VA/DoD CLINICAL PRACTICE GUIDELINE FOR 

THE MANAGEMENT OF CHRONIC KIDNEY 

DISEASE IN PRIMARY CARE 

Department of Veterans Affairs

Department of Defense

QUALIFYING STATEMENTS

The Department of Veterans Affairs and the Department of Defense guidelines are based upon the best 

information available at the time of publication. They are designed to provide information and assist 

decision making. They are not intended to define a standard of care and should not be construed as one.

Neither should they be interpreted as prescribing an exclusive course of management. 

This Clinical Practice Guideline is based on a systematic review of both clinical and epidemiological 

evidence. Developed by a panel of multidisciplinary experts, it provides a clear explanation of the logical 

relationships between various care options and health outcomes while rating both the quality of the 

evidence and the strength of the recommendation. 

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 these guidelines is responsible for evaluating the 

appropriateness of applying them in the setting of any particular clinical situation.

These guidelines are not intended to represent TRICARE policy. Further, inclusion of recommendations 

for specific testing and/or therapeutic interventions within these guidelines does not guarantee 

coverage of civilian sector care. Additional information on current TRICARE benefits may be found at 

www.tricare.mil or by contacting your regional TRICARE Managed Care Support Contractor. 

Version 3.0 – 2014 

December 2014 Page 1 of 117
Prepared by:

The Management of Chronic Kidney Disease

Working Group

With support from:

The Office of Quality, Safety and Value, VA, Washington, DC

& 

Office of Evidence Based Practice, US Army Medical Command

Version 3.0 – 2014 

Based on evidence reviewed through December 2013

December 2014 Page 2 of 117
Table of Contents

Introduction............................................................................................................................................. 5

Background.............................................................................................................................................. 6

About this Clinical Practice Guideline........................................................................................................ 7

Methods............................................................................................................................................................ 7

Conflict of Interest............................................................................................................................................ 8

Reconciling 2008 CPG Recommendations........................................................................................................ 8

Scope of this CPG.............................................................................................................................................. 9

Highlighted Features of this CPG....................................................................................................................10

Implementation ..............................................................................................................................................10

Guideline Working Group....................................................................................................................... 11

Algorithm .............................................................................................................................................. 12

Recommendations................................................................................................................................. 14

Evaluation for Chronic Kidney Disease .................................................................................................... 17

Background.....................................................................................................................................................17

Military Occupational Risk of CKD ..................................................................................................................17

Periodic Evaluation .........................................................................................................................................18

Acute Kidney Injury Avoidance ............................................................................................................... 20

Background.....................................................................................................................................................20

Prevention of Contrast-induced Nephropathy (CIN) in Patients with CKD ....................................................20

Intravenous Isotonic Crystalloid Solutions .....................................................................................................21

Oral versus IV Volume Expansion ...................................................................................................................22

Emerging and Alternative Interventions.........................................................................................................22

N-acetylcysteine (NAC)...................................................................................................................................23

Renal Replacement Therapy...........................................................................................................................24

Short-Term Statin Therapy .............................................................................................................................24

Theophylline Therapy .....................................................................................................................................25

Summary.........................................................................................................................................................26

Self-Management Strategies................................................................................................................... 27

Background.....................................................................................................................................................27

Dietary Sodium Restriction.............................................................................................................................27

Dietary Protein Restriction .............................................................................................................................28

Weight Loss.....................................................................................................................................................29

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Exercise...........................................................................................................................................................30

Health Education ............................................................................................................................................31

Smoking Cessation..........................................................................................................................................32

Summary.........................................................................................................................................................33

Clinical Management Strategies.............................................................................................................. 34

Background.....................................................................................................................................................34

Model of Care .................................................................................................................................................34

Immunization..................................................................................................................................................36

Nephrotoxins and Adverse Drug Events Avoidance .......................................................................................37

Correction of Acidosis.....................................................................................................................................41

Blood Pressure Targets...................................................................................................................................41

Renin-Angiotensin Aldosterone System (RAAS) Blockade..............................................................................43

Statins for Cardiovascular Risk Reduction ......................................................................................................50

Glycemic Control.............................................................................................................................................54

Iron Therapy ...................................................................................................................................................56

Safety and Efficacy of Erythropoiesis-Stimulating Agents..............................................................................57

Correction of Vitamin D Deficiency ................................................................................................................59

Active Vitamin D Use ......................................................................................................................................60

Phosphate Binders..........................................................................................................................................62

Calcimimetics..................................................................................................................................................63

Summary ............................................................................................................................................... 64

