH outcome.
Paricalcitol group of one study
showed slightly reduced time tolower PTH outcome
Unable to assess

Laboratory measurements
Calcium and Ca  P
Phosphorus
PTH

2 RCTs357 (180)

ALP, b-ALP

1 RCT

91 (47)

Bicarbonate
Adverse events—
2 RCTs—357 (180)

Very serious
limitations (2)h—DirectDirectg

NA

DirectSparseVery low

—

—

—

—

Kidney International (2009) 76 (Suppl 113), S50–S99

Balance of potential benefits and harm:
No evidence regarding benefit of calcitriol compared with other active vitamin D sterols for clinical outcomes. There is no difference
between these treatments for Ca, P, or PTH—
Limited evidence; no difference inproportion of pts with hypercalcemia,
hyperphosphatemia and/or elevatedCa  P

Moderate

Depends ontype ofoutcomeQuality of overall evidence:
Moderate to very low for biochemical outcomes
Absent for other surrogate outcomes
Absent for patient-centered outcomes

AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; N, numberof subjects; NA, not applicable; PTH, parathyroid hormone; pts, patients; PTx, parathyroidectomy; RCT, randomized controlled trial.
This evidence profile does not include studies of calcitriol vs placebo in CKD stage 5D (refer to summary table entry for Baker (1986)101) or studies in pediatric patients (refer to summary table entry for Salusky (1998)18).
b
Other considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
c
One grade B, one grade C.
dSecondary, not prespecified analyses, of one study, Sprague (2003)392 showed statistically significant difference in proportion of individuals with repeated episodes of high Ca or Ca  P.
e
Two grade C. In study by Sprague (2003)392 reportedly no difference in hyperphosphatemia, but definition or numbers were not provided.
fFairly consistent between studies, that is, no difference for proportions.
gHowever, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
h
One grade C.
achapter 4.2

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Table 34 | Evidence profilea for calcitriol vs vitamin D analogs in CKD stage 5D

Kidney International (2009) 76 (Suppl 113), S50–S99

Table 35 | Evidence matrix for calcimimetics in CKD stage 5D
Methodological quality
A
OutcomeB

Author N (on agent) F/U AuthorC

N (on agent)

Mortality

—

—

—

—

Clinical CVD and CeVD
Hospitalization
QoL
Fractures
PTx
Bone density
Bone histology
Vascular/valvular Calcification
Lab: Ca, P, PTH

—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—
—

Lab: ALP, b-ALP
Lab: Bicarbonate
Adverse events

—
—

—
—

—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
— Block (2004)387
Lindberg (2005)388
Moe (2005)395— Block (2004)387
—
—

—
—
—
—
—
—
—
—
—
741 (371)
395 (294)+0b741 (371)—

F/U

AuthorAdverse event reporting

N (on agent)
386

1184 (697)———
Cunningham (2005)386—
Cunningham (2005)386—
Cunningham (2005)386—
Cunningham (2005)386———
Malluche (2008)389——
6 months—
6 months
6 months
6 months————
1184 (697)876 (Xa)1184 (697)1184 (697)—
48 (32)———Cunningham (2005)

—
—

F/U

Author387

612 months Block (2004)
Lindberg (2005)388——
612 months—
612 months—
612 months—
612 months———
24 months
—
—
—
—
—

—
—

N

F/U

—
—
—
—
—
—
—
—
—
—
—

6 months
6 months
—
—
—
—
—
—
—
—
—

—
—
—
—
—
—
741 (371) 6 months
Block (2004)387
Lindberg (2005)388 396 (294) 6 months
Malluche (2008)389 48 (32) 24 months

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
N analyzed may be less than N randomized.
aUnclear reporting regarding the number of individuals who received study drug.
b
N for Moe (2005)395 is equal to the N from Block (2004)387 + Lindberg (2005)388.

chapter 4.2

S87

Summary of findings

OutcomeMortality
Clinical CVD andCeVDAll-cause
hospitalization
Quality of life

Fractures
PTx
Bone density
Bone histology

Vascular/valvular
Calcification

Consistency
across studies

Directness of theOtherevidence generaliz- consiability/applicability derationsa

Quality ofevidencefor outcome

NA

Direct

—

Low

—

—

—

—

Very serious
limitations (2)b
Very serious
limitations (2)b

NA

Direct—Low

NA

Direct—Low

NA

DirectSparse data Very Low

NA

Sparse data Very Low——

Some uncertainty
about directnessc
—
—

—
—

—
Very Low

—

—

—

—

Direct—Moderate

Direct—Moderate

Direct—Moderate

Directf—

Moderate

Direct—Moderate

Lower b-ALP

—

—

—

—
Higher rates of nausea and vomiting Depends onwhich may limit ability to continue
outcometreatment

No. ofTotal Nstudies and (N onstudy design study drug)

Methodologicalquality ofstudies

1 report of
4 RCTs01184 (697)

Very serious
limitations (2)b—

1 report of
4 RCTs1 report of
4 RCTs1184 (697)—876 (ND)

1 report of
4 RCTs1 report of
4 RCTs0
1 RCT1184 (697)—
48 (19)Very serious
limitations (2)b
Very serious
limitations (2)b
—
—

0

—

—

1184 (697)

Qualitative and quantitativedescription of effectImportanceof outcome

HR 0.81 (CI 0.45–1.45) in
100 patient-years—

CriticalHR 1.03 (CI 0.87–1.22) in 100
patient-years
Statistically significant benefit in
KDQOL Cognitive Functioning andin SF-36 Physical Component
Summary, Bodily Pain and General
Health Perception, No benefit forother SF-36 domains
HR 0.46 (CI 0.22–0.95) in 100
patient-years
HR 0.07 (CI 0.01–0.55) in 100
patient-years—
Overall changes in biopsies
were not very different between
groups. No statistical comparisons—High

Improved ability to lower PTH
while also lowering Ca, P

Moderate

Critical

High

High
High
Moderate
Moderate

Moderate

Laboratory measurements
Calcium
Phosphorus
Kidney International (2009) 76 (Suppl 113), S50–S99

Ca  P

3 reports of
3 RCTs1136 (665)

PTH
ALP, b-ALP

1 RCT

741 (391)

Bicarbonate
Adverse events

0
3 reports of
3 RCTs—1136 (665)

Serious limitations No major
inconsistenciese(1)dSerious limitations No major
inconsistenciese(1)dSerious limitations No major
inconsistenciese(1)dSerious limitations No major
inconsistenciese(1)dSerious limitations NA
(1)g
—
—

Balance of potential benefits and harm:
Improved ability to lower PTH while also lowering Ca, P in short term (up to 1 year); uncertainty about benefit
or harm for patient-centered clinical outcomes

Quality of overall evidence:
Moderate for biochemical outcomes
Very Low for other surrogate outcomes
Low for patient-centered outcomeschapter 4.2

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Table 36 | Evidence profile for calcimimetics in CKD stage 5D

Kidney International (2009) 76 (Suppl 113), S50–S99

Table 36 | Continued
ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease;HR, hazard ratio; KDQOL, Kidney Disease Quality of Life Instrument; N, number of subjects; NA, not applicable; ND, not documented; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial; SF-36,
Medical Outcomes Study Short Form 36.
aOther considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
b
One grade C.
cProtocol indicated for parathyroidectomies.
dThree grade B.
e
No major inconsistencies between Block (2004)387 and Lindberg (2005)388.
f
However, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
g
One grade B.

chapter 4.2

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chapter 4.3

http://www.kidney-international.org& 2009 KDIGO

Chapter 4.3: Treatment of bone withbisphosphonates, other osteoporosis medications,and growth hormone
Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

INTRODUCTION

Abnormal bone is a common component of CKD–MBD.
Patients with CKD have an increased risk of fracturescompared with age-matched controls, with a resultant
significant disability and mortality.82,90,158 In children, linear
height deficit (short stature) is one of the cardinal features ofprogressive CKD, and is also a component of CKD–MBD.
Both fractures and abnormal linear growth can lead to adecreased quality of life, and therefore, treatments to reducethese complications of CKD–MBD are needed. However,clinical studies in patients with CKD stages 4–5 are very
limited.

RECOMMENDATIONS

4.3.1 In patients with CKD stages 1–2 with osteoporosis
and/or high risk of fracture, as identified byWorld Health Organization criteria, we recommend
management as for the general population (1A).
4.3.2 In patients with CKD stage 3 with PTH in the normal
range and osteoporosis and/or high risk of fracture, as
identified by World Health Organization criteria, wesuggest treatment as for the general population (2B).
4.3.3 In patients with CKD stage 3 with biochemical
abnormalities of CKD–MBD and low BMD and/or
fragility fractures, we suggest that treatment choices
take into account the magnitude and reversibility ofthe biochemical abnormalities and the progression of
CKD, with consideration of a bone biopsy (2D).
4.3.4 In patients with CKD stages 4–5D having biochemical
abnormalities of CKD–MBD, and low BMD and/or
fragility fractures, we suggest additional investigation with bone biopsy prior to therapy with
antiresorptive agents (2C).
4.3.5 In children and adolescents with CKD stages 2–5D
and related height deficits, we recommend treatment
S90

with recombinant human growth hormone when
additional growth is desired, after first addressing
malnutrition and biochemical abnormalities of
CKD–MBD (1A).
Summary of rationale for recommendations

Patients with late stages of CKD have a high risk offractures that are painful and disabling.
K In
patients with age-related osteoporosis, surrogate
measurements such as low BMD relate to clinicaloutcomes. This does not necessarily apply in patientswith CKD stages 3–5D, in whom the fracture risk is high,regardless of BMD.
K In postmenopausal osteoporosis, medication-related increases in BMD are not always directly responsible for
reductions in fracture incidence. Improved BMD does
not necessarily parallel bone quality, which isan important factor contributing to bone fragility
fractures.
K Studies evaluating medications for the treatment of
postmenopausal osteoporosis (risedronate, alendronate,
teriparatide, and raloxifene) specifically excluded
patients with an elevated serum creatinine level, HPT,or abnormal ALPs. However, post hoc analyses found thatthese drugs had similar efficacy, improved BMD, andreduced fractures in individuals with a moderately
reduced eGFR compared with those with a mildly
decreased or normal eGFR.
K No studies meeting evidence-based criteria have evaluated these therapies in patients with CKD stages 3–5D
who have biochemical evidence of CKD–MBD.
K There are multiple additional factors that contribute to
fractures in patients with CKD stages 3–5D comparedwith those in the general population. The bone isfrequently of abnormal quality because of metabolic
abnormalities specific to CKD stages 3–5D and therapies
K

Kidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.3

that are used. In addition, patients with CKD may havean increased risk of falling.
K The pathogenesis of bone disease in patients withCKD–MBD is different from that in postmenopausal osteoporosis; therefore, extrapolating results ofstudies from osteoporosis to patients with CKD stages
3–5D may not be valid, especially with concerns of longterm safety. Thus, when evaluating treatment options for
low BMD and/or fracture prevention, patients with CKD
stages 1–3 who have no evidence of CKD–MBD must be
differentiated from patients with CKD stages 3–5D who
do have evidence of CKD–MBD.
K In children, linear growth abnormalities are common andcan be corrected with rhGH.
BACKGROUND
Fractures and bone quality

Fractures occur when the bone is subjected to a force that isgreater than the bone strength. Bone strength reflects theintegration of two main features: BMD and bone quality.407409 These ‘quality’ factors include the rate of boneturnover or remodeling, bone shape and architecture,trabecular connectivity, mineralization, collagen cross-linking, crystal size, intrinsic biomechanical properties ofstrength and toughness, amount of microdamage, andviability of bone cells. For example, in some diseases suchas osteopetrosis and skeletal fluorosis, bone fracture incidence is increased, despite high BMD, because bone quality
is poor.
Bone quality in CKD

The pathogenesis of bone disease in patients with CKD–MBD
is different from that in postmenopausal osteoporosis.410 In
patients with CKD–MBD, BMD does not predict fracture risk
as it does in the general population (as detailed in Chapter
3.2), implying an abnormal bone quality. This limits theability to extrapolate data from studies of patients with
postmenopausal osteoporosis to patients with CKD–MBD.
For example, in a report of 1429 bone biopsies from patientswith CKD stage 5D, 52 patients had osteoporosis, and 49 ofthem had adynamic bone disease.411 Another biopsy study ofpatients with CKD found low bone volume in 46% of thepatients, who were younger than the usual patients with
idiopathic osteoporosis. Regression analysis revealed that the
duration of amenorrhea, being Caucasian, and the OPG/
RANK-L ratio influenced bone volume. This study also
showed low bone-formation rates in those with low bonevolumes.231 Many patients with CKD have abnormal
mineralization and increased osteoid. These findings are very
different from studies of patients with postmenopausal
osteoporosis, who frequently show increased bone turnoverand rarely show abnormal mineralization.
Similarly, CKD–MBD may alter bone and cartilage
structure and function in children, resulting in an abnormal
linear growth in children. Thus, the management of bonedisease in patients with CKD is challenging.
Kidney International (2009) 76 (Suppl 113), S50–S99

Gonadal hormones and bone strength

Many women with CKD have hypoestrogenism, and thus
it may seem logical to administer patients estrogen. In
postmenopausal women from the general population, estrogen-replacement therapy has been conclusively shown to
reduce the incidence of hip, vertebral, and nonvertebral
fractures.412 However, the combined administration of
estrogen and progestin may also increase the risk of breast
cancer, thromboembolic events, and coronary and cerebrovascular disease, with risks dependent on age and years sincemenopause.413 A current theory is that estrogen can help
prevent CACs if given to women who have normal coronary
arteries, but can cause plaque rupture and myocardial
infarctions in women who already have coronary arterydisease.414 Given that women with CKD frequently havecoronary artery disease, the Work Group felt that these drugs
should be used with caution. In premenopausal women with
CKD, there are not enough data to make any recommendations with regard to estrogen use. Similarly, men withadvanced CKD may have reduced testosterone levels,415
which also may contribute to abnormal bone. However, there
are no studies that have specifically evaluated the effect of
testosterone therapy on bone in CKD patients.
Abnormal height and CKD

Linear height deficit (short stature) is one of the cardinalfeatures of progressive CKD in pediatric patients. On thebasis of the NAPRTCS 2006 Data Report,252 more than onethird of patients are less than the third percentile for height.
Baseline kidney function, by height Z-score, shows that there
are patients with severe height deficits, even though they havea relatively good function (425 ml/min). Of patients with acalculated CrCl between 50 and 75 ml/min, 18.2% (379/1720)
had a height Z-score worse than –1.88. The mechanismsof linear growth failure include the presence of chronic
metabolic acidosis, renal osteodystrophy, nutrient wasting,chronic inflammation, functional hypogonadism (in someadolescents), and dysregulation of the growth hormone–insulin-like growth factor-1 endocrine axis. Since 1988, rhGH
has been licensed by the Food and Drug Administration in
the United States for the treatment of linear growth failurein children with CKD.
RATIONALE

4.3.1 In patients with CKD stages 1–2 with osteoporosis
and/or high risk of fracture, as identified by World
Health Organization criteria, we recommend management as for the general population (1A).
Although osteoporosis is a major cause of disability amongolder men and women, studies from around the world havereported that many patients with osteoporotic fractures are
not receiving treatment. The majority of patients withfragility fractures admitted to hospitals are not treated.416
The disease is considered to be a consequence of aging,
despite the fact that therapies can reduce fracture incidence
S91chapter 4.3

and improve the quality of life. Approximately 85% of elderly
women with postmenopausal osteoporosis have CKD.122
Often patients with osteoporosis and CKD stages 1–2 areignored, even though studies show that medications can
reduce fractures and improve the quality of life. The WorkGroup felt it was important to indicate that bisphosphonates,
raloxifene, and teriparatide could be used in these patientswith early CKD, who otherwise would be appropriate
candidates for therapy in the absence of CKD.