Knowledge Gaps and Recommended Research........................................................................................ 65

Appendix A: Evidence Review Methodology............................................................................................ 67

Conducting the Systematic Review.................................................................................................................68

Convening the Face-to-Face Meeting.............................................................................................................89

Grading Recommendations............................................................................................................................89

Drafting and Submitting the Final CPG...........................................................................................................92

Appendix B: Pharmacotherapy with ACEIs or ARBs.................................................................................. 93

Appendix C: Evidence Table.................................................................................................................... 94

Appendix D: Participant List.................................................................................................................. 101

Appendix E: Acronyms List.................................................................................................................... 103

References........................................................................................................................................... 105

December 2014 Page 4 of 117
Introduction

The Department of Veterans Affairs (VA) and Department of Defense (DoD) Evidence Based Practice 

Working Group (EBPWG) was established and first chartered in 2004, with a mission to advise the 

“...Health Executive Council on the use of clinical and epidemiological evidence to improve the health of 

the population across the Veterans Health Administration (VHA) and Military Health System,” by 

facilitating the development of clinical practice guidelines for the VA and DoD populations. [1] This 

Clinical Practice Guideline (CPG) is intended to provide primary care clinicians with a framework by 

which to evaluate the individual needs and preferences of patients who are experiencing chronic kidney 

disease (CKD), leading to improved clinical outcomes.

In 2008, the VA and DoD published a CPG for the Management of Chronic Kidney Disease (2008 CKD

CPG), which was based on evidence reviewed through 2007. Since the release of that guideline, a 

growing body of research has expanded the general knowledge and understanding of CKD. Recognition 

of the complex nature of this condition has led to the adoption of new strategies to manage and treat 

patients with CKD, as well as the development and use of new pharmacotherapies. 

Consequently, a recommendation to update the 2008 CKD CPG was initiated in August 2013. The 

updated CPG includes objective, evidence-based information on the patient-centered approach to 

management of CKD, the benefits and harms of pharmacologic and non-pharmacologic therapies, the 

management of comorbid conditions, and best practices for care delivery. It is intended to assist health

care providers in all aspects of patient care. The system-wide goal of evidence-based guidelines is to 

improve the patient’s health and wellbeing by guiding health providers who are taking care of patients 

with CKD along the management pathways that are supported by evidence and are thus considered the 

highest standard of care. The expected outcome of successful implementation of this guideline is to:

• Formulate an efficient and effective assessment of the patient's condition

• Optimize the use of therapy to reduce disease progression, reduce symptoms of CKD, and

enhance patient functionality

• Minimize preventable complications and morbidity

• Emphasize the use of personalized, proactive, patient-driven care

December 2014 Page 5 of 117
Background

Chronic kidney disease is one of the most common serious medical conditions affecting adults in the 

United States (US). The Centers for Disease Control and Prevention (CDC) estimate that more than 10% 

of adults in the US—over 20 million people—have CKD, [2] which is defined as having an estimated 

glomerular filtration rate (eGFR) of <60 mL/min/1.73m2 or albuminuria (albumin excretion rate [AER] of 

≥30 mg/24 hours or albumin:creatinine ratio [ACR] of ≥30 mg/g), kidney transplantation, or any of 

several other less common reasons (e.g., urine sediment abnormalities, electrolytes and other 

abnormalities due to tubular disorders, histologic abnormalities, structural abnormalities identified by 

imaging). [3] Patients may suffer from mild illness without symptoms to severe illness associated with 

increased risk of death or progression to end-stage renal disease (ESRD) requiring dialysis or kidney 

transplantation. The risk of developing CKD increases among people over 50 years of age and peaks 

after 70 years of age. [2] In many patients the disease is caused by, or associated with, other conditions 

including diabetes, hypertension, cardiovascular disease, malnutrition, and anemia. Early intervention 

and management is important to stabilize or at least slow down progressive kidney damage, which 

worsens the prognosis of patients with CKD. 

The prevalence of CKD in the Veteran population is estimated to be a third higher than in the general 

population, due to demographic factors and the higher rates of comorbidities associated with CKD, such 

as diabetes mellitus and hypertension. [4] The Veterans Health Administration (VHA) currently cares for 

over 200,000 Veterans with moderate to severe kidney disease in their 153 medical treatment facilities 

or 800 community-based outreach clinics (CBOCs) across the US. [4] In 2002, the National Kidney 

Foundation published treatment guidelines that identified five stages of CKD based on declining eGFR

measurements. [5] Subsequently, the International Society of Nephrology released guidelines in 2013 

which further classified stage 3 CKD patients. [6] The stages of CKD are described in Table 1 below. For a 

given stage of CKD, the categories A1-A3 will increase the risk of CKD progression.

Table 1. Stages of CKD [3,5,6] 

Stage

Stages eGFR

(mL/min/1.73 m2)

Description

G1 Greater than or equal to 90 Kidney damage with normal or increased GFR

G2 60-89 Kidney damage with mildly decreased GFR

G3a 45-59 Mildly to moderately decreased GFR

G3b 30-44 Moderately to severely decreased GFR

G4 15-29 Severely decreased GFR

G5 Less than 15 or dialysis Kidney failure

Albuminuria

Category Range

(mg albumin/g creatinine) 

Description

A1 <30 mg/g Normal to mildly increased

A2 30-300 mg/g Moderately increased

A3 >300 mg/g Severely increased

December 2014 Page 6 of 117
About this Clinical Practice Guideline 

This guideline represents a significant step toward improving the treatment and management of 

patients with CKD in the VA and DoD populations. As with other CPGs, however, challenges remain, 

including the need to develop effective strategies for guideline implementation and to evaluate the 

effect of guideline adherence on clinical outcomes. This guideline is directed for VA and DoD primary 

care physicians involved in the care of Service Members or Veterans who are at risk for or have known 

CKD. The purpose of this guideline is:

• To enhance clinician awareness of risk factors for CKD;

• To highlight evidence-based approaches that prevent acute kidney injury, which is a contributor

to the development of CKD; and

• To identify pharmacologic and treatment strategies that have been shown to delay the

progression of CKD to end-stage renal disease.

This CPG is not intended to serve as a standard of care. Standards of care are determined on the basis of 

all clinical data available for an individual case and are subject to change as scientific knowledge and 

technology advances and patterns evolve. This CPG is based on information available at the date of 

publication, and is intended to provide a general guide to best practices. The guideline can assist care 

providers, but the use of a CPG must always be considered as a recommendation, within the context of 

a provider’s clinical judgment, for the care of an individual patient.

Methods

The methodology used in developing the 2014 CPG follows the Guideline for Guidelines, [7] an internal 

document of the VA and DoD Evidence-Based Practice Working Group (EBPWG). The current document 

is an update to the 2008 VA/DoD Clinical Practice Guideline for the Management of Chronic Kidney 

Disease. This document provides information regarding the process of developing guidelines, including 

the identification and assembly of the Guideline Champions (Champions) and other subject matter 

experts from within the VA and DoD, known as the Work Group, and ultimately, the development and

submission of an updated CKD CPG.

The Champions and Work Group for this CPG were charged with developing evidence-based clinical 

practice recommendations and writing and publishing a guideline document to be used by primary care 

providers within the VA/DoD health care system. Specifically, the Champions for this guideline were 

responsible for identifying the key questions of greatest clinical relevance, importance, and interest for 

the management of patients with CKD. In addition, the Champions assisted in:

1. Providing direction on inclusion and exclusion criteria for the evidence review

2. Assessing the level and quality of the evidence

3. Identifying appropriate disciplines of individuals to be included as part of the Work Group

4. Directing and coordinating the Work Group

5. Participating throughout the guideline development and review processes

The VA Office of Quality, Safety and Value, in collaboration with the Office of Evidence Based Practice, 

US Army Medical Command, the proponent for CPGs for the DoD, identified three clinical leaders, Drs. 

December 2014 Page 7 of 117
Susan Crowley and Suzanne Watnick from VA and Dr. Eric Barnes from DoD, as Champions for the 2014 

CPG. 

The Lewin Team (Team), including DutyFirst Consulting, ECRI Institute and Sigma Health Consulting, LLC, 

was contracted by the VA and DoD to support the development of this CPG and conduct the evidence 

review. The team held the first conference call in August 2013, with participation from the contracting 

officer’s representatives (COR), leaders from the VA Office of Quality, Safety and Value and the DoD 

Office of Evidence Based Practice, and the Champions. During this call, the project team discussed the 

scope of the guideline initiative, the roles and responsibilities of the Champions, the project timeline, 

and the approach for developing specific research questions on which to base a systematic review about 

the management of CKD. The group also identified a list of clinical specialties and areas of expertise that 

are important and relevant to the management of CKD, from which Work Group members were 

recruited. The specialties and clinical areas of interest included: Clinical Dietetics, Geriatrics, Family 

Medicine, Internal Medicine, Nephrology, Nursing (including advance practice nursing), Pharmacy and 

Social Work.