In clinical trials of osteoporosis medications, fracture rates
are decreased by about 50%. This suggests that about half of
the individuals did not respond to therapy, and investigators
would like to identify which patients are most likely to have abenefit. A recent post hoc evaluation of a large alendronate
study found fracture benefit in women with the highest tertileof baseline bone turnover markers, but no difference infracture rate in those with baseline low markers of boneturnover.248

Osteoporosis in the general population
Overview. It was beyond the scope of this report to review

Bisphosphonates
Overview. Bisphosphonates have been studied extensively

all the studies on osteoporosis. The WHO has developed aclinical risk prediction algorithm that will help physicians
determine the risk of a fracture within the subsequent decade(http://www.shef.ac.uk/FRAX/index.htm; last accessed on 25
March 2009); treatment decisions will depend on the costand long-term studies on efficacy and safety; moreover, theexact thresholds for intervention are not yet determined.185
Currently, it is cost effective to prescribe alendronate forpatients with a BMD T-score lower than –2.5 or who haveexperienced a vertebral compression fracture or nontraumatic hip fracture.417 In patients with osteoporosis, theapproved drugs reduce fracture incidence by about 50%. A
recent meta-analysis did not find any drug that was superior
to others.418 We focus on medications for which there aredata in patients with CKD. It is important to remember thatvitamin D and calcium supplements have been used asco-therapies in all of the major clinical trials.
Importance of bone turnover. Idiopathic osteoporosis,
seen most often in elderly men and women, has a multifactorial pathophysiology. The bone turnover, for example,
ranges from high to suppressed. Within the cancellous
bone, the trabeculae become thin and disconnected, andlose the normal plate-like structure.419 Further perforationsof the trabecular plates can lead to an accelerated loss ofstrength. Medications that inhibit the osteoclastic resorptionof the bone prevent this deterioration of bone strength.420
Most of the currently effective medications for osteoporosis(bisphosphonates, estrogen, calcitonin, and raloxifene) act
by inhibiting resorption; as a consequence, bone formation issecondarily decreased. Thus, there are only minor changes, ifany, in bone volume. Fractures are prevented because
trabecular perforations are prevented. The decreased bone
resorption and formation also leads to more mineralizationin the bone, so that the bone becomes harder. This may also
contribute to improving bone strength,421 although overmineralization is associated a with more brittle bone.422
The reason BMD increases in patients with osteoporosis
who are treated with antiresorbing medications is that bone
becomes more mineralized. In clinical trials of antiresorbing
medications, the decrease in fracture rate is not entirely
explained by changes in BMD. Changes in the serum markers
of bone cell activity suggest that fracture reduction is moreclosely related to a decrease in bone turnover than to anincrease in BMD.247,249

and have been shown to effectively decrease bone fracturesin patients with osteoporosis in studies with durations up
to 5 years.
Pharmacokinetics. Several features with regard to bisphosphonate actions and pharmacokinetics are important in thecontext of CKD. Bisphosphonates bind very tightly tomineral, with a half-life of over 10 years.423 In patients withnormal kidney function, about half of the administered doseis bound to the bone and the rest is excreted within several
hours by the kidney, hence most of the tissues have only abrief exposure to the drugs.423 Serum calcium decreases andPTH increases.
Vascular calcifications. Although bisphosphonates areusually prescribed for bone diseases, the first-generation
bisphosphonate (etidronate) inhibits calcification and has
been used to treat ectopic calcifications. Vascular calcifications are an important component of CKD–MBD, andtherefore, the effects of bisphosphonates on extraskeletal
calcifications are important, and there may be differences
between etidronate and the newer aminobisphosphonates.
The effect of ibandronate on aortic calcifications was alsostudied in two 3-year RCTs involving 474 women with
postmenopausal osteoporosis. One trial used oral doses andthe other i.v. doses. Aortic calcifications increased significantly in both studies in the women taking ibandronate,
although a similar increase was also seen in the patientstaking a placebo.424 Another study of CACs, measured using
EBCT, found increased calcium deposition in 56 elderly
women after 2 years of alendronate, but the rate was not
significantly greater than that in control women.425 There areno published studies of aminobisphosphonates and vascular
calcification in patients with CKD stages 4–5D, although theolder bisphosphonate etidronate did prevent arterial calcification progression in a small uncontrolled study of dialysis
patients.426
Adverse events. Oral doses commonly cause uppergastrointestinal irritation. Intravenous dosing commonly
causes an acute-phase reaction with fever, leukopenia, andbone pain. Severe hypocalcemia has been reported whenthese medications are administered to patients with avitamin D deficiency.427,428
Unusual adverse effects of bisphosphonates include
osteonecrosis of the jaw, ocular inflammation, atrial fibrillation, esophageal ulceration, bone pain, and nephrotic

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chapter 4.3

syndrome. It is important to realize that the clinical trials inpatients with osteoporosis that show a decreased incidence of
fractures with bisphosphonates have controls for only 5 years.
Currently, there is a debate with regard to the possibility ofoversuppression of bone formation with long-term use ofbisphosphonates. There are several anecdotal reports ofunusual fractures in patients who took bisphosphonates andwhose bone biopsies showed no tetracycline labels. Theremay be a higher risk of subtrochanteric fractures, noted in asmall study from Singapore429 and New York.430 Ten-year
observational studies of patients who have taken bisphosphonates, however, have not revealed any increased
incidence of fractures.431 Further follow-up of these patients
will be important.
Intermittent administration of 1–34 PTH

The only currently available medication that increases theformation of new bone is teriparatide (recombinant human
1–34 PTH). This anabolic drug has a totally different
mechanism of action than bisphosphonates: the BMD
increases because there is more bone.432,433 The duration of
the anabolic effect of PTH is about 12–18 months; thereafter,bone-formation rates return to baseline.432 An earlier or
concurrent use of bisphosphonates attenuates the anabolic
effect within cancellous bone.434,435 Teriparatide is particularly effective in cancellous bone.125 Early studies suggested
that PTH could increase cancellous bone at the expense ofcortical bone;436 the effects have been shown to be complex
in cortical bone, with an increase in cortical thickness,432 as
well as an increase in cortical porosity437 and a decrease in
the volumetric density of the hip as measured by quantitative
computed tomography (qCT).434 Bone density at the radiusdecreases with teriparatide.125,434,435 This could have implications for the treatment of patients with CKD, who
frequently have lower BMD at the radius compared withother skeletal sites (see Chapter 3.2). Furthermore, it is notknown if 1–34 PTH will be anabolic in patients who alreadyhave high PTH, or in patients with PTH resistance.
Raloxifene

Raloxifene is a selective estrogen receptor modulator that is
approved for treatment of postmenopausal osteoporosis.
Several large clinical trials have documented a reduction invertebral fracture incidence, but not in nonvertebral
fractures.438,439 This drug acts through estrogen receptors
in the bone, but is antagonistic to estrogen effects in thebreast and uterus. Similar to estrogen, there is enhanced
coagulation and more frequent episodes of thrombophlebitis.
The lipid profile improves (lower low-density lipoproteincholesterol and higher high-density lipoprotein cholesterol),but the effect on CVD in women with preexisting coronary
artery disease is similar to that of placebo. In women who
have documented coronary artery disease or a history of
myocardial infarction, the risk of a fatal stroke was increased
with raloxifene.439 The incidence of strokes was not increased
in studies of women with osteoporosis or of women withKidney International (2009) 76 (Suppl 113), S50–S99

a high risk of breast cancer. The incidence of breast cancer,
particularly estrogen-receptor-positive cases, is about half ofthat seen with placebo and similar to the beneficial effect onbreast cancer found with tamoxifen.440 Side effects include
hot flashes and leg cramps. Raloxifene is not indicated in
premenopausal women because it may interfere with native
estrogen.
4.3.2 In patients with CKD stage 3 with PTH in thenormal range and osteoporosis and/or high risk offracture, as identified by World Health Organization
criteria, we suggest treatment as for the general
population (2B).
There are no clinical trials of antiresorbing drugs specificallydesigned for patients with CKD stages 3–5, and such patientswere specifically excluded from most osteoporosis treatment
trials. However, because of the use of serum creatinine, and
not GFR, as an inclusion criteria, patients with CKD stages
3–4 by eGFR were inadvertently enrolled in these studies.
Importantly, in all of these studies, patients were excluded if
the PTH was elevated or if there were other biochemical
abnormalities of CKD–MBD. Specifically, post hoc analyses oftrials of bisphosphonates, teriparatide, or raloxifene haveevaluated the effect of these agents on BMD and fractures,
and are discussed below.
Bisphosphonates in CKD

Two post hoc analyses of trials in patients with osteoporosis
have been published (Tables 37, 38 and Supplementary Tables
39–42). Miller et al.126 reported a pooled analysis of nine
trials using risedronate for treatment of osteoporosis. The
primary trials were designed to exclude patients withsignificant systemic disease, hence individuals with serum
creatinine 41.1 times the upper limit of normal were
excluded. The individuals were elderly; therefore, most ofthem had some age-related decline in renal function as
estimated by the Cockcroft and Gault method. There were4071 patients with CKD stage 3, with a mean age of 77 years,
and 572 patients with CKD stage 4, with a mean age of
83 years, with a mean serum creatinine of 1.3 mg/dl. Thesepatients showed a reduction in vertebral fracture rates andimprovements in bone density, which were similar to thosewith eGFR above 80 ml/min per 1.73 m2; however, in the
CKD stage 4 patients, there was no difference in the femoral
neck bone density with risedronate compared to placebo.
In most of the primary studies, one-third of the patientswere treated with 2.5 mg/d of risedronate, but these patientswere not included in this pooled analysis. Bone biopsies were
measured in 57 patients, but only 14 had moderate decreases
in eGFR and none had CKD stage 4. Mineralizing surface
decreased 68% with risedronate. No data with regard to otheraspects of the bone biopsies were reported. An important
limitation of this study is that the nonvertebral fracture rates
were not mentioned, even though they are included in the
primary reports.
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chapter 4.3

This study provides C-quality evidence that risedronate iseffective in elderly women with age-related CKD stage 3.
Dropout rates were not represented and the end points fromthe studies were different; nevertheless, the results werepooled. Finally, the fracture data were incomplete as paired
X-ray data were not uniformly available. These results may
not apply to men or younger women. The evidence for
efficacy in CKD stage 4 is weak, because these women did notshow the classical bone abnormalities seen in patients withCKD stage 4. First, they were excluded if serum PTH or ALP
values were higher than normal. Second, the mean eGFR was
27 ml/min per 1.73 m2 and the interquartile range was
24.5–28.7 ml/min per 1.73 m2, hence the eGFR was barely
lower than that in CKD stage 4. Third, the mean age was 83
years, by which time the Cockcroft–Gault method becomesless accurate. Using the MDRD method, the average woman
in the CKD stage 4 group had an eGRF of 42 ml/min per
1.73 m2, hence most of these women did not meet theKDOQI definition of CKD stage 4. Fourth, fewer than half ofthe patients in the CKD stage 4 group had vertebral fractures
measured. Finally, patients with severe CKD usually havemore bone loss in the cortical bone (measured at the femoralneck) relative to cancellous bone (measured at the spine).
Femoral neck bone density did not show any improvementwith risedronate in the CKD stage 4 group.
A similar post hoc analysis of an osteoporosis trial was
reported by Jamal et al.127 Data from the alendronate fractureintervention trial were re-analyzed according to GFR as
estimated by a modified equation using lean body mass fromdual-energy X-ray absorptiometry studies. Verification of thismethod was not included in the report. In this study, as wellas in the one conducted by Miller et al.,126 the intent of theoriginal trial was to exclude women with kidney disease, but
because of their age many individuals did have mild-tomoderate decreases in eGFR. Data extrapolated from a figurein the paper show that fewer than 20 individuals had CKD
stage 4, and those with abnormal serum calcium, PTH, or
ALP values were excluded. This makes it unlikely that any
patient had CKD–MBD. The authors found that the womenwith an eGFR less than 45 ml/min per 1.73 m2 had similar
improvements in BMD and decreases in relative fracturerisk than those with higher eGFR. The original study was
powered to detect differences in fracture rates, but there wasinadequate power to detect a fracture benefit in this subgroup
analysis. The study was graded as C quality, as the sample size
was small and dropout rates were not provided.
Teriparatide in CKD

Miller et al.126 reported a post hoc study that used data fromthe Fracture Prevention Trial125 (Supplementary Tables 43–45)
to evaluate patients with postmenopausal osteoporosis,
excluding patients with a serum creatinine42 mg/dl. Using
the Cockcroft–Gault formula, the patients were divided on
the basis of kidney function into normal (GFR480 ml/min
per 1.73 m2, N ¼ 885), mildly impaired (GFR 50–79 ml/min
per 1.73 m2, N ¼ 444), or moderately impaired (GFR
S94

30–49 ml/min per 1.73 m2, N ¼ 83); five patients with an
eGFR less than 30 ml/min per 1.73 m2 were in the study, but
not in the analysis. These women did not carry a diagnosis of
kidney disease, and they were thin and elderly. Importantly,
the study excluded individuals with elevations in serum
calcium, phosphorus, or PTH, or with vitamin D deficiency.
The two treatment arms (different doses of teriparatide) werecombined in the analysis. The study found that vertebral
fracture incidence, detected by changes in radiographs, wasgreater in individuals with an abnormal renal function
compared with those with a normal renal function for all
levels of abnormal GFR; however, this difference was notfound for nonvertebral fragility fracture. Teriparatide reduced
vertebral fracture incidence in all groups; there were nononvertebral fractures in the group with a moderately
decreased eGFR. In addition, teriparatide improved lumbar
spine BMD, femoral neck BMD, and collegen cross-linkbiomarkers in a similar manner in normal, mild, andmoderately impaired GFR. The treatment increased serum
calcium and uric acid in all subgroups, but the percentage ofpatients with hypercalcemia and hyperuricemia was greater inthe moderately impaired GFR group.
Owing to the post hoc nature of this study, the different
groupings of GFR depending on the end point of the study,
and the inability to generalize to the ‘usual’ CKD stage 3
patient because of the exclusion criteria of abnormal
biochemistries of CKD–MBD, the study was considered to
be of low (‘C’) quality. In women with postmenopausal
osteoporosis who have normal serum biochemistry levels,
CKD stages 2–3 do not seem to be a contraindication toteriparatide therapy.
Raloxifene in CKD

A post hoc study used data from the Multiple Outcomesof Raloxifene Evaluation trial to evaluate the efficacyof raloxifene in patients with reduced kidney function(Supplementary Tables 43–45).441 The original trial included
7705 postmenopausal women aged 31–80 year. Women wererandomly assigned to receive placebo, raloxifene 60 mg/d,or raloxifene 120 mg/d, in addition to daily calcium
supplements of 500 mg and 400–600 IU of vitamin D. The
trial included women at least 2 years postmenopausal, withosteoporosis defined by low BMD or radiographical evidenceof vertebral fractures. Women with a serum creatininelevel42.6 mg/dl (225 mmol/l) at baseline were excluded. For
the post hoc analysis, some sites that did not use the central
lab for creatinine were excluded, with a total of 7316 postmenopausal women being included. CKD was defined using
the Cockcroft–Gault formula, and divided by kidney function
into CrCl460 ml/min (N ¼ 2343), CrCl 45–59 ml/min(N ¼ 3293), or CrClo45 ml/min (N ¼ 1480). In the lattergroup, the median CrCl was 40.6 (range 20–44.9) and only 55
individuals had CrClo30 ml/min; thus, this group represents
CKD stage 3 patients. Importantly, the study excluded individuals with elevations in serum PTH, or with vitamin D
deficiency, and the levels of PTH were normal in all of theKidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.3

CKD groups. The two treatment arms (different doses ofraloxifene) were combined in the analysis. The study foundthat femoral neck and spine BMD increased with raloxifene
compared with treatment using placebo. The femoral neckBMD increase was greatest in patients with lower CrCl
compared with those in other kidney disease groups, but thisdifference disappeared when the MDRD formula was usedinstead of that of Cockcroft–Gault. There was a significant
reduction in vertebral fractures in the overall cohort of
raloxifine-treated patients, with no difference in the three(CrCl) groups. The odds ratio for vertebral fracture was 0.60
for those with a normal kidney function, 0.54 with eGFR
45–59 ml/min per 1.73 m2, and 0.74 if eGFR was o45 ml/min
per 1.73 m2. In the latter group, this was not significant, but
only 282 women were in that group. In contrast, there was nodifference in nonvertebral fracture incidence in raloxifenetreated patients compared with those on placebo in theoverall cohort (consistent with the results of the primarystudy), or within the groups defined by eGFR. AEs weregreater in patients with a reduced kidney function, but there
was no difference based on treatment assignment. This study
was graded to be of ‘B’ quality, limited because of the post hoc
analyses.
4.3.3 In patients with CKD stage 3 with biochemical
abnormalities of CKD–MBD and low BMD and/or
fragility fractures, we suggest that treatment choices
take into account the magnitude and reversibility ofthe biochemical abnormalities and the progression of
CKD, with consideration of a bone biopsy (2D).
At CKD stage 3, some patients have already developed
abnormalities of CKD–MBD, in particular, secondary HPT.
The large randomized trials of osteoporosis medications
detailed above excluded those with known kidney disease, butmany of the patients had early CKD stage 3. As kidney diseaseprogresses, bone disease changes from idiopathic osteoporosis to renal osteodystrophy. This disease progression has notbeen characterized very well and is probably variable frompatient to patient, but it seems to begin around a GFR of
40–50 ml/min per 1.73 m2, when the biochemical manifestations of CKD–MBD initially appear.28,233 The clinical trials ofbisphosphonates, raloxifene, and teriparatide have excluded
individuals with abnormal PTH values, hence the beneficial
effects of these therapies cannot be assumed to apply topatients whose disease has progressed to those stages of CKD
when biochemical abnormalities, and related bone remodeling abnormalities start to appear (that is, CKD–MBD, see
Chapter 3.2). Given the heterogeneity of this population interms of progressive CKD, duration of CKD, and severity of
CKD–MBD, these patients must be evaluated on an
individual basis. The Work Group recommends that
secondary HPT be addressed first, as in Chapter 4.2. In
patients in whom HPT has been corrected, the GFR is stable,
and the risk of a fracture outweighs the potential long-termrisk of inducing an irreversible low bone turnover, therapy
Kidney International (2009) 76 (Suppl 113), S50–S99

with bisphosphonates may be considered. However, bisphosphonates are likely to prevent fractures only in those patients
who have increased bone resorption. Therefore, the WorkGroup recommends consideration of a bone biopsy wheneverfeasible.
4.3.4 In patients with CKD stages 4–5D, having biochemical abnormalities of CKD–MBD, and low BMD and/or fragility fractures, we suggest additional investigation with bone biopsy prior to therapy with
antiresorptive agents (2C).
The effectiveness of long-term bisphosphonate, teriparatide,or raloxifene therapy in CKD stages 4–5D with biochemical
abnormalities of CKD–MBD is currently unknown. The
Work Group could therefore not recommend the routine useof these agents, especially in light of safety concerns that arehighlighted below.
Bisphosphonates in CKD stages 4–5D

A small study of 12 dialysis patients given pamidronate foundreduced serum calcium and increased PTH.442 A recent
abstract presented by Amerling et al.443 found that patientswith CKD stages 2–5 who were taking oral alendronate had
low-turnover bone disease with absent tetracycline uptake.
These patients had all been referred to the renal clinic. Thus,
the bisphophonates could cause adynamic bone disease inpatients with CKD–MBD. This is an important consideration
for patients with CKD–MBD stage 5D, in whom theprevalence of low-turnover bone disease is high (28% of
patients, range 4–60%; see Chapter 3.2).
We have no definite evidence that bisphosphonates areharmful to patients with CKD stages 4–5. Bisphosphonates
could potentially be beneficial to those with a low bonedensity and a high bone turnover, with well-controlled serum
PTH and minerals. An RCT is needed for this population. In
addition, the pharmacodynamics of these drugs in CKD
should be better defined.
Teriparatide in CKD stages 4–5D

There are no data on teriparatide in patients with CKD stage 3
who have biochemical abnormalities (high serum PTH,
abnormal serum ALPs or 25(OH)D), and also no data inpatients with CKD stages 4–5. There is a theoretical concernthat preexisting HPT would be exacerbated by teriparatide,and the anabolic effects may not be able to overcome theresorptive effects. Moreover, patients with CKD–MBD show
resistance to skeletal actions of PTH, hence they may not
respond to intermittent injections of usual 1–34 PTH doses.
One could speculate that teriparatide might be useful inpatients with surgical hypoparathyroidism and adynamic bonedisease, but there is currently no evidence to support this.
Raloxifene in CKD stages 4–5D

There was a single RCT evaluating raloxifene in dialysis
patients,444 with 25 patients randomized to 60 mg/d
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chapter 4.3

raloxifene and 25 randomized to placebo for 1 year. The
patients were postmenopausal by at least 2 years, and the
BMD T-score was below 2.0 s.d. In the raloxifene-treatedpatients, the results showed a significant improvement inlumbar spine, but not hip BMD, after 1 year. Serum levels of
pyridinoline (a marker of bone resorption) and of lowdensity lipoprotein cholesterol decreased after 6 months in
the raloxifene-treated patients compared with those onplacebo. There were no side effects noted. This study was
graded of ‘B’ quality because of small sample size and thequestion of generalizability of the end point of BMD, as BMD
in dialysis patients may not predict fracture risk as it does in
the general population. This small study was not felt to beadequate for raloxifene to be recommended for routine use
in dialysis patients.
From the physiological point of view, raloxifene is
expected to be beneficial to bone in postmenopausal womenwith CKD–MBD, and reduction in breast cancer could be an
important additional benefit. However, raloxifene increases
the risk of thromboembolism, and larger studies are needed
to determine whether the risks of thromboembolism or
dialysis access thrombosis are seen in women with CKD
stage 5D. There are also insufficient data with regard to thepharmacokinetics of raloxifene in dialysis patients. The drug
is excreted through hepatic metabolism, unlike bisphosphonates. The effect of abnormal protein binding has notbeen studied, but this is an important factor for estrogen. The
free estradiol levels in women with CKD stage 5D are twice ashigh as in women with normal kidney function when given
the same dose.204 Most importantly, the patients enrolled
in the MORE trial441 had no biochemical evidence ofCKD–MBD, and thus fracture efficacy may not be generalizable to patients with CKD stages 3–5D with CKD–MBD, inwhom bone quality may be altered for reasons other thanestrogen deficiency.
4.3.5 In children and adolescents with CKD stages 2–5D
and related height deficits, we recommend treatment
with recombinant human growth hormone when
additional growth is desired, after first addressing
malnutrition and biochemical abnormalities of
CKD–MBD (1A).
There was a 2006 Cochrane Review on the use of rhGH inchildren with CKD.19 We searched using PEDS PICCOD
criteria to determine if there were additional RCT studies
not included or published, and found none. The Cochrane
article19 reviewed 15 RCTs (629 children) that comparedrhGH therapy with placebo. No studies have been publishedsince then. These studies showed an improvement in heights.d. score, height velocity, and height velocity s.d. score.
Depending on the study, the effects were evaluated at 6, 12, or
24 months, with positive results at all time points. However,across all growth outcomes, there was a consistent pattern of
waning effect with longer duration of treatment. Thus, rhGH

S96

administration is efficacious in standard measures of growthin children. Available RCT data suggest that children withCKD should be treated with 28 IU/m2/week of rhGH.
Compared with a dose of 14 IU/m2/week, the larger dose
increases height by about 1.5 cm/year over 1 year, but
increasing the dose to 56 IU/m2/week did not result in astatistically significant improvement in growth indices.
However, these conclusions are based on only 18 patients.
There are limited bone biopsy data in children treated with
rhGH. The consistency of the positive benefits of rhGH
across studies and in AEs was considered a high-quality
evidence, leading to a strong guideline recommending its use
in children with CKD height deficits.
The benefits to growth need to be balanced with AEs andthe difficulty of adhering to a daily subcutaneous injection
regimen. In a recent case series of children with CKD treatedwith rhGH for 2 years, children who responded to rhGH
reported that they would choose treatment again, and those
who did not respond generally reported that they would notchoose treatment again.445 These data suggest that treatment
response overrides concerns about injections. Adherence totreatment was time dependent, so that 41% of parents
reported noncompliance at 1 year, whereas 91% reported
missing injections at 2 years (when response to treatment had
waned). When most parents are asked to trade-off the growthpotential of their children against the burden of daily
injections, they opt for rhGH treatment. In general, AEs
were usually minor.

RESEARCH RECOMMENDATIONS

The following research studies are needed:
K A randomized, placebo-controlled clinical trial of men
and women with CKD stages 4–5D, with controlled
serum PTH, phosphorous, and calcium but low bonedensity, treated with bisphosphonates. The study should
evaluate bone density, bone biopsy in at least a subset,
serum PTH, calcium and ALP, fracture incidence, andmeasures of vascular calcification.
K A pharmacokinetic study of postmenopausal women withCKD stage 5D should evaluate serum levels of raloxifene
and teriparatide after administration.
K An RCT in women with CKD stages 4–5D comparing theeffects of raloxifene vs placebo on bone density, bonebiopsy in at least a subset, serum PTH, calcium, phosphorous, ALP, cholesterol, incidence of fractures, breast
cancer, heart disease, stroke, and blood/access clots.
K A prospective study of patients with CKD stage 5D withadynamic bone disease and low serum PTH levels using
teriparatide to determine markers of bone formation andresorption, bone biopsies, and serum calcium/phosphorous/ALP.
K An RCT of pediatric CKD–MBD patients treated with rhGH
therapy compared with those on placebo to evaluate bone
histomorphometry, height, skeletal age, and fractures.

Kidney International (2009) 76 (Suppl 113), S50–S99

chapter 4.3

SUPPLEMENTARY MATERIALSSupplementary Table 39. Summary table of the treatment of
CKD–MBD with bisphosphonates in CKD stages 3–5—description of
population at baseline.
Supplementary Table 40. Summary table of the treatment of CKD–MBD
with bisphosphonates in CKD stages 3–5—intervention and results.
Supplementary Table 41. Adverse events of bisphosphonates in CKD
stages 3–5.
Supplementary Table 42. Ongoing RCTs examining the effect ofbisphosphonates on CKD–MBD.

Kidney International (2009) 76 (Suppl 113), S50–S99

Supplementary Table 43. Summary table of the treatment of
CKD–MBD with other bone treatments in CKD stages 3–5 and 5D—
description of population at baseline.
Supplementary Table 44. Summary table of the treatment of
CKD–MBD with other bone treatments in CKD stages 3–5 and 5D—intervention and results.
Supplementary Table 45. Adverse events of other bone treatments in
CKD stages 3–5 and 5D.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki

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chapter 4.3

S98

Table 37 | Evidence matrix of bisphosphonates vs placebo/control in CKD stages 3–5
Methodological quality of outcome
A
OutcomeB

C

Adverse event reporting

AuthorN (on agent)

F/U

AuthorN (on agent)

F/U

AuthorN (on agent)

F/U

AuthorN (on agent)

F/U

Mortality
Clinical CVD
Hospitalization
CKD clinical outcomes
QoL
Clinical fractures
Radiological fractures

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

Bone histology
Vascular/valvular calcification
GFR loss
Lab: Ca, P
Lab: ALP, b-ALP
Lab: PTH, Vit D, Bicarb
Adverse events

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
—
—

—
—
—
—
—
36 months
36 months
22–25 months—
36 months
22–25 months——
22–25 months
22–25 months
—
—
—

—
—
—
—
—
—
—

—
—

—
—
—
—
—
581 (Xa)
581 (Xa)
2658 (Xa)—
581 (Xa)4643 (2335)——
4643 (2335)
4643 (2335)
—
—
—

—
—
—
—
—
—
—

PTx
Bone density

—
—
—
—
—
Jamal (2007)127
Jamal (2007)127
Miller (2005)126—
Jamal (2007)127
Miller (2005)126——
Miller (2005)126
Miller (2005)126
—
—
—

—
—
—
—
—
—
Miller (2005)126

—
—
—
—
—
—
4643 (2335)

—
—
—
—
—
—
25 months

Kidney International (2009) 76 (Suppl 113), S50–S99

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; GFR, glomerular filtration rate; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
N randomized may be higher than N analyzed.
aUnclear reporting regarding the number of individuals who received study drug.

Kidney International (2009) 76 (Suppl 113), S50–S99

Table 38 | Evidence profile of bisphosphonates vs placebo/control in CKD stages 3–5
Summary of findings
No. of studies
and study
designTotal N (Non study
drug)

Methodologicalquality of studies

Mortality—
Clinical CVD and CeVDb —All-cause hospitalization —CKD clinical outcomes —Quality of life
—

—
—
—
—
—

Fractures
Clinical

581 (?)

OutcomeRadiological

PTxBone density

Bone histology
Vascular/valvular
calcification
GFR loss

Consistency
across studies

Directness of theevidence generalizability/ applicability

Other considerationsa

Quality of evidence
for outcome

Qualitative and quantitativedescription of effectImportanceof outcome

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

CriticalCritical
High
High
High

Very serious
limitations (2)cSerious limitations
(1)f

NA

Some uncertaintyd

Sparse (1)eVery low

No statistically significant differenceHigh

No important
inconsistencies

Some uncertainty

d

None

Low

High

—
5224 (2335+?)—
Serious limitations(1)f—
No important
inconsistencies—
Some uncertaintyd

—
None

—
Low

Likely benefit. Benefit in MA andconsistent point estimate inadditional RCT—
Overall benefit in BMD in lumbar
and femoral sites

—
—

—
—

—
—

—
—

—
—

—
—

—
—

Moderate
Moderate

4643 (2335)

Serious limitations(1)gNo important
inconsistencies

Some uncertaintyd

None

Low

Overall no significantly greater loss ofkidney function over 12 years offollow-up

Moderate

1 MA of
9 RCTs4643 (2335)

NA

Some uncertaintyd

None

Low

NA

Some uncertainty

d

None

Low

—
—
—
—
—
CKD: 1 RCTs
Non-CKD:
Trials, Case
Reports,
Reviews, etc.

—
—
—
—
—
4643+ (2335+)

Serious limitations(1)gSerious limitations
(1)g
—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

—
—
—
—
—

1 RCT
1 MA of
9 RCTs +1 RCT—
1 MA of
9 RCTs +1 RCT——
1 MA of
9 RCTs3239 (?)

High
Moderate

Laboratory measurements
Calcium
Phosphorus
Ca  P
PTH
25 OH Vit D
1,25 Vit D
ALP, b-ALP
Adverse events

Balance of potential benefits and harm:
Benefits and harm cannot be determined with any certainty

No statistically significant difference
Moderate—————
In non-CKD patients, a number ofclinical and laboratory AEs, some ofthem potentially severe, have beenreportedh. Evidence from trials of
CKD patients is limited

Depends on
outcomeQuality of overall evidence:
Low for biochemical outcomes
Low for other surrogate outcomes
Absent for patient-centered outcomeschapter 4.3

S99

AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; BMD, bone mineral density; Ca  P, calcium–phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD,
cardiovascular disease; GFR, glomerular filtration rate; MA, meta-analysis; N, number of subjects; NA, not applicable; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial.
aOther considerations include imprecise or sparse data (1), high probability of reporting bias (1). For observational studies, other considerations include strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
bClinical cardiovascular and cerebrovascular disease.
c
One grade C.
d
The majority of patients in the studies were postmenopausal women with eGFR below 60 ml/min per 1.73 m2 and excluded those with known kidney disease or SCr 122 mmol/l (1.27 mg/dl) or 41.1 times the upper limit of normal.
e
One study with less than 1000 patients.
f
Two grade C.
g
One grade C.
h
GI upset, esophageal ulcers, bone pain, osteonecrosis of the jaw, osteomalacia, acute phase reaction to i.v. drugs (fever, myalgias, and transient leucopenia), atrial fibrillation, nephrotic syndrome, ocular inflammation, hypocalcemia,
increased PTH, and hyperphosphatemia.

chapter 5

http://www.kidney-international.org& 2009 KDIGO

Chapter 5: Evaluation and treatment of kidneytransplant bone disease
Kidney International (2009) 76 (Suppl 113), S100–S110; doi:10.1038/ki.2009.193

Grade for qualityof evidence

Grade for strengthof recommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (see Chapter 2 section on ungraded statements).

identified, it is reasonable to increase the frequencyof measurements to monitor for efficacy and sideeffects (not graded).
It is reasonable to manage these abnormalities as forpatients with CKD stages 3–5 (not graded) (seeChapters 4.1 and 4.2).

INTRODUCTION

As the number and survival of kidney transplant recipients
increase, new challenges arise for overall management.
Chronic kidney disease–mineral and bone disorder(CKD–MBD) is a common morbidity in patients with akidney transplant, and pre-existing CKD–MBD may adversely
affect bone health, even with normal kidney allograftfunction. In addition, most kidney transplant recipients havesome degree of CKD, and thus CKD–MBD may be present.
However, transplant-specific therapies, especially corticosteroids, may further affect CKD–MBD management.

5.3

5.4

RECOMMENDATIONS

5.1

5.2

In patients in the immediate post-kidney-transplant
period, we recommend measuring serum calcium
and phosphorus at least weekly, until stable (1B).
In patients after the immediate post-kidney-transplant period, it is reasonable to base the frequency ofmonitoring serum calcium, phosphorus, and PTH on
the presence and magnitude of abnormalities, andthe rate of progression of CKD (not graded).
Reasonable monitoring intervals would be:
K In CKD stages 1–3T, for serum calcium andphosphorus, every 6–12 months; and for PTH,
once, with subsequent intervals depending on
baseline level and CKD progression.
K In CKD stage 4T, for serum calcium and phosphorus,
every 3–6 months; and for PTH, every 6–12 months.
K In
CKD stage 5T, for serum calcium andphosphorus, every 1–3 months; and for PTH,
every 3–6 months.
K In CKD stages 3–5T, measurement of alkaline
phosphatases annually, or more frequently in thepresence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for CKD–
MBD, or in whom biochemical abnormalities are

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5.5

5.6

In patients with CKD stages 1–5T, we suggest that
25(OH)D (calcidiol) levels might be measured, andrepeated testing determined by baseline values andinterventions (2C).
In patients with CKD stages 1–5T, we suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for thegeneral population (2C).
In patients with an estimated glomerular filtration
rate greater than approximately 30 ml/min per 1.73 m2,
we suggest measuring BMD in the first 3 months after
kidney transplant if they receive corticosteroids or haverisk factors for osteoporosis as in the general population (2D).
In patients in the first 12 months after kidneytransplant with an estimated glomerular filtration
rate greater than approximately 30 ml/min per
1.73 m2 and low BMD, we suggest that treatment withvitamin D, calcitriol/alfacalcidol, or bisphosphonates
be considered (2D).
K We suggest that treatment choices be influenced
by the presence of CKD–MBD, as indicated byabnormal levels of calcium, phosphorus, PTH,
alkaline phosphatases, and 25(OH)D (2C).
K It is reasonable to consider a bone biopsy to guidetreatment, specifically before the use of bisphosphonates due to the high incidence of adynamic
bone disease (not graded).
There are insufficient data to guide treatment after
the first 12 months.
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5.7

5.8

In patients with CKD stages 4–5T, we suggest that
BMD testing not be performed routinely, because
BMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B).
In patients with CKD stages 4–5T with a known
low BMD, we suggest management as for patientswith CKD stages 4–5 not on dialysis, as detailed in
Chapters 4.1 and 4.2 (2C).