The guideline development process for the 2014 CPG update consisted of the following steps:

1. Formulating evidence questions (Key Questions)

2. Conducting the systematic review

3. Convening a face-to-face meeting with the CPG Champions and Work Group members

4. Drafting and submitting a final CPG about the management of CKD to the VA/DoD EBPWG

Appendix A provides a detailed description of each of these tasks.

Conflict of Interest

At the start of this guideline development process and at other key points throughout, the project team 

was required to submit disclosure statements to reveal any areas of potential conflict of interest in the 

past two years, including verbal affirmations of no conflict of interest at regular meetings. The project 

team was also subject to random web-based surveillance (e.g., ProPublica). If there was a positive (yes) 

conflict of interest response (actual or potential), then action was taken by the co-chairs and evidencebased practice program office, based on the level and extent of involvement to mitigate the conflict of 

interest. Actions ranged from restricting participation and/or voting on sections related to a conflict, to 

removal from the Work Group. Recusal was determined by the individual, co-chairs, and evidence-based 

practice office. No member of the final project team had any conflict of interest

Reconciling 2008 CPG Recommendations

Evidence-based CPGs should be current, which typically requires revisions based on new evidence or as 

scheduled subject to time-based expirations. For example, the US Preventive Services Task Force

(USPSTF) has a process for refining or otherwise updating its recommendations pertaining to preventive 

services. [8] Further, the inclusion criteria for the National Guideline Clearinghouse specify that a 

guideline must have been developed, reviewed or revised with the past five years. 

The CKD Guideline Work Group focused largely on developing new and updated recommendations 

December 2014 Page 8 of 117
based on the evidence review conducted for the priority areas addressed by the Key Questions. In 

addition to those new and updated recommendations, the Guideline Work Group considered the 

current applicability of other recommendations that were included in the previous 2008 CKD CPG, 

subject to evolving practice in today’s environment. Subject to Guideline Work Group consensus, 

recommendations that were no longer relevant to the current practice environment, or were otherwise 

out of scope for this CPG, were not carried forward to this CPG. Recommendations that were considered 

to be relevant to the current practice environment and still in scope for this CPG, and that required no 

substantive (i.e., entailing clinically meaningful) rewording, were carried forward in this CPG. The 

wording was, however, modified slightly to be best utilized in today’s clinical environment and to uphold 

the GRADE recommendation format. For these modified recommendations, the Guideline Work Group 

referred to the available evidence as summarized in the body of the 2008 CKD CPG and did not assess 

the evidence review that was conducted for the 2008 CKD CPG. These “modified carryover” 

recommendations are noted in the recommendations list. 

The Guideline Work Group recognized the need to accommodate the transition in evidence rating 

systems from the 2008 CKD CPG to the current CPG. In order to report the strength of all 

recommendations using a consistent format (i.e., the GRADE system) the Guideline Work Group 

converted the USPSTF strengths of the recommendation accompanying the carryover recommendations 

from the 2008 guideline to the GRADE system. As such, the Guideline Work Group considered the 

strength of the evidence cited for each recommendation in the 2008 CKD CPG as well as harms and 

benefits, values and preferences, and other implications, where possible. In some instances, peerreviewed literature published since the 2008 CKD CPG was considered along with the evidence base 

used for that CPG. Where such newer literature was considered when converting the strength of the 

recommendation from the USPSTF to GRADE system, it is noted in the discussion that follows the 

corresponding recommendation.

The guideline Work Group recognizes that, while there are practical reasons for incorporating findings 

from a previous systematic review or previous recommendations [9] or recent peer-reviewed 

publications into an updated CPG, doing so does not involve an original, comprehensive systematic 

review and, therefore, may introduce bias. 

Scope of this CPG

Regardless of setting or the availability of professional expertise, any patient in the health care system 

should be offered the interventions that are recommended in this guideline after taking into 

consideration the patient’s specific circumstances. 

Guideline recommendations are intended to be patient-centered. Thus, treatment and care should take 

into account a patient’s needs and preferences. Good communication between health care 

professionals and the patient is essential and should be supported by evidence-based information 

tailored to the patient’s needs. The information that patients are given about treatment and care should 

be culturally appropriate and also available to people with limited literacy skills. It should also be

December 2014 Page 9 of 117
accessible to people with additional needs such as physical, sensory or learning disabilities.