Summary of rationale for recommendations

The risk of fractures after kidney transplant is high.
The etiology of transplant bone disease is multifactorial
and most patients have pre-existing CKD–MBD.
K In non-kidney-transplant recipients, a low BMD or lossof BMD predicts fracture, but data are lacking for kidneytransplant recipients.
K There are no randomized controlled trial (RCT) data
examining bone-specific therapies on patient-level
outcomes, including mortality or fractures, in patients
receiving kidney transplantation.
K Treatment with calcium, calcitriol, or vitamin D analogs,
and/or bisphosphonates, has been suggested to improve
BMD in kidney transplant recipients. However, bonebiopsy studies are limited.
J A small study of calcitriol showed worsened boneturnover, but improved mineralization.
J A small study of treatment with bisphosphonates
showed worsened bone turnover and mineralization.
K It is unclear how to identify those kidney transplantpatients who would benefit more or less from specifictreatments, making it difficult to assess the risk–benefit
ratio of those treatments.
K The absence of RCTs that show fracture prevention andheterogeneity within post-kidney-transplantation bonedisease prevents the generalization of therapeutic strategies across patients and extrapolation from non-kidneytransplant studies. Therefore, this remains a weakrecommendation.
K
K

BACKGROUND
Biochemical abnormalities

Biochemical abnormalities are common after transplant, butless documented than in patients on dialysis. It is probably
useful to distinguish the time period immediately after
kidney transplant, with rapidly changing GFR and concomitantly given therapies, from the subsequent time period whena more stable graft function has been achieved. The
magnitude of CKD–MBD before transplant, the degree ofkidney function recovery, and the effects of immunosuppressive and other therapies create a heterogeneous patient
population. The scope and magnitude of the biochemical
abnormalities of CKD–MBD fluctuate dramatically in theearly post-transplant period compared with the late posttransplant period, the latter depending on the level of kidney
Kidney International (2009) 76 (Suppl 113), S100–S110

function. Hypophosphatemia occurs in a large proportion ofpatients immediately after transplantation, but once kidney
function has become stabilized, serum phosphorus returns to
the normal range in most of them. Serum calcium tends toincrease after transplant and then stabilizes at the higher endof the normal range within 2 months. PTH levels decreasesignificantly during the first 3 months after transplant but
typically stabilize at elevated values after 1 year. Low levelsof 1,25(OH)2D typically do not reach normal values until
almost 18 months after transplant.446 There are no large
databases in which these data are routinely collected andtherefore can be systematically evaluated. Thus, most reports
are single-center studies.
Bone

Abnormalities of bone are nearly uniformly observed, but the
etiology and pathology are widely variable. Post-transplantbone disease represents an important complication observedin a substantial proportion of patients. Early studies haveshown a rapid decrease in BMD in the first 6–12 months
after successful kidney transplantation, and continued loss—
albeit at a lower rate—for many years.447 As a consequence,
fractures are common and associated with substantial
morbidity.
The etiology of transplant bone disease is multifactorial.
Patients come to transplantation with pre-existing bonedisease of CKD (CKD–MBD), which is not always improvedby transplantation. In addition, new insults to bone occur,
including the potentially deleterious effects of various
immunosuppressive agents, the impaired kidney function(CKD) frequently observed in kidney transplant patients, andother factors particular to each patient, such as postmenopausal status, presence of diabetes, smoking, physicalactivity, and duration of dialysis and transplantation.448
Previous studies in kidney transplant patients have shown acorrelation between the cumulative dose of glucocorticoids
and BMD. On the basis of a few bone biopsy studies intransplant patients, glucocorticoids seem to be the primary
determinant of subsequent bone volume and turnover. Thus,
the cumulative and mean prednisone dose correlated
negatively with bone turnover, whereas there was nocorrelation with cyclosporine cumulative dose or serum
PTH.449 The possible role of calcineurin inhibitors, suchas cyclosporine or tacrolimus, remains incompletely
studied, with contradictory reports on their effects on boneturnover.449
Vascular calcification

Arterial calcification is also common after a kidneytransplant, but is often due to the effects of the uremic stateand dialysis rather than the transplant itself and, overall, ispoorly studied in this population. In renal transplant
recipients (CKD stages 1–5T), only one prevalence study
was identified, showing a prevalence of calcification of
24.4%.450 Although this cross-sectional study was large(n ¼ 1117), calcification was assessed by a posterio-anterior
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plain abdominal X-ray examination of the aorto-iliac
region, which is likely to be less sensitive than computed
tomography-based imaging methods and gives only semiquantitative information. In addition, one of the majordifficulties in interpreting calcification in the transplant
population is the carryover effect from CKD stage 5 or stage
5D. Currently, only one preliminary study is available,suggesting that the progression of cardiovascular calcification
may be halted after renal transplantation.451 Thus, muchremains to be learned.
The following tables are found at the end of this chapter:
Table 39 summarizes the RCTs of treatments in children withCKD (stages 1–5T). The evidence matrix, a table that
describes the methodologic quality of the included studies,and the evidence profile, a table that provides an overall
assessment of the quality of the evidence and balance ofpotential benefits and harm are Tables 40, 41 for calcitriol orvitamin D analogs; and Tables 42, 43 for bisphosphonates.
Studies of treatments for CKD-MBD in transplant recipients
reviewed for this topic are further described in detail in the
Supplementary Tables 46–53.

Reasonable monitoring intervals would be:
K In CKD stages 1–3T, for serum calcium andphosphorus, every 6–12 months; and for PTH,
once, with subsequent intervals depending on
baseline level and CKD progression.
K In CKD stage 4T, for serum calcium and phosphorus,
every 3–6 months; and for PTH, every 6–12 months.
K In CKD stage 5T, for serum calcium and phosphorus,
every 1–3 months; and for PTH, every 3–6 months.
K In CKD stages 3–5T, measurement of alkaline
phosphatases annually, or more frequently in thepresence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for CKD–MBD,
or in whom biochemical abnormalities are identified, it is reasonable to increase the frequencyof measurements to monitor for efficacy and sideeffects (not graded).
It is reasonable to manage these abnormalities asfor patients with CKD stages 3–5 (not graded) (seeChapters 4.1 and 4.2).

RATIONALE

5.1

In patients in the immediate post-kidney-transplant
period, we recommend measuring serum calcium
and phosphorus at least weekly, until stable (1B).

Similar to what has been described for CKD stage 3–5 patientswith CKD–MBD, in kidney transplant recipients, serum levelsof calcium, phosphorus, total CO2, and PTH should be closely
monitored in all patients regardless of graft function. During
the first week after kidney transplantation, serum levels of
calcium and phosphorus should be measured at least weekly.
Many, if not most, kidney transplant recipients develop
persistently low levels of serum phosphorus (o3.1 mg/dl
or 1.0 mmol/l) in the post-transplant period. They should
be considered for treatment with phosphate supplementation. However, phosphate administration is not withoutrisk, and caution should be exerted, as it may exacerbate an
already existing secondary hyperparathyroidism (HPT).
Therefore, every attempt should be made to prescribe theminimum doses. Patients with severe secondary HPT before
the transplant will continue to have excessive PTH secretionfrom large hyperplastic glands. With a new kidney, there will
now be enhanced renal reabsorption of calcium
and hypercalcemia may ensue. Also, there will be reduced
tubular phosphate reabsorption. Thus, during the immediate
post-transplant period, wide fluctuations of serum calcium
and phosphorus may be seen and thus frequent monitoringis needed.
5.2

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In patients after the immediate post-kidney-transplant period, it is reasonable to base the frequency ofmonitoring serum calcium, phosphorus, and PTH on
the presence and magnitude of abnormalities, andthe rate of progression of CKD (not graded).

Patients with a kidney transplant usually have some degreeof CKD and, therefore, CKD–MBD may be present. However, there are no clinical trials that have specificallyaddressed the optimal frequency of monitoring in the CKDor CKD transplant population. Thus, on the basis of theprevalence of abnormalities and the risks associated withthose abnormalities, the management of the biochemical
abnormalities of CKD–MBD after transplant should be
similar to that proposed for nontransplant CKD.
A recent study of 303 kidney transplant recipients in the
United States found that 11–25% of patients had abnormal
serum calcium or CaXP in the first year after transplant, and
24% of recipients with an eGFR between 40 and 60 ml/min per
1.73 m2 had intact PTH levels 4130 pg/ml (13.8 pmol/l) at 1
year after kidney transplant.452 Another series from the United
Kingdom453 evaluated 244 kidney transplant recipients: 104 in
the first year, and the remainder more than 1 year after
transplant. Hypercalcemia was present in 40% of recently transplanted recipients and 25% of long-term patients. Hypophosphatemia was very common in the immediate post-transplant
period, but normalized within the first year in most series,
although a urinary phosphate leak often remained despite
normal serum levels.454 A larger cohort from Switzerland455
evaluated 823 kidney transplant recipients, on average 7 years
after transplant. They found that only 27% of the population had a PTH within normal range (that is, 15–65 pg/ml(1.6–6.9 pmol/l)), whereas 70% had HPT (PTH465 pg/ml(46.9 pmol/l)) and 2.8% were hypoparathyroid (PTH
o15 pg/ml (o1.6 pmol/l)). Serum phosphorus was within
normal range in 74% of the patients (0.85–1.45 mmol/l), andincreased in only 3.6% of the patients. Finally, serum calcium
was within normal range in most patients (85.9%), with
only 2.8 and 11.3% of the patients being hypocalcemic andKidney International (2009) 76 (Suppl 113), S100–S110

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hypercalcemic, respectively. Thus, disorders of mineral metabolism may persist many years after transplantation.
There is a paucity of data describing the risk relationship ofbiochemical abnormalities of CKD–MBD and mortality inpatients after kidney transplantation. A study in Austria of 773
patients with kidney transplant found no relationship between
serum calcium, phosphorus, or PTH and mortality.456
However, they did find that patients with the highest quintileof phosphorus had increased risk of kidney allograft loss.
Similarly, those with the highest quintile of calcium also had
increased risk of kidney allograft loss, which is similar to otherreports in which hypercalcemia was associated with both graft
loss and recipient death.452 Clearly, more data are needed to
fully understand the possible significance of these relationships.
From a management perspective, there are no RCTs thatspecifically enrolled transplant recipients who met our
inclusion criteria. Thus, approaches similar to those in
nontransplant CKD should be taken, with some special
considerations. Hypercalcemia after kidney transplantation isusually due to HPT that persists from the preceding CKD
period. Increased serum calcium concentration can persist for
years after transplantation. In patients with nonsuppressible
nodular parathyroid hyperplasia, persistently elevated PTHlevels after restoration of normal renal function with atransplant may have a primary role in maintaining a highbone turnover. Parathyroid gland hyperplasia, especiallyautonomous parathyroid growth, does not easily resolve after
establishment of sufficient renal function, except in mild cases
or when secondary to vitamin D deficiency. In 30–50%
of transplant recipients, abnormal PTH secretion persists.
When it causes hypercalcemia, it may require parathyroidectomy.457460 In general, the same principles we have discussed for the management of patients with CKD stages 3–5
with CKD–MBD will apply for patients with CKD stages 3–5T.
5.3

In patients with CKD stages 1–5T, we suggest that
25(OH)D (calcidiol) levels might be measured, andrepeated testing determined by baseline values andinterventions (2C).

25(OH)D levels were measured in 244 renal transplant
recipients and divided into two groups: 104 recently transplanted (less than 1 year) and 140 long term.453 Vitamin D
insufficiency (15–30 ng/ml or 40–75 nmol/l) was present in 29
and 43% of recent and long-term kidney transplant recipients,
deficiency (4.8–15.6 ng/ml or 12–39 nmol/l) in 56 and 46%, andsevere deficiency (o4.8 ng/ml or 12 nmol/l) in 12 and 5%,
respectively. Thus, vitamin D deficiency is common after
transplant, and an initial assessment of status is reasonable.
5.4

In patients with CKD stages 1–5T, we suggest thatvitamin D deficiency and insufficiency be correctedusing treatment strategies recommended for thegeneral population (2C).

Vitamin D deficiency and insufficiency are associated withcardiovascular disease, autoimmune disorders, malignancies,
Kidney International (2009) 76 (Suppl 113), S100–S110

bone disease and musculoskeletal weakness, and insulin
resistance.461 Unfortunately, there are no RCTs of vitamin D
supplementation in patients with a kidney transplant evaluating end points other than bone health (see recommendation
5.6 for bone health). However, given the magnitude of vitamin
D deficiency and the high prevalence of many of the disorders
associated with vitamin D deficiency in the general population,
the Work Group felt that it was reasonable to treat deficiency, if
found. Thus, supplementation with either ergocalciferol orcholecalciferol is recommended, but the optimal treatment
regimen is not known,462 and neither is the sufficient level ofcalcidiol well defined (see Chapter 3.1). It is also important topoint out that the primary source of vitamin D is sunlight, andthat the increased risk of skin cancer in kidney transplantpatients mandates the use of appropriate sun-screen protection, further increasing the need for oral intake of vitamin D.463
5.5

In patients with an estimated glomerular filtration
rate greater than approximately 30 ml/min per
1.73 m2, we suggest measuring BMD in the first 3
months after kidney transplant if they receive
corticosteroids, or have risk factors for osteoporosis
as in the general population (2D).

Post-transplant bone disease is a complex disorder that
extends beyond simple alterations in BMD. It includes
systemic and local derangements of bone and mineralmetabolism that can be detected and treated appropriately.
The management of bone disease after kidney transplantation
should take into account its pathophysiology, with particularfocus on three different phases: (i) optimal treatment of
CKD–MBD before kidney transplantation; (ii) prevention ofbone loss during the first year after transplantation; and (iii)
treatment of decreased bone mass thereafter.
There are no studies that directly address fracture
prevention, hospitalizations, or mortality related to
CKD–MBD in kidney transplant recipients. There is only
one study that shows low BMD, as assessed by dual energy
X-ray absorptiometry (DXA), to be predictive of fracture risk
in kidney transplant recipients. This recent study evaluated
238 renal transplant patients with CKD stages 1–5T who
underwent 670 DXA investigations of the hip. Fractures wereassessed by a questionnaire. Osteopenia and an absolute bonedensity below 0.9 g/cm2 in the hip region conferred anincreased risk of fracture.464 However, the Work Group feltthat this study was inadequate to determine whether DXA
had a high enough predictive value of fracture to be routinely
used, because of the bias of repeated DXA evaluations
counted as independent measures and the nonsystematic
assessment of fractures. It is worth noting that reductions in
BMD have been associated with an increased fracture rate instudies of osteoporosis in women in association with postmenopausal status, in men treated with glucocorticoids, andin heart- or liver-transplant recipients. However, the etiology
of post-transplant kidney bone disease is likely influenced by
CKD–MBD from the pretransplant dialysis period, andongoing CKD–MBD after transplant, given that most patients
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have some impairment of kidney function. Thus, the studies
from the general population and other solid organ transplantation may not be generalizable to the kidney transplant
population. In addition, there are no treatments in thesepatients that show fracture reduction (see Recommendation
5.6). Thus, the Work Group felt that DXA should be reservedfor high-risk populations, including those receiving significant doses of corticosteroids, or those with risk factors forosteoporosis in the general population (see Chapter 3.2). In
addition, the Work Group felt that DXA screening after
transplant should only be done in individuals with a wellfunctioning allograft (CKD stages 1–3T), as patients withCKD stages 4–5T will be more likely to have abnormal bonequality from CKD–MBD, with unknown impact on thepredictive value of DXA.
5.6

In patients in the first 12 months after kidneytransplant with an estimated glomerular filtration
rate greater than approximately 30 ml/min per
1.73 m2 and low BMD, we suggest that treatment
with vitamin D, calcitriol/alfacalcidol, or bisphosphonates be considered (2D).
K We suggest that treatment choices be influenced
by the presence of CKD–MBD, as indicated byabnormal levels of calcium, phosphorus, PTH,
alkaline phosphatases, and 25(OH)D (2C).
K It is reasonable to consider a bone biopsy to guidetreatment, specifically before the use of bisphosphonates due to the high incidence of adynamic
bone disease (not graded).
There are insufficient data to guide treatment after
the first 12 months.

As detailed below, unfortunately, there are no RCTs thatshow the beneficial or harmful effects of bone-protective
agents on patient-level outcomes, in particular fractures,
hospitalizations, or mortality. Studies that examined theeffects of calcitriol or vitamin D analogs to prevent transplantbone disease found an improvement in BMD and no adverse
events (AEs) of bone.465468 Studies that examined the effectsof bisphosphonates to prevent transplant bone disease found
an improvement in BMD,165,469 but possible AEs of bone
histology, increasing the risk of adynamic bone disease.469
There are only inconsistent or low-quality data showing
positive effects of vitamin D, calcitriol, vitamin D analogs,
or bisphosphonates on BMD in established transplant bonedisease.470,471 Given that BMD is not a well-validated surrogate marker of fracture risk in the transplant patient (and is
not even an accepted end point for drug treatments in thegeneral population), and that no studies evaluate fracture as
an end point in transplant recipients, this recommendation
can only be weak. In addition, clinicians should be aware of
the complexity and heterogeneity of transplant bone diseaseand consider the use of bone biopsy and other biochemical
abnormalities of CKD–MBD to guide therapeutic choices
rather than only focusing on DXA.
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Preventive therapy
Use of vitamin D, calcitriol, and its analogs.

Each of the trials
in which vitamin D, calcitriol, or its analogs were administered as preventive therapy assessed changes in BMD as theprimary outcome.
There were no studies evaluating vitamin D therapy
specifically in kidney transplant recipients that met our
inclusion criteria, but a meta-analysis published in 1999, in
patients treated with steroids for multiple reasons, supported
efficacy in improving BMD of the lumbar spine.465 Thismeta-analysis compared all RCTs lasting at least 6 months(and reporting extractable results) of patients receiving oralcorticosteroids and treated with vitamin D. The study founda moderate beneficial effect of vitamin D plus calcium vs no
therapy or vs calcium alone (nine trials: effect size 0.60; 95%
CI 0.34, 0.85; Po0.0001). In a comparison of vitamin D withother osteoporosis therapies, bisphosphonates were more
effective than vitamin D (six trials: effect size 0.57; 95% CI
0.09, 1.05). Thus, the Work Group felt that vitamin D
supplementation is a reasonable and safe treatment choice forpatients with low BMD.
In three studies in renal transplant recipients,466–468 apositive change in BMD was observed in the calcitriol andalfacalcidol groups vs the ‘no treatment’ or placebo groups.
No fracture data were recorded in any of these studies. The
RCTs are detailed in Tables 40, 41 and Supplementary Tables
46–49. No clinically important clinical outcomes such asmortality, hospitalizations, or fractures were evaluated. Only
BMD as a surrogate marker for fractures was determined. In
addition, most of the studies either lacked or did not define
randomization, or there were inconsistencies between the
text and the tables. Some studies did not provide any baseline
data or the data were incomplete. Thus, the overall quality ofthe evidence was classified as low. As reported, no significant
AEs were observed, except for mild hypercalcemia in the
study by Josephson et al.468 No patients were withdrawn fromthe study because of secondary effects. No deleterious effecton kidney graft function was observed.
Bisphosphonates. Two studies in 152 patients evaluatedthe role of bisphosphonates as preventive therapy after
kidney transplantation (Tables 42, 43; Supplementary
Tables 50–53).
Protocols between the studies were different, making overall
comparisons nearly impossible. In the study of Coco et al.,469
patients received IV pamidronate at baseline and at 1, 2, 3, and6 months after transplantation. Rapid decrease of lumbar
spine BMD was prevented in the pamidronate group. Nochanges in hip BMD were observed. There were no differencesin the number of fractures between the groups after 1 year. The
bone biopsy data are detailed below. The second study by
Grotz et al.165 evaluated IV ibandronate at baseline and at 3, 6,
and 9 months after transplantation. Loss of trabecular andcortical bone assessed by BMD was prevented by ibandronate.
Fewer vertebral deformities by X-ray were observed in theibandronate group than in the controls. No significant side
effects or decreased GFR were reported.
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In the study by Coco et al.,469 bone biopsies were
performed at the time of transplant in 21 patients and in
14 patients after 6 months, six in the pamidronate group andeight in the control group. The mean activation frequency
after 6 months was significantly lower in the pamidronatetreated patients than in the controls. All of the pamidronate
patients had adynamic bone disease on the 6-month biopsy;
four patients with initial HPT and one with mixed uremic
osteodystrophy developed adynamic disease. In the control
group, three of eight patients had adynamic bone disease andthe rest were mixed. The bone turnover improved in five ofeight (62%) patients among the control biopsies and in noneof the pamidronate biopsies. It worsened in one control
biopsy (12%) and in five of six (83%) pamidronate biopsies.
Mineralization lag time determination was not available forthe first biopsy. In the second biopsy, three subjects had
prolonged mineralization lag time, indicating either osteomalacia or very little tetracycline uptake. In the control
group, none of the biopsies had increased osteoid thickness,
although several had elevated mineralization lag time. The
data provided do not allow a clear interpretation ofmineralization. Mean bone volume was normal in bothgroups. In the pamidronate group, there was no change frombaseline. The mean bone volume in the control groupdecreased from 28.6 to 25.7 (10%), but this was not
significant. Overall, the histology suggests development ofadynamic bone disease in these patients, but the results arelimited by a small number of subjects with a short follow-up
time. It is also not clear whether the potential benefit frompreserving bone volume and fracture reduction outweighs
the potential harm of decreased bone formation and/or
prolonged mineralization.
Overall, the quality of the preventive studies withbisphosphonates was ranked as moderate. Some of thestudies showed limited fracture data and/or bone biopsy
information. The observation in the study by Coco et al. thatpatients showed early evidence and progression to adynamic
bone disease in some patients should raise caution about theindiscriminate use of bisphosphonates in renal transplantpatients.

suppression of serum PTH, together with an increase inserum calcium (but within normal limits), as compared with
the no-treatment group. The bone biopsy results showed thatbone turnover was better in 43% of the control biopsies and
12% of the calcitriol biopsies, but worse in 28% of the control
biopsies and 50% of the calcitriol biopsies. The study also
described a decrease in osteoclast surfaces that represents asecondary index of turnover. Therefore, if a decrease in theosteoclast surface is accompanied by a drop in the boneformation rate into the adynamic range, then the overallturnover is worse.
No evidence of AEs was recorded with respect to changes
in serum calcium, phosphorus, or intact PTH. No patientswere withdrawn from the study because of AEs. A gradualdecrease in GFR assessed by creatinine clearance wasobserved in both the control and treatment groups.
Bisphosphonates. Only one study examined the effect ofbisphosphonates in long-term kidney transplant patientswith established osteopenia or osteoporosis (Tables 42, 43).
Jeffery et al. evaluated 117 patients with reduced BMD(T score p1). Patients were randomized to daily oralalendronate and calcium vs calcitriol and calcium.471 There
was no untreated control group in this study. One year oftherapy was completed by 90 patients. Both treatments
showed significant increases in lumbar spine and femur
BMD. No differences between groups were shown. No
information was provided on the number of patients who
did not finish the study. No significant AEs or alterations in
kidney function were reported. The quality of evidence of thisstudy was ranked between moderate and low.
In a recent, nonrandomized controlled study byConley et al., the use of bisphosphonates was retrospectively
evaluated in 554 kidney transplant patients who had
at least two BMD analyses. Patients who received bisphosphonates after the first year of transplantation showed
improved BMD, but did not have a reduced fracture rate
when compared with those who did not receive theantiresorptive agents.472
Thus, the Work Group could not make any recommendations for long-term treatment strategies.

Long-term treatment
Calcitriol. There was only one study in long-term renal

SPECIAL CONSIDERATIONS IN CHILDREN

transplant patients (those patients 412 months fromtransplant) that evaluated the effect of calcitriol plus calcium
carbonate vs no treatment (Tables 40, 41).470 This study
enrolled 45 patients, with only 30 of them completing thetrial. This RCT met our inclusion criteria because bonebiopsies were an evaluated end point. The mean time after
transplantation was 118.7 months in the treatment group and
133 months in the control group. Although significant
improvement in BMD was observed after 1 year in thetreatment group, no differences were observed between thetreatment and nontreatment groups. No fracture data werereported. Thus, the overall quality of the evidence is low. After
1 year of treatment, patients in the treatment group had a
Kidney International (2009) 76 (Suppl 113), S100–S110

One study reviewed treatments provided to 60 pediatric renaltransplant patients (CKD stages 1–5T).473 In this four-arm
study (see Table 39), the effect of alfacalcidol±calcitonin on
BMD, as assessed by DXA, and on selected biochemicalmarkers was compared to that of alendronate. No differenceswere found. No fracture data were collected. Another 30
patients from the same investigators were given either
alfacalcidol or placebo therapy and DXA, and selectedbiochemistries were assessed.474 It is not clear whether thesepatients were separate from those reported in the first study
cited above. Again, there were no differences in outcomes.
Given the paucity of data about CKD stages 1–5T, andthe inherent inaccuracy in the use of DXA in pediatric
CKD, there is insufficient evidence to recommend specific
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treatments for post-transplant renal bone disease in children
at this point in time.
5.7

In patients with CKD stages 4–5T, we suggest that
BMD testing not be performed routinely, because
BMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B).

In patients with CKD stages 4–5T, there is an increased
likelihood of more severe underlying bone abnormalities of
CKD–MBD that further decrease the utility of DXA indetermining the underlying bone disorder. The data
supporting routine use of DXA in a well-functioning
allograft are weak (see above), and thus the Work Groupfelt that the additional confounder of CKD–MBD did notallow a recommendation for routine use of DXA in thesepatients.
5.8

In patients with CKD stages 4–5T with known low
BMD, we suggest management as for patients withCKD stages 4–5 not on dialysis, as detailed in
Chapters 4.1 and 4.2 (2C).

Despite not recommending routine DXA in patients withCKD stages 4–5T, the Work Group acknowledged that thesepatients might still have undergone such an assessment.
When the DXA reveals low BMD, the patients should befully evaluated and managed as for patients without akidney transplant as detailed in Chapters 4.1 and 4.2.
Importantly, these patients should be referred to as having
low BMD, as opposed to osteoporosis,475 as the latter term
often leads to treatments as in the general population withosteoporosis such as bisphosphonates. However, bisphosphonates can decrease bone turnover and therefore may
theoretically worsen adynamic bone disease. As detailed in
Chapters 3.2 and 4.3, bisphosphonates accumulate in bone
for many years, and thus patients should be evaluated with abone biopsy to ensure normal turnover before their use.

RESEARCH RECOMMENDATIONSProspective studies in patients with CKD stages 3–5T shouldbe performed to determine the level of BMD that ispredictive of fractures and whether or not the predictive value
is affected by other parameters of CKD–MBD, such as HPT.
K RCTs should be performed in patients with CKD stages
3–5T with low BMD at the time of kidney transplant toevaluate the effects of bisphosphonates or calcitriol andvitamin D analogs. The study should be of sufficient time(at least 1 year) to evaluate the effect on BMD change andpatient-level outcomes, such as hospitalization, fractures,
all-cause mortality, cardiovascular morbidity and mortality, and quality of life.
K RCTs should be performed in patients with CKD stages
3–5T with low serum calcidiol levels at the time of kidneytransplant to evaluate the effect of vitamin D supplementation on change in BMD and patient-level outcomes, such as
all-cause mortality, hospitalization, fracture, cardiovascularmorbidity and mortality, and quality of life.
K

SUPPLEMENTARY MATERIAL
Supplementary Table 46. Summary table of RCTs examining treatment of
CKD–MBD with calcitriol or vitamin D in CKD stages 1–5T—description of
population at baseline.
Supplementary Table 47. Summary table of RCTs examining treatment of
CKD–MBD with calcitriol or vitamin D in CKD stages 1–5T—intervention
and results.
Supplementary Table 48. Summary table of RCTs examining treatment of
CKD–MBD with calcitriol or vitamin D in CKD stages 1–5T—bone biopsy results.
Supplementary Table 49. Adverse events of vitamin D, calcitriol, or vitamin
D analogs in CKD stages 1–5T.
Supplementary Table 50. Summary table of RCTs examining treatment of
CKD–MBD with bisphosphonates vs control or calcitriol in CKD stages
1–5T—description of population at baseline.
Supplementary Table 51. Summary table of RCTs examining the treatment
of CKD–MBD with bisphosphonates vs control or calcitriol in CKD stages
1–5T—intervention and results.
Supplementary Table 52. Summary table of RCTs examining the treatment
of CKD–MBD with bisphosphonates vs control or calcitriol in CKD stages
1–5T—bone biopsy results.
Supplementary Table 53. Adverse events of bisphosphonates in CKD
stages 1–5T.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/kiTable 39 | RCTs of treatments for CKD–MBD in children with CKD stages 1–5TAuthor (year)

N

Population

F/U

Study design

Arm 1 (arm 3)

Arm 2 (arm 4)

Outcomes473

El-Husseini (2004)60

CKD 1–5T

12 months

RCT

El-Husseini (2004)474

30

CKD 1–5T

12 months

RCT

Alfacalcidol(calcitonin)
Alfacalcidol

Alendronate(control)Control

DXA, Biochemicalmarkers
DXA, Ca, P, PTH, CrCl

CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; CrCl, creatinine clearance; DXA, dual energy X-ray absorptiometry; F/U, follow-up;
N, number of subjects; PTH, parathyroid hormone; RCT, randomized controlled trial.

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Kidney International (2009) 76 (Suppl 113), S100–S110

Kidney International (2009) 76 (Suppl 113), S100–S110

Table 40 | Evidence matrix of calcitriol or vitamin D analogs vs placebo or calcium alone in CKD stages 1–5T
Methodological quality
A

B

AuthorN (onagent)

F/U

Mortality
Clinical CVD
Hospitalization
CKD clinical outcomes

—
—
—
—

—
—
—
—

QoL
Fractures——

PTx
Bone density

C

Adverse event reporting

AuthorN(on agent)

F/U

—
—
—
—

—
—
—
—

—
—
—
—

—
—
—
—

—
—
—
—

—
—
—
—

—
—
—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
Torres(2004)467 a—
90 (45)—
12 months——
113 (65) 6 months

Bone histology

—

—

—

—

—

—

Vascular/valvular
calcification
GFR loss

—

—

—

—

—

—

—
De Sevaux(2002)466 a
Josephson (2004)468 a
Cuento-Manzano(2000)470 b
—

—

—

—

—

—

—

Lab: Ca, P, PTH,
ALP, b-ALP

—

—

—

De Sevaux(2002)466 a
Torres(2004)467 a
Torres(2004)467 a

113 (65)

6 months

De Sevaux (2002)466 a
Torres (2004)467 a—

113 (65) 6 months
90 (45) 12 months——

90 (45)

12 months

90 (45)

12 months

Outcome

Lab: Bicarbonate
Adverse events

—

—

—

N (on
agent)

Author—F/UN(on agent) F/U

Author———De Sevaux (2002)466 a
Torres (2004)467 a
Cuento-Manzano(2007)470 b—
De Sevaux (2002)466 a
Torres (2004) 467 a
Cuento-Manzano(2000)470 b
—
—

—
—
—
113 (65)
90 (45)45 (23)———6 months
12 months
12 months—
113 (65)
90 (45)45 (23)—6 months
12 months
12 months

—
—

—
—

64 (26)30 (16)

12 months
12 months

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

De Sevaux (2002)466 a
Torres (2004)467 a
Josephson (2004)468 a
Cuento-Manzano(2000)470 b

113 (65)
90 (45)64 (26)45 (23)——6 months
12 months
12 months
12 months

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chapter 5

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; GFR, glomerular filtration rate; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
Note: Number randomized may be higher than number analyzed; this evidence matrix does not include studies of cholecalciferol vs control in CKD stages 1–5T (refer to summary table entry for Wissing, 2005).
a
Early post-transplant (prevention).
bLong-term kidney transplant recipients.

Outcome
Mortality
Clinical CVD andCeVDAll-cause
hospitalization
CKD clinicaloutcomes
Quality of life
Fractures
PTx
Bone density
Bone histology

Vascular/valvular
calcification
GFR loss

Summary of findings

Number of studies
and study design

Total N (N onstudy drug)

Methodologicalquality of studies

Directness ofthe evidence
Consistency across generalizability/
studiesapplicability

—
—

—
—

—
—

—
—

—
—

—
—

—
—

—
—

CriticalCritical

—

—

—

—

—

—

—

—

High

Very low

Unable to assess

High

Other
considerationsb

Quality ofevidence foroutcomeQualitative and quantitative description of Importance ofeffectoutcome—- - - - - - - - - - —- - - - - - - - -—- - - - - - - - - - —- - - - - - - - - - -—- - - - - - - - - - —- - - - - - - - - AEs from 3 RCTs
248 (133)
Very serious———
limitations (2)
—
—
—
—
—
—
—
—
—
—
—
—
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - AEs from 2 RCTs
203 (110)
Very serious———
limitations (2)
—
—
—
—
—
—
No major
Direct—3 RCTs (early)
267 (135)
Very seriouscinconsistencies
limitations (2)NA
DirectSparse data
1 RCT (LT)30 (16)
Very serious
limitations (2)c

—

—

High

Very Low

Unable to assess

High

—
Low

—
High
Two studies showed statistically significant Moderate
improvement of BMD. One was inconclusive
Calcitriol caused more adynamic disease
Moderateand placebo showed more improvement inturnover. Mineralization better with calcitriol,
therefore overall results are complex—
Moderate

Very low

—

—

—

—

—

—

—

2 RCTs (early)

203 (110)

Very serious
limitations (2)dNA

Direct—Low

Serious limitations(1)eSerious limitations(1)e—Serious limitations(1)eSerious limitations(1)eSerious limitations(1)g

No majorinconsistencies
No majorinconsistencies—
No majorinconsistencies
No majorinconsistencies
NA

Direct—Moderate

Direct—Moderate—
Directf———
Moderate

Direct—Moderate

DirectSparse data

Low

Similar levels of CrCl at 6 months or
1 yearModerate

Laboratory measurements
Calcium

2 RCTs (early)

203 (110)

Phosphorus

2 RCTs (early)

203 (110)Ca  PPTH—
2 RCTs (early)—
203 (110)

ALP, b-ALP

2 RCTs (early)

203 (110)Bicarbonate

1 RCT (early)

90 (45)Adverse events

3 RCTs (early)
1 RCT (late)

267 (135)
30 (16)

Kidney International (2009) 76 (Suppl 113), S100–S110

Balance of Potential Benefits and Harm:
No evidence of benefit
Potential for hypercalcemia

Two studies show no difference in Ca, P, or
ALP. One study showed no change in PTH,
the other showed lower PTH with treatment. Moderate
One study showed no difference inbicarbonate

Hypercalcemia was seen more in treatment Depends on
outcomearms in two studies and lead to a 3%
discontinuation on one of the studies. No
conclusions can be made with any certainty
regarding graft function, acute rejection, newfractures or bone symptoms
Quality of Overall Evidence:
Moderate for biochemical outcomes
Low for other surrogate outcomes
Absent for patient-centered outcomes

AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; BMD, bone mineral density; CaXP, calcium-phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CrCl,
creatinine clearance; CVD, cardiovascular disease; GFR, glomerular filtration rate; LT, long term; N, number of subjects; NA, not applicable; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT, randomized controlled trial.
aThis evidence profile does not include studies of cholecalciferol vs control in CKD stages 1–5T (refer to summary table entry for Wissing, 2005).
b
Other considerations include: Imprecise or sparse data (1), high probability of reporting bias (1). For observational studies: other considerations include: strong association (+1 or +2), dose–response gradient (+1), all plausible
confounders would have reduced the effect (+1).
c
One grade B, two grade C.
d
Two grade C.
e
Two grade B.
f
However, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.
g
One grade B.

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Table 41 | Evidence profilea of calcitriol or vitamin D analogs vs placebo or calcium alone in CKD stages 1–5T

Kidney International (2009) 76 (Suppl 113), S100–S110

Table 42 | Evidence matrix of bisphosphonates vs control in CKD stages 1–5T
Methodological quality
A
OutcomeMortality
Clinical CVD
Hospitalization
CKD clinical outcomes
QoL
Clinical fractures
Radiological fractures

AuthorB

N (on agent)

F/U

—
—
—
—
—
—
—

N (on agent)

—
—
—
—
—
—
—

—
—
—
—
—
—
—

PTx
Bone density
Bone histology
Vascular/valvular
calcification
GFR loss—
Grotz (2001)165———
80 (40)
—
—

—

—

—

—

—

Lab: Ca, P, PTH

—

—

—

Lab: ALP, b-ALP

—

—

—

Grotz (2001)165
Coco (2003)469
Grotz (2001)165
Coco (2003)469

80 (40)72 (36)80 (40)72 (36)Adverse events

—
—
—
—
—
—
—

AuthorC——
12 months Coco (2003)469—
Coco (2003)469
—
—

—
—
—
—
—
—
—
—
50 (Xa)50 (Xa)—F/U

Author

—
—
—
—
—
—
—

Adverse event reporting

N (on agent)

F/U

Author165

N (on agent)

F/U

80 (40)——80 (40)———

12 months——
12 months
—
—
—

—
—
—
—

—
—
—
—

—
—
—
—
—
Grotz (2001)165
Grotz (2001)165
Coco (2003)469——
12 months—
12 months
—
—
—

—
—
—
—
—
80 (40)80 (40)72 (36)—————Grotz (2001)
—
—
—
—
—
Grotz (2001)165——
12 months—
12 months—
12 months
—
—
—
—
—
—
—
—

Grotz (2001)165
Coco (2003)469
12 months—
12 months
12 months—
12 months

80 (40)72 (36)—

12 months
12 months
—

—

—

—

—

—

—

—

—

—

—

—

Grotz (2001)165
Coco (2003)469

80 (40)72 (36)

12 months
12 months—

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, follow-up; GFR, glomerular filtration rate; N, number of subjects; PTH, parathyroid hormone;PTx, parathyroidectomy; QoL, quality of life.
Note: N analyzed may be less than N randomized; This evidence matrix does not include studies of bisphosphonate vs vitamin D in CKD stages 1–5T (refer to summary table entry for Jeffery, 2003).
aUnclear reporting regarding the number of individuals who received study drug.

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Outcome

Number ofstudies andstudy design

Total N (N onstudy drug)

Methodologicalquality of studies

Mortality

AE from 1 RCT

80 (40)Consistency acrossstudies

Directness of theevidence
generalizability/
applicability——

Summary of findings
Otherconsiderationsb

Quality ofevidence foroutcomeQualitative and quantitativedescription of effectImportanceof outcome—

Very low

Unable to assess

Critical——Very serious
limitations (2)
—

—

—

—

—

—

Critical

—

—

—

—

—

—

—

—

High

AE from 1 RCT

80 (40)——

Very low

Unable to assess

High

—

Very serious
limitations (2)
—

—

—

—

—

—

—

—

High

Very serious
limitations (2)dVery serious
limitations (2)e—Serious limitations
(1)g
—

NA

DirectSparse data

Very low

Unable to assessHigh

No majorinconsistenciesf—
No majorinconsistencies—

DirectSparse data

Very low

Unable to assess

High—
Direct———Moderate

High
Moderate

—

—

—

—

—

—

—

—

—

—
Treatment arms show improvement in BMD
at different sites. Effect size is variable
Pamidronate biopsies developed adynamic
bone but volume was slightly better—

Moderate

152 (76)

Serious limitations(2)hNo majorinconsistencies

Direct—Low

Similar levels of CrCl at 1 year

Moderate

152 (76)

Serious limitations(1)i
Serious limitations(1)jSerious limitations(1)i—
Serious limitations(1)i

No majorinconsistencies
No majorinconsistencies
No majorinconsistencies—

Direct—Moderate

No significant difference over 1 year
follow-up

Moderate

One study in early transplant shows astatistically significant reduction in acuterejection episodes with ibandronate vs Ca.
Trend toward greater GI discomfort withbisphosphonates compared with control

Depends on
outcomeClinical CVD andCeVDc
All-cause
hospitalization
CKD clinicaloutcomes
Quality of life
Fractures
Clinical

1 RCT

80 (40)Radiological

2 RCTs152 (76)

PTx
Bone density—
2 RCTs—152 (76)

Bone histology

1 RCT

50 (X)

Vascular/ valvular
calcification
GFR loss—
2 RCTsModerate

Laboratory measurements
Calcium

2 RCTsPhosphorus

2 RCTs152 (76)PTH

2 RCTs152 (76)

CaXP
ALP, b-ALP—
2 RCTs—152 (76)

Adverse events

Kidney International (2009) 76 (Suppl 113), S100–S110

Balance of Potential Benefits and Harm:
Evidence regarding benefit of bisphosphonates in BMD at different sites
No evidence demonstrating a difference in GFR loss, Ca, P or PTH
Limited data showing association with acute rejection or GI discomfort

Direct—Moderate

Directk—

Moderate———
Moderate

Quality of Overall Evidence:
Moderate for biochemical outcomes
Moderate for other surrogate outcomes
Absent for patient-centered outcomes

AE, adverse event; ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; BMD, bone mineral density; CaXP, calcium-phosphorus product; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CKD–MBD, chronic kidneydisease-mineral and bone disorder; CrCl, creatinine clearance; CVD, cardiovascular disease; GFR, glomerular filtration rate; GI, gastrointestinal; N, number of subjects; NA, not applicable; PTH, parathyroid hormone; PTx, parathyroidectomy; RCT,
randomized controlled trial.
aThis evidence profile does not include studies of bisphosphonate vs vitamin D in CKD stages 1–5T (refer to summary table entry for Jeffery, 2003).
b
Other considerations include: Imprecise or sparse data (1), high probability of reporting bias (1). For observational studies: other considerations include: strong association (+1 or +2), dose–response gradient (+1), all plausible confounders
would have reduced the effect (+1).
c
Clinical cardiovascular and cerebrovascular disease.
d
One grade C.
e
Two grade C.
fConsistencies in direction on effect.
g
One grade A, one grade B.
hTwo grade C.
i
Two grade B.
j
Two grade B.
kHowever, limited certainty about the directness of PTH due to bias in PTH assays, and biological variability of PTH values and effect of different PTH fragments.

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Table 43 | Evidence profilea for the treatment of CKD–MBD with bisphosphonates vs control in CKD stages 1–5T

chapter 6

http://www.kidney-international.org& 2009 KDIGO

Chapter 6: Summary and research recommendations
Kidney International (2009) 76 (Suppl 113), S111–S114; doi:10.1038/ki.2009.194

As detailed throughout this guideline, there is a paucity ofhigh-quality studies evaluating the clinical benefit of various
treatments given to patients with chronic kidney disease–mineral and bone disorder (CKD–MBD). Table 44 summarizes the number and quality of randomized controlled trials
by end points. More detailed summaries are provided inTable 45 and (Supplementary Tables 54 and 55). As CKD–
MBD is unique to patients with CKD stages 3–5D and stages
1–5T, we unfortunately do not have treatment studies in thegeneral population that we can apply to the managementof our patients. The Work Group a priori decided that weshould focus only on randomized controlled trials with atleast 6 months’ duration and sufficient sample size to guidetreatment decisions. Therefore, additional randomized controlled trials of shorter duration are not included in this table.
However, it is unlikely that these shorter studies provided
high-quality evidence on clinical end points. Owing to
the paucity of randomized controlled trials in this field, theWork Group made the attempt to also use observational
studies with large sample size of treatment effects that wererelevant to the guideline treatment questions, under thecondition that they showed a relative risk of 42.0 or o0.5

for patient-centered outcomes. No observational treatment
studies meeting these criteria were identified.
This guideline contains mostly level 2 recommendations.
These are formulated on the basis of the expert judgmentof the Work Group and the review of evidence that is eitherof low quality or that does not examine patient-centeredend points. As detailed in Chapter 2, there are importantdifferences in the implications for level 1 and level 2
recommendations (Chapter 2).
The grading of recommendations adopted for the guideline is shown in Table 46 (also shown in Chapter 2).
It is important to reinforce that level 2 recommendations
are not meant to be used for quality performance measuresby dialysis providers or payers. Level 2 recommendations
should also not be considered mandatory for a specifictherapeutic approach. Instead, level 2 recommendations aremeant to guide clinicians in caring for patients, andthese recommendations must be validated by future
research. It is also important that the grade for the strengthof the recommendation and the quality of the evidence
corresponding to each statement (see Chapter 2) be included
whenever a recommendation is reproduced or communicated.

Table 44 | Summary of cumulative evidence matrix with patient-centered outcomes, other surrogate outcomes, andbiochemical outcomes
Methodological quality of outcome
A
Number of studies

B
Number of studies

C
Number of studies

Patient-centered outcomes
Mortality
Clinical CVD
Hospitalization
CKD clinical outcomes
QoL
Fractures
PTx

—
—
—
—
—
—
—

2
—
—
—
—
1
—

1
—
2
—
1
7
1

Other surrogate outcomes
BMD
Bone histomorphometry
Vascular/valvular calcification
GFR loss

1
2
—
—

6
5
5
—

7
6
3
12

Biochemical outcomes
Lab: Serum Ca, P
Lab: Serum ALP, b-ALP
Lab: PTH, Vit D, bicarb
Total

3
1
1
8

19
12
20
70

7
5
3
55

Outcome

Total

15

47

71

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Bicarb, bicarbonate; BMD, bone mineral density; Ca, calcium; CKD, chronic kidney disease; CVD,
cardiovascular disease; GFR, glomerular filtration rate; P, phosphorus; PTH, parathyroid hormone; PTx, parathyroidectomy; QoL, quality of life; Vit D, vitamin D.
Kidney International (2009) 76 (Suppl 113), S111–S114

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chapter 6

Table 45 | Cumulative evidence matrix for all treatment studies by outcome
Methodological quality of outcome
A

B

C

Outcome

AuthorN (on agent) F/U

AuthorN (on agent) F/U

AuthorN (on agent) F/UMortality———

Block (2007)265
St Peter (2008)267 a

127 (60)
2102 (1051)

44 months
28 months

Cunningham (2005)386

1184 (697)

6–12 months

Clinical CVD

—

—

—

—

—

—

—

—

—

1184 (697)2103 (1053)

6–12 months
20 months

—

—

386

Hospitalization

—

—

—

—

—

—

Cunningham (2005)
Suki (2007)266 a

CKD clinicaloutcomes

—

—

—

—

—

—

—

QoL

—

—

—

—

—

—

Cunningham (2005)386

441

2658 (X )1184 (697)
76 (38)581 (Xb)
80 (40)72 (36)731 (485)

22–25 months
6–12 months
60 months
36 months
12 months
12 months
21 months——

Cunningham (2005)386

1184 (697)

6–12 months

12 months
12 months
12 months
12 months—
36 months

Miller (2005)126
Jamal (2007)127
Raggi (2005)346
Asmus (2005)344
De Sevaux (2002)466
Josephson (2004)468
Miller (2007)476

4643 (2335)
581 (Xb)
111 (51)
114 (55)
113 (65)64 (26)731 (485)

22–25 months
36 months
12 months
21 months
6 months
12 months
21 months—

Ishani (2008)

PTx

—

—

—

—

Bone density

Grotz (2001)165

80 (40)

12 months

Coco (2003)469
50 (Xb)Jeffery (2003)471
117 (46)
Torres (2004)467
90 (45)477
Wissing (2005)
90 (46)444
Hernandez (2003)
50 (25)441
Ishani (2008)
4973 (3293)

Bone histology

Ferreira (2008)104 91 (44)Barreto (2008)288 101 (41)—Lab: Ca, P

Coyne (2006)377 220 (107)
Coburn (2004)376 55 (27)
Culleton (2007)314 52 (26)

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—

6–12 months

Miller (2005)
Cunningham (2005)386
Baker (1986)101
Jamal (2007)127
Grotz (2001)165
Coco (2003)469
Miller (2007)476—

GFR lossb

36 months——

1184 (697)4973 (3293)

Fractures

Vascular/Valvular —Calcification

126

13.5 months Freemont (2005)13
12 months Spasovski (2006)98
Salusky (2005)17
Malluche (2008)103

63 (30)24 (12)29 (15)211 (51)

12 months
12 months
8 months
24 months

Hamdy (1995)97
134 (72)
Nordal (1988)102
30 (15)Baker (1986)101
76 (38)
Salusky (1998)18
46 (16)
Coco (2003)469
72 (36)
470
Cuento-Manzano (2000)
30 (16)389
Malluche (2008)
48 (32)

24 months
8 months
60 months
12 months
12 months
12 months
24 months

Quinibi (2008)287
Chertow (2002)284/
Chertow (2003)357
Raggi (2004)345
Block (2005)285
Russo (2007)286

203 (103)
200 (99)

12 months
12 months

Baker (1986)101
Asmus (2005)344

76 (38)114 (55)

60 months
21 months

132 (62)148 (73)
90 (30)

12 months
18 months
24 months

Barreto (2008)288

101 (41)

12 months

—

—

—

—

Miller (2005)126
Coyne (2006)377
Hamdy (1995)97
Coburn (2004)376
Grotz (2001)165
Coco (2003)469
Jeffery (2003)471
De Sevaux (2002)466
Torres (2004)467
Miller (2007)476
Wissing (2005)477
Russo (2007)286

4643 (2335)
220 (107)
176 (89)
55 (27)80 (40)72 (36)117 (46)113 (65)
90 (45)731 (485)
90 (46)90 (30)

22–25 months
6 months
24 months
6 months
12 months
12 months
12 months
6 months
12 months
21 months
12 months
24 months

6 months
6 months
6 months

Block (2004)387
741 (371)
Lindberg (2005)388 395 (294)Moe (2005)395
0aBaker (1986)101
76 (38)
Hamdy (1995)97
176 (89)392
Sprague (2003)
266 (133)
13
Freemont (2005)
98 (49)284
Chertow (2002)
200 (99)285
Block (2005)
148 (73)
Grotz (2001)165
80 (40)Coco (2003)469
72 (36)
De Sevaux (2002)466 113 (65)

6 months
6 months
6 months
60 months
24 months
3–8 months
12 months
12 months
18 months
12 months
12 months
6 months

Miller (2005)126
Hayashi (2004)391
Finn (2006)349
Suki (2007)266
Asmus (2005)344
Barreto (2008)288

4643 (2335)
91 (47)1359 (682)2103 (1053)
114 (55)
101 (41)

22–25 months
12 months
24 months
20 months
24 months
12 months—

Kidney International (2009) 76 (Suppl 113), S111–S114

chapter 6

Table 45 | Continued
Methodological quality of outcome
A
Outcome

AuthorB

N (on agent) F/U

C

AuthorN (on agent) F/U

Torres (2004)467
Wissing (2005)477
Russo (2007)286
Quinibi (2008)287
Ferreira (2008)104
Malluche (2008)103
Kooienga (2009)374

90 (45)90 (46)90 (30)203 (103)
91 (44)211 (51)322 (214)

AuthorN (on agent) F/U

12 months
12 months
24 months
12 months
13.5 months
24 months
24 months

Lab: ALP, b-ALP Coyne (2006)377

220 (107)

6 months

Block (2004)387
741 (371)
Coburn (2004)376
55 (27)
Hamdy (1995)97
176 (89)
Baker (1986)101
76 (38)Grotz (2001)165
80 (40)Coco (2003)469
72 (36)286
Russo (2007)
90 (30)466
De Sevaux (2002)
113 (65)
467
Torres (2004)
90 (45)287
Quinibi (2008)
203 (103)
104
Ferreira (2008)
91 (44)
Malluche (2008)103 211 (51)

6 months
Raggi (2005)346
6 months
Hayashi (2004)391
24 months Finn (2006)349
60 months Barreto (2008)288
12 months Kooienga (2009)374
12 months
24 months
6 months
12 months
12 months
13.5 months
24 months

111 (51)
91 (47)1359 (682)
101 (41)322 (214)

12 months
12 months
24 months
12 months
24 months

Coyne (2006)377

220 (107)

6 months

Block (2004)387
741 (371)
Lindberg (2005)388 395 (294)Moe (2005)395
0aBaker (1986)101
76 (38)
Hamdy (1995)97
176 (89)392
Sprague (2003)
266 (133)
13
Freemont (2005)
98 (49)284
Chertow (2002)
200 (99)285
Block (2005)
148 (73)165
Grotz (2001)
80 (40)Coco (2003)469
72 (36)
De Sevaux (2002)466 113 (65)
Torres (2004)467
90 (45)
Wissing (2005)477
90 (46)314
Culleton (2007)
52 (26)286
Russo (2007)
90 (30)287
Quinibi (2008)
203 (103)
104
Ferreira (2008)
91 (44)
Malluche (2008)103 211 (51)
Choncol (2009)379
404 (302)

6 months
Finn (2006)349
6 months
Asmus (2005)344
6 months
Hayashi (2004)391
60 months
24 months
3–8 months
12 months
12 months
18 months
12 months
12 months
6 months
12 months
12 months
6 months
24 months
12 months
13.5 months
24 months
8 months

1359 (682)
114 (55)
91 (47)24 months
24 months
12 months

Lab: PTH,
Vit D, Bicarb

ALP, alkaline phosphatase; b-ALP, bone-specific alkaline phosphatase; Bicarb, bicarbonate; Ca, calcium; CKD, chronic kidney disease; CVD, cardiovascular disease; F/U, followup; GFR, glomerular filtration rate; N, number of subjects; P, phosphorus; PTH, parathyroid hormone; PTx, parathyroidectomy; QoL, quality of life; Vit D, vitamin D.
All single studies of a specific comparison are shown in gray.
a
N for Moe (2005)395 study is equal to the N from Lindberg (2005)388+Block (2004)387bUnclear reporting regarding the number of individuals who received the study drug.

Table 46 | Grading of recommendations
Grade for qualityof evidence

Grade for strength ofrecommendationa

Strength

Wording

Level 1

Strong‘We recommendyshould’

Level 2Weak

‘We suggestymight’

A
B
C
D

Quality of evidenceHigh
Moderate
Low
Very lowa

In addition the Work Group could also make ungraded statements (See Chapter 2 section on ungraded statements).

Only then will the true state of the evidence be recognizedby all.
Given that the majority of the recommendations in thisdocument are level 2, it should be obvious that muchadditional high-quality research is needed in the field of
CKD–MBD to resolve uncertainties and allow the formulaKidney International (2009) 76 (Suppl 113), S111–S114

tion of more level 1 recommendations in the future. In
each of the individual chapters, there are several research
recommendations. The Work Group also felt that it was
important to prioritize research, and determined that futurestudies such as those below are of critical importance toadvance the field and improve patient care.
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chapter 6

Develop a risk-stratification tool based on CKD–MBD
components and evaluate its predictive accuracy for clinicaloutcomes in patients with CKD stages 3–5, 5D, and 3–5T.
K Determine whether, in patients with CKD–MBD, a single
measurement of bone mineral density (measured by dual
energy X-ray absorptiometry or quantitative computed
tomography) and serial changes in bone mineral density
can predict fractures.
K Determine whether the presence or absence of vascular/
valvular calcification in patients with CKD–MBD is anappropriate stratification and selection tool to identify
individuals who may benefit from specific interventions.
K Determine whether the effect of an intensive CKD–MBD
treatment approach (for example, protocol-driven combination therapy to achieve specific serum phosphorus
and parathyroid hormone targets) vs a less intensive
treatment approach (for example, protocol-driven
combination therapy allowing higher serum phosphorus
and parathyroid hormone targets) vs standard care improvesclinical outcomes in patients with CKD stages 3–5D.
K Determine whether treating down to normal serum
phosphorus levels (as compared with phosphorus levelsof 5.5–6.5 mg/dl; 1.78–2.10 mmol/l) with the use of
combinations of different phosphate binders and otherapproaches improves clinical outcomes in patients withCKD stages 4–5D and 4–5T.
K Determine whether treatment to a lower vs higher serum
parathyroid hormone target improves or worsens clinicalK

S114

outcomes in patients with CKD stages 3–5, CKD stage
5D, and CKD stages 3–5T.
K Determine whether treatment with vitamin D (ergocalciferol or cholecalciferol) or calcidiol [25(OH)D], compared with calcitriol or vitamin D analogs, improvesclinical outcomes in patients with CKD stages 3–5, CKD
stage 5D, and CKD stages 1–5T.
K Determine which phosphate binders and other serum
phosphorus-lowering treatments are able to improvesurvival in patients with CKD stages 3–5D and CKD
stages 3–5T.
K Determine whether treatment with bisphosphonates,
teriparatide, or raloxifene reduces fractures or vascular
calcification in patients with CKD stages 3–5D and CKD
stages 1–5T.
K Determine
whether strategies to reverse adynamic
bone disease by measures such as endogenous stimulation of parathyroid hormone secretion (for example,
using low-calcium dialysate) or exogenous teriparatide
administration, affect clinical outcomes in patients withCKD stages 4–5D or CKD stages 1–5T, compared withplacebo.
SUPPLEMENTARY MATERIAL

Supplementary Table 54. Summary of cumulative evidence matrix ofadverse events.
Supplementary Table 55. Adverse event reporting.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki

Kidney International (2009) 76 (Suppl 113), S111–S114http://www.kidney-international.org

biographic and disclosure information& 2009 KDIGO

Biographic and disclosure information
Kidney International (2009) 76 (Suppl 113), S115–S119; doi:10.1038/ki.2009.195

Sharon M Moe, MD, FASN, FAHA, FACP (Work Group CoChair), is Professor of Medicine and Vice-Chair for Researchat Indiana School of Medicine and staff physician at
Roudebush VA Medical Center in Indianapolis, IN. She
obtained her medical degree from the University of Illinois
and completed her nephrology fellowship at the University of
Chicago. Her biomedical research focuses on the relationshipof kidney disease, vascular calcification, bone, and disordersof mineral metabolism. Among the many honors she hasreceived are the following: Endowed Lecture Recipient at
Royal College of Physicians, Edinburgh; Trustee Teaching
Award from Indiana University School of Medicine; Elected
Member of American Society for Clinical Investigation;
Elected Councilor for the American Society of Nephrology;
and the 2009 Garabed Eknoyan Award from the NKF.
Dr Moe has served on several journal boards and is a memberof numerous professional organizations and NIH committees. She has also authored articles for many prominent
publications including: American Journal of Kidney Diseases,
Journal of the American Society of Nephrology, Journal of Boneand Mineral Research, Kidney International and Nephrology
Dialysis Transplantation.
Advisor/Consultant: Amgen; DiaSorin; Genzyme; INEOS;
Litholink; ShireRoyalties: Amgen
Speaker: Amgen; Genzyme
Grant/Research Support: Amgen; Genzyme; INEOS; Shire
Tilman B Drüeke, MD, FRCP (Work Group Co-Chair), isInserm Research Director Emeritus and former Associate
Professor of Medicine at Hôpital Necker in Paris, France. He
began his medical studies at the University of Frankfurt in1961 and graduated from the Medical School of Tübingen in
1967. Dr Drüeke later completed his postdoctoral andresearch fellowships at the Department of Nephrology,Hôpital Necker. Since 1983, he has been Director of Researchat Inserm. From 1986 to 1998, he was the director of Inserm
Unit 90 at Hôpital Necker. In 1998, he was elected as Fellowof the Royal College of Physicians of Edinburgh. He is anhonorary member of the Gesellschaft für Nephrologie and of
the Polish Society of Nephrology. He was elected as Professor
honoris causa by Saints Cyril and Methodius University,
Skopje, Republic of Macedonia, in 2008. He was a council
member of the Société de Néphrologie (SN), European Renal
Association-European Dialysis and Transplant Association(ERA-EDTNA), and International Society of Nephrology(ISN), and a member of the Scientific Program Committeeof the American Society of Nephrology in 1999 and 2009.
His nephrology interests include chronic renal failure,
Kidney International (2009) 76 (Suppl 113), S115–S119

hemodialysis, metabolic and endocrine abnormalities ofchronic kidney disease (CKD), and cardiovascular diseases.
He served as Editor-in-Chief for NDT (1999–2005) andcurrently serves as Associate Editor for CJASN. Dr Drüeke isalso an editorial board member for Journal of the American
Society of Nephrology and Kidney International, a reviewer for
numerous other journals, and the author of more than 450
peer-reviewed articles.
Advisor/Consultant: Amgen; Fresenius Medical care; Genzyme;
INEOS; Leo; Mitsubishi; Roche; Theraclion
Speaker: Amgen; Chugai; Genzyme; Kirin; Roche
Grant/Research Support: Amgen; Genzyme; Shire
Geoffrey A Block, MD, has dual appointments as Director of
Clinical Research at Denver Nephrologists, PC, and as
Associate Clinical Professor of Medicine at the Universityof Colorado Health Sciences Center in Denver, CO. He
completed his fellowship at the University of Michigan and is
an executive committee member for the Global Bone andMineral Initiative. In 2004, Dr Block was awarded theAcademic Publications Award by the University of Colorado.
His special research interests include examining vascular
calcification and clinical outcomes associated with the use ofphosphate binders and treatments for secondary HPT.
Advisor/Consultant: Amgen; Cytochroma; Genzyme
Speaker: Genzyme
Grant/Research Support: Amgen; Fresenius; Genzyme;
Novartis; Shire
Jorge B Cannata-Andı́a, MD, PhD, is Professor of Medicine
and Head of the Bone and Mineral Research Unit, Servicio
Metabolismo Óseo y Mineral, Hospital Universitario Central
de Asturias, Universidad de Oviedo, Spain. In addition, heholds an appointment with the Bone and Mineral Metabolism
Service at Institute Reina Sofia of Investigation in Oviedo,
Spain. Dr Cannata-Andı́a is Immediate Past President of the
ERA-EDTA and an author of over 70 journal articles.
Advisor/Consultant: Amgen; Shire
Speaker: Abbott; Genzyme; Shire
Grant/Research Support: Abbott; Amgen
Grahame J Elder, MB, BS, PhD, FRACP, is a renal physician
whose principal interest is metabolic bone disease associatedwith CKD and following kidney and kidney pancreastransplantation. He works in the Department of Renal
Medicine at Westmead Hospital and the Bone and Calcium
Clinic at St Vincent’s Hospital, Sydney. He was appointed to
the Bone and Mineral Program at the Garvan Institute for
Medical Research, where he completed his PhD studies on
S115

biographic and disclosure information

the molecular genetics and physiology of osteoporosis. He
has been involved in writing evidence-based guidelines (theCaring for Australasians with Renal Impairment guidelines)
and Cochrane reviews in the area of bone and mineralmetabolism. He has served on the education committee ofKidney Health Australia, is the director of clinical renal
research at Westmead Hospital, and is also a subject editor of
the journal Nephrology.
Advisor/Consultant: Abbott; Amgen; Genzyme; Shire/Orphan Australia
Speaker: Abbott; Amgen
Grant/Research Support: Roche
Masafumi Fukagawa, MD, PhD, FASN, is currently
Associate Professor and Director of the Division of
Nephrology and the Kidney Center at Kobe University
School of Medicine (Japan). Dr Fukagawa received his MD in1983 from the University of Tokyo School of Medicine.
Following clinical training in internal medicine and then in
nephrology at the University Hospital and affiliated hospitals,
he was a research fellow (cell biology, pediatric nephrology,
and cardiology) at Vanderbilt University School of Medicine,
TN (USA) until 1995. In 2000, Dr Fukagawa was appointed
as Director of Nephrology in Kobe. Dr Fukagawa’s major
research interest is mineral metabolism. He chaired acommittee for Japanese clinical guidelines for CKD-MBD.
He is currently International Editor of the Clinical Journal of
the American Society of Nephrology, and also serves as an
editorial board member and reviewer for international
journals.
Advisor/Consultant: Abbott Japan; Bayer Japan; Kyowa
Hakko Kirin Co. Ltd; Novartis Pharma Co. Ltd
Speaker: Bayer Japan; Chugai Pharmaceutical Co. Ltd;
Kyowa Hakko Kirin Co. Ltd
Grant/Research Support: Chugai Pharmaceutical Co. Ltd;
Kyowa Hakko Kirin Co. Ltd
Vanda Jorgetti, MD, PhD, is currently Attending Physicianof the Nephrology Department of the University of São Paulo
Hospital das Clı́nicas and is responsible for the Renal
Osteodystrophy Laboratory at the University of São Paulo,
Brazil. She completed fellowships in Internal Medicine andNephrology in São Paulo and in Renal Osteodystrophy at
Hôpital Necker in Paris, France. She received her PhD fromthe University of São Paulo in 1992. Dr Jorgetti is a memberof the Brazilian Society of Nephrology, Brazilian Society forBone and Mineral Metabolism, and American Society forBone and Mineral Research. She receives and analyzes bonebiopsies from various Brazilian states as well as from othercountries in Latin America. In addition, she has trained
numerous doctors from Brazil and other countries who workin this area. Her interests include renal bone disease, mineralmetabolism, and bone histomorphometry.
Advisor/Consultant: Abbott; Genzyme
Speaker: Genzyme
Grant/Research Support: Abbott; Genzyme; Mantecorp
S116

Markus Ketteler, MD, is Division Chief of Nephrology at
Klinikum Coburg, Germany. He earned his medical degree atthe University of Heidelberg and completed his internshipand residency at the Department of Nephrology andHypertension, University Hospital Steglitz, Free University
Berlin. Dr Ketteler was a consultant (Nephrology/Internal
Medicine) at the Department of Nephrology and Clinical
Immunology, University Hospital Aachen, where he oversaw
the Hemodialysis/Transplantation Unit. His major researchinterests include pathomechanisms of vascular calcificationsin uremia, bone disease in renal transplant recipients, and therole of nitric oxide in experimental glomerulonephritis. Dr
Ketteler has received numerous awards during his career,
including the Award of the European Dialysis and Transplantation Association (EDTA): ‘Best Abstract’ and 2002
Bernd Tersteegen Award (DDNAe). He is a member ofnumerous professional societies and serves on the editorial
board of the Journal of the American Society of Nephrology,
Kidney International, Nephrology, Dialysis and Transplantation, and others.
Advisor/Consultant: Abbott; Amgen; Fresenius Medical
Care; Genzyme; Shire
Speaker: Abbott; Amgen; Fresenius Medical Care; Genzyme;
Shire
Grant/Research Support: Abbott; Amgen; Genzyme
Craig B Langman, MD, is the Isaac A Abt, MD, Professor of
Kidney Diseases at the Feinberg School of Medicine, Northwestern University and Head of Kidney Diseases at Children’sMemorial Hospital, Chicago, IL. He received his medical
degree from Hahnemann University and completed his
fellowship in Pediatric Nephrology at the Children’s Hospitalof Philadelphia, University of Pennsylvania. His researchareas have included nephrolithiasis and also disorders ofcalcium, phosphorus, and vitamin D metabolism in infants,
children, and adolescents. Dr Langman has published morethan 170 articles, chapters, and reviews, and currently serves
as Associate Editor of the American Journal of Nephrology,
and on the editorial boards of Clinical Journal of the American
Society of Nephrology, European Journal of Pediatrics, andPediatric Nephrology. He is also listed in every edition of Best
Physicians in America, Pediatric Kidney Disease. Dr Langman
also serves on many advisory boards, including Brittle BoneFoundation; Cystinosis Research Network; National Kidney
Foundation; National Osteoporosis Foundation; and Oxalosis and Hyperoxaluria Foundation.
Advisor/Consultant: Genzyme
Speaker: Abbott; Genzyme
Grant/Research Support: Amgen
Adeera Levin, MD, FRCPC, is Clinical Professor of Medicine
at the University of British Columbia, and co-director of theClinical Investigator Program at the University of British
Columbia. She is the Executive Director of the British
Columbia Provincial Renal Agency, an organization thatmanages and coordinates the care of patients with kidney
Kidney International (2009) 76, (Suppl 113), S115–S119

biographic and disclosure informationdisease in the province of British Columbia. Dr Levincurrently serves as Chair of the Curriculum Committee for a
new innovative program for the training of Canadian clinicalscientists in kidney disease (KRESCENT) and is on the Boardof Directors and Executive Committee of Kidney Disease:
Improving Global Outcomes (KDIGO), an internationalgroup providing collaborative structure for outcomes research and guideline development in CKD. Her research andclinical activities focus on CKD, comorbidities associatedwith CKD, mechanisms of disease, and health outcomes
research. Dr Levin is a recent recipient of the National Kidney
Foundation’s Garabed Eknoyan Award (2008) and has
authored over 135 peer-reviewed publications and numerous
book chapters. She is also presently on the editorial board for
Nephrology, Dialysis, and Transplantation, the Journal of theAmerican Society of Nephrology, and American Journal of
Kidney Diseases and is a reviewer for Circulation, New
England Journal of Medicine, Annals of Internal Medicine,
Canadian Family Practice, and Kidney International.
Advisor/Consultant: Abbott; Amgen; Genzyme; Ortho Biotech; Shire
Speaker: Abbott; Amgen; Genzyme; Ortho Biotech; Shire
Grant/Research Support: Abbott; Amgen; Genzyme; Ortho
Biotech; Shire
Alison M MacLeod, MBChB, MD, FRCP London and
Edinburgh, is Professor in the Department of Medicine andTherapeutics at the University of Aberdeen Medical School,
UK. She completed her fellowship at the Royal Colleges ofPhysicians of London and Edinburgh, and has interests inepidemiology of CKD, acute kidney injury, and evidencebased medicine in nephrology. Her research group also
conducts systematic literature reviews and she is a member ofthe Editorial Board of the Cochrane Review Group. Dr
MacLeod is a current committee member of the European
Renal Registry Executive Committee, Anaemia Managementin Chronic Kidney Disease–National Institute for Health andClinical Excellence, Scientific Committee, and European
Renal Association Congress. In addition, she is Chairmanof the Scottish Intercollegiate Guidelines Network, Diagnosis
and Management of Chronic Renal Failure and a member ofthe Executive Committee of KDIGO.
Dr MacLeod has reported no relevant financial relationships.
Linda McCann, RD, CSR, LD, is the Senior Director of
Quality at Satellite Health Care Inc., Mountain View, CA. She
completed her internship in General Dietetics with work
toward a Master’s degree at Indiana University/Purdue
University Medical Center. She is currently on the Kidney
Disease Outcomes Quality Initiative and KDIGO advisoryboards and has previously served as Chairperson of the
NKF Council on Renal Nutrition (CRN), member of theNKF Board of Directors, as well as other local and national
NKF and CRN committees. Ms McCann has particularinterests in areas relating to nutrition, bone and mineraldisorder, and dialysis adequacy. Among the many awards she
Kidney International (2009) 76 (Suppl 113), S115–S119

has received are the following: NKF-CRN Recognized Renal
Dietitian (1992), NKF-CRN Special Recognition Award(1998), and NKF-CRN Joel D Kopple Award, and Distinguished Lectureship in Renal Nutrition (2003). Ms McCannis a Certified Specialist in Renal Nutrition and has also
published numerous papers in journals and book chapters on
this topic.
Advisor/Consultant: Amgen; Genzyme
Speaker: Amgen; Baxter Healthcare; The France Foundation;
Genzyme; Prime Medica
Peter A McCullough, MD, MPH, FACC, FACP, FCCP,
FAHA, is Consultant Cardiologist and Chief, Division of
Nutrition and Preventive Medicine at William Beaumont
Hospital, Royal Oak, and Clinical Professor of Health
Science, Oakland University, Rochester, MI, USA. He
completed his medical degree at the University of Texas
Southwestern Medical School in Dallas, residency at the
University of Washington in Seattle, cardiology fellowship at
William Beaumont Hospital, and master’s degree in publichealth at the University of Michigan.
At Beaumont Hospital, Dr McCullough leads an active
clinical and research team that focuses on innovative
approaches in preventive medicine. He is an internationallyrecognized authority on the role of CKD as a cardiovascularrisk state with B500 medical publications, including B300
peer-reviewed manuscripts and abstracts. His works haveappeared in the New England Journal of Medicine, the Journalof the American Medical Association, and numerous specialty
journals. As a leader in preventive medicine with a personal
dedication to health and fitness, Dr McCullough hascompleted 12 marathons in the United States, Europe, andCanada.
Advisor/Consultant: Amgen; Fresenius; Genzyme; Shire
Grant/Research Support: Abbott Labs
Susan M Ott, MD, is Associate Professor of Medicine,
Division of Metabolism, Endocrinology and Nutrition at the
University of Washington Medical Center in Seattle, WA,
USA. She obtained her medical degree from the University ofWashington where she also completed a nephrology fellowship. Her current research interests include clinical and bone
histomorphometric studies of bone metabolism; effects ofcontraception and lifestyle on bone density in adolescents;
mineralization density of bone; bone histomorphometry of
women with breast cancer; and renal osteodystrophy. Dr Ott
has authored over 100 journal publications, book chapters,
and commentaries.
Advisor/Consultant: Zymogenetics
Speaker: Eli Lilly
Angela Yee-Moon Wang, MD, PhD, FRCP, is Honorary
Clinical Associate Professor and Associate Consultant
in the Department of Medicine, University of Hong Kong,
Queen Mary Hospital. Dr Wang received her medical
degree from the University of New South Wales in Sydney,
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biographic and disclosure information

Australia, and is currently an editorial board member of the
Journal of the American Society of Nephrology, Clinical Journalof the American Society of Nephrology, Journal of Diabetes,
Journal of Nephrology and Renal Transplantation. Dr Wangalso serves on the advisory board of the Journal of Nephrology.
Her areas of interest include the studying of cardiovascularcomplications in CKD, cardiac biomarkers in CKD, residual
renal function in PD, and nutrition in PD. Dr Wang is arecipient of numerous research-related awards, including theJohn F Maher Award (2006) and the Best Abstract Award
from the World Congress of Nephrology (2005).
Advisor/Consultant: Baxter Renal
Speaker: Baxter, Korea; Baxter, Taiwan; Boehringer
Ingelheim, UK
Grant/Research Support: Abbott Laboratories Ltd; Baxter
RenalJosé R Weisinger, MD, FACP, is Professor of Medicine andDirector of the Clinical Research Center, Division of
Nephrology, Hospital Universitario de Caracas, Universidad
Central de Venezuela. He is Past-President of the Venezuela
Society of Nephrology, Latin American Society of Nephrology, and former Head, Division of Nephrology, Hospital
Universitario de Caracas. Dr Weisinger is currently on theeditorial board for the Clinical Journal of the American Societyof Nephrology; Current Opinion in Nephrology and Hypertension; Nefrologı́a Latinoamericana; Nephrology, Dialysis andTransplantation; and The Open Urology and Nephrology
Journal. He is a recipient of numerous awards including the
Sandoz Prize of Medicine, ‘Luis Razetti’ Prize of Medicine,Francisco de Venanzi Prize for Research in Medicine, Victor
Raul Miatello Award, Distinguished Career in Nephrology by
the Latin-American Society of Nephrology and Hypertension,and Distinguished Career in Nephrology by the Venezuela
Society of Nephrology. Dr Weisinger’s research interests include
post-transplant bone disease, postmenopausal uremic bonedisease, and kidney stones and bone disease. Dr Weisinger has
recently joined Baptist Health South Florida (South Miami andDoctors Hospital) in Miami, Florida, USA.
Advisor/Consultant: Fresenius Medical Care; Genzyme;
Novartis; Roche
Speaker: Fresenius Medical Care; Genzyme; Novartis; Roche
David C Wheeler, MD, FRCP, currently holds an academic
position (Reader in Nephrology) at the University College
London Medical School, a role that combines clinicalpractice, research, and teaching. He qualified from Birmingham University in 1980 and trained in nephrology in the
United Kingdom. In 1992, he was awarded a Medical
Research Council Training Fellowship and spent 2 years in
Boston, MA, where he focused on exploring the mechanismsof progression of kidney disease. On his return, he worked for
6 years as Consultant Nephrologist at the University Hospitalin Birmingham before taking up his current position in 2000.
Dr Wheeler is a member of the Executive Committee of
KDIGO and has served on the advisory board of the US
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Kidney Disease Outcomes Quality Initiative. He is deputy
editor of Nephrology, Dialysis Transplantation, UK national
co-coordinator for the Study of Heart and Renal Protection, amember of the Steering Committee of the EValuation Of
Cinacalcet therapy to Lower CardioVascular Events(EVOLVE) study and past Chairman of the UK Renal
Association Clinical Practice Guidelines Committee.
Advisor/Consultant: Abbott; Amgen; Genzyme, Vifor
Speaker: Abbott; Amgen, Fresenius; Genzyme; Shire
Grant/Research Support: Amgen; Genzyme
KDIGO CO-CHAIRS

Kai-Uwe Eckardt, MD, is Professor of Medicine and Chief ofNephrology and Hypertension at the University of Erlangen–Nuremberg, Germany. He received his MD from theWestfälische Wilhelms-Universität Münster, Germany. In
1993, following postgraduate training in internal medicine,pathology, and physiology, he was appointed AssistantProfessor of Physiology at the University of Regensburg,
Germany. Subsequently, he continued his training in internal
medicine and nephrology at the Charité, Humboldt University
in Berlin, where he was appointed Associate Professor of
Nephrology in 2000. His major scientific interests are in themolecular mechanisms and physiological/pathophysiologicalrelevance of oxygen sensing and the management of anemia.
Professor Eckardt is subject editor of Nephrology, Dialysis andTransplantation and serves on the editorial board of several otherjournals. He contributed to the development of the European
Best Practice Guidelines (EBPG) for Anemia Management andis a member of the executive committee of KDIGO. Dr Eckardt
is associated with CREATE and TREAT studies.
Advisor/Consultant: Affymax; Amgen; Ortho Biotech; Roche
Speaker: Amgen; Ortho Biotech; Roche
Grant/Research Support: Ortho Biotech; Roche
Bertram L Kasiske, MD, is Professor of Medicine andMedical Director of Kidney and Pancreas Transplantation at
the University of Minnesota. He received his medical degreefrom the University of Iowa and completed his Internal
Medicine residency and fellowship training in Nephrology atHennepin County Medical Center where he is also currently
the Director of Nephrology and Medical Director of Kidney
Transplantation. His primary research interests include
areas relating to immunosuppression, dyslipidemia, andcardiovascular diseases in transplant recipients. He is a
co-investigator in the randomized controlled trial (RCT) of
homocysteine (Folic Acid for Vascular Outcome Reduction
In Transplantation (FAVORIT)), Study of Heart and Renal
Protection, and the US Renal Data System. Dr Kasiske hasserved as Medical/Scientific Representative to the Boardof Directors of United Network for Organ Sharing (UNOS),
and is presently the Work Group Co-Chair of KDIGOClinical Practice Guideline for the Care of Kidney Transplant
Recipients. He has published over 200 journal articles
and most recently contributed book chapters in The Kidney:
Physiology and Pathophysiology, Brenner and Rector’s
Kidney International (2009) 76, (Suppl 113), S115–S119

biographic and disclosure information

The Kidney, and Kidney Transplantation: Principles andPractice.
Advisor/Consultant: Astellas; Litholink; Novartis; Wyeth
Grant/Research Support: Bristol Myers Squibb; MerckSchering Plough
EVIDENCE REVIEW TEAM

Katrin Uhlig, MD, MS, is the Director, Guideline Development at the Tufts Center for Kidney Disease Guideline
Development and Implementation, Boston, MA, AssistantProfessor of Medicine at Tufts University School of Medicine,and a staff nephrologist at Tufts Medical Center. Dr Uhlig
completed her training in internal medicine, nephrology, andrheumatology in Germany (Aachen University Hospital andMunich University Hospital) and the United States (Georgetown University Medical Center and Tufts Medical Center).
Since 2001, she has been participating in or directing theevidence review for Kidney Disease Outcomes Quality
Initiative and KDIGO guidelines. In 2005, she co-chaired
the KDIGO Evidence Rating Group to develop a consensus
on grading of KDIGO guidelines. From 2006 to 2007, she
served as Co-Editor of the American Journal of Kidney
Diseases. Her focus in teaching and research is in evidencebased medicine, systematic review, clinical practice guideline
development, and critical literature appraisal.
Dr Uhlig has reported no relevant financial relationships.

Kidney International (2009) 76 (Suppl 113), S115–S119

Ranjani Moorthi, MD, MPH, MS, served as a research
fellow at the Tufts Center for Kidney Disease Guideline
Development and Implementation in Boston, MA,from June 2006 to July 2008. She participated in the
conduct of systematic reviews and critical literatureappraisals for this guideline. Her research interests
include phosphorus and calcium metabolism and theirrelationship with vascular access outcomes in hemodialysis(HD) patients.
Dr Moorthi has 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. She assists in the development of clinicalpractice guidelines and conducts systematic reviews andcritical literature appraisals.
Ms Earley has reported no relevant financial relationships.
Rebecca Persson, BA, served as a research assistant at
the Tufts Center for Kidney Disease Guideline Development
and Implementation in Boston, MA, until 2008. She assisted
in the development of clinical practice guidelines
and conducted systematic reviews and critical literatureappraisals.
Mrs Persson has reported no relevant financial relationships.

S119

acknowledgments

http://www.kidney-international.org& 2009 KDIGO

Acknowledgments
We gratefully acknowledge the careful assessment of the draft
guideline by external reviewers. The Work Group considered
all of the valuable comments made and, where appropriate,
the suggested changes were incorporated into the final
publication. The following individuals provided review ofthe draft guideline:
Omar Abboud, Ali Abu-Alfa, Nasrulla Abutaleb, Vidya
Acharya, Sharon Adler, Teresa Adragao, Anil Agarwal, Tadao
Akizawa, Ahmed Akl, Mona Al-Rukhaimi, Dennis Andress,
Mustafa Arici, Mariano Tomas Arriola, Ione Ashurst, Kamal
Badr, Ashraf Bakr, Rasheed A Balogun, Bryan Becker,
Ezequiel Bellorin-Font, Bassam Bernieh, Jordi Bover, Pauline
Branley, Johann Braun, Tom Cantor, Laurence Carroll, Sue
Cary, Philippe Chauveau, Christine Chmielewski, Maria
Coco, Giorgio Coen, Martine Cohen-Solal, Danilo Concepcion, Ricardo Correa-Rotter, Daniel Coyne, Mario Cozzolino,
Paul Crawford, Angel LM de Francisco, Paul E de Jong,
Dominic de Takats, Jean-Yves De Vos, Bastian Dehmel,
Stephen Della Croce, James Delmez, Patrick D’Haese,
Guillermo Rosa Diez, Tammy Drasher, Thomas Dudley,
Mahmoud El-Khatib, Pieter Evenepoel, Jarraya Faical, MarieClaude Faugere, Hassan Fehmi, Arnold Felsenfeld, Anı́bal
Ferreira, Joseph Flynn, Melissa Foster, Eugene Freund, Daniel
Froment, Maurizio Gallieni, Catherine Garvey, David Goltzman, Janelle Gonyea, William G Goodman, Carmen Gracida,
Christine Gries, Gordon Guyatt, Martin Haas, Debra Hain,
William E Haley, Rebecca Hays, Tan Seng Hoe, Pascal
Houillier, Keith Hruska, Alastair Hutchison, Michael
Joannidis, Michelle Josephson, Takatoshi Kakuta, Kamyar
Kalantar-Zadeh, Nada Kanaan, Deepa Kariyawasam,Frederick Kaskel, Sheila Koszycki, Josef Kovarik, Csaba P

S120

Kovesdy, Jean-Marie Krzesinski, Robyn Langham, Rakesh
Lattupalli, Daniel Lavanchy, Edgar Lerma, Elizabeth Lindley,Gérard London, Victor Lorenzo, Robert Mactier, Fabio
Malberti, Hartmut H Malluche, Barbara Marzell, Darius
Mason, Pablo Massari, Sandro Mazzaferro, Nancy McAfee,
Lesley McPhatter, David Mendelssohn, Cecilia Mengarelli,Jose A Menoyo, Paul Miller, Donald Molony, Alexander
Morton, Rosa Maria Affonso Moysés, Michal Mysliwiec,
Corina Nailescu, Mooppil Nandakumar, Lavinia Negrea,
Armando Luis Negri, Yoshiki Nishizawa, Maurizio Nordio,
Michal Nowicki, Gregorio T Obrador, Donal O’Donoghue,
Ercan Ok, Klaus Olgaard, Katie Pallotta, Jutta PasslickDeetjen, Drasko Pavlovic, Adriana Penalba, Ronald Pisoni,
Momir Polenakovic, Friedrich K Port, Raymond D Pratt,
Erasmia Psimenou, L Darryl Quarles, Brana Radovic, Paolo
Raggi, Helmut Reichel, Cesar Restrepo, Sally Rice, Bruce
Robinson, Mariano Rodriguez, Edward Ross, Jacques
Rottembourg, Nicola Ruddock, Domenico Russo, Isidro B
Salusky, David Sane, Ajit Sawhney, Brigitte Schiller, Rebecca
Schmidt, Robert W Schrier, Takashi Shigematsu, Yvo Sijpkens,
Justin Silver, Goce Spasovski, David M Spiegel, Stuart Sprague,
Wadi N Suki, Harold M Szerlip, Francesca Tentori, Alison
Thomas, Trent Tipple, Yoshihiro Tominaga, Marcello Tonelli,Armando Torres, Yusuke Tsukamoto, C Thomas Tucker,
Ramiro Valdez, Raymond Vanholder, Sergio Vega, John Viel,
José Vinhas, Lezaic Visnja, Rowan Walker, Gail Wick, Andrzej
Wiecek, Jerry Yee, Camille Yuscak, Carmine Zoccali.
Participation in the review does not necessarily constitutean endorsement of the content of this report by the abovementioned individuals, or by the organization or institutionthat they represent.

Kidney International (2009) 76 (Suppl 113), S120

http://www.kidney-international.org

references& 2009 KDIGO

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