This CPG is designed to assist primary care providers in managing or co-managing patients with CKD 

Stages 1-4. Moreover, the patient population of interest for this CPG is adults (men and women), that 

are eligible for care in the VHA and DoD health care delivery system. It includes deployed and nondeployed Veterans as well as active duty Service Members. This CPG does not provide recommendations 

for the management of CKD in children or adolescents. 

Highlighted Features of this CPG

The VA/DoD Guideline for the Management of CKD in Primary Care, first published in 2001, was the first 

such guideline in the US. 

The 2014 edition is the third update to the original CPG, specifically targets primary care clinicians, and 

provides best practice recommendations for the care of populations with CKD stages 1 through 4. A 

particular strength of this CPG is the multidisciplinary stakeholder involvement from its inception, 

ensuring representation from the broad spectrum of clinicians engaged in an ideal patient-aligned care 

team. 

The literature review of interventional studies encompassed a seven year period between 2007 and 

2013, and targeted 12 key questions focusing on the means by which the delivery of health care by the 

primary care clinician could be optimized for patients with CKD. Emphasizing prevention and promotion 

of wellness, the list of recommendations is tightly mapped to the key questions. Importantly, this list is 

also closely harmonized with those of complementary VA/DoD guidelines for the management of

comorbid conditions known to precede or develop from CKD. Furthermore, in recognition of the need 

for cautious generalization from select randomized controlled trial (RCT) populations to the aging 

Veteran with competing comorbidities, the framework for recommendations used in this CPG 

considered factors beyond the strength of the evidence, including balancing desired outcomes with 

potential harms of treatment, equity of resource availability, and the potential for variation in patient 

values. A straightforward algorithm accompanies the guideline to facilitate its translation into effective 

primary care practice.

Implementation 

This CPG and algorithm are designed to be adapted by individual health care providers with

consideration of local needs and resources. The algorithm serves as a guide that providers can use to 

determine the best interventions and timing of care for their patients in order to optimize quality and 

improved clinical outcomes. 

Although this CPG represents the practice on the date of its publication, medical practice is evolving and 

this evolution requires continuous updating based on published information. New technology and more 

research will improve patient care in the future. The CPG can assist in identifying priority areas for 

research and optimal allocation of resources. Future studies examining the results of CPGs may lead to 

the development of new practice-based evidence.

December 2014 Page 10 of 117
Guideline Working Group

Guideline Working Group

VA DoD

Susan T. Crowley, MD, FASN* (Co-Chair) LT Col. Eric Barnes, DO, FASN*(Co-Chair)

Suzanne Watnick, MD* (Co-Chair) Lt Col. Heidi Clark, MS, RD*

Christopher Barrett Bowling, MD Corinne K.B. Devlin, MSN, RN, FNP-BC*

Sarah Campoy, DNP, ANP-BC* MAJ Khayanga Namasaka, MD

Nicole Cheran, RD Annie T. Nguyen, PharmD*

Elaine Furmaga, PharmD* D. Nick Patterson, PharmD, BCPS*

Adriana Hung, MD, MPH* LCDR Robert Selvester, MD

Areef Ishani, MD*

Michelle Kasenfang, RN

Gaurang Shah, MD, FACP, FASN*

Douglas Slotkoff, MD*

Janette Williams-Smith, LCSW

Office of Quality, Safety and Value

Veterans Health Administration

Office of Evidence Based Practice

US Army Medical Command

Eric Rodgers, PhD, FNP, BC

Rene Sutton, BS, HCA

Ernest Degenhardt, COL USA (Ret.) MSN, RN, 

ANP, FNP

Corinne K. B. Devlin, MSN, RN, FNP-BC

Lewin Group ECRI Institute

Cliff Goodman, PhD

Christine Jones, MS, MPH

Hillary Kleiner, MPH

Erin Gardner, BS

Sneha Rangarao, MPH

Mariam Siddiqui, BS

Anjali Jain, MD

James Reston, PhD

Nancy Sullivan, BA

Edmond Baganizi, MB BCh, MPH

Jeff Oristaglio, PhD

Sigma Health Consulting, LLC

Fran Murphy, MD, MPH

*Indicates members of the core editing panel. Additional contributor contact information is available in Appendix

D.

December 2014 Page 11 of 117
Algorithm 

This CPG includes an algorithm which is designed to maximally facilitate clinical decision making for the 

management of CKD. The use of the algorithm format as a way to represent patient management was 

chosen based on the understanding that such a format can allow for efficient diagnostic and therapeutic 

decision making, and has the potential to change patterns of resource use. The algorithm format allows 

the provider to follow a linear approach in assessing the critical information needed at the major 

decision points in the clinical process, and includes:

• An ordered sequence of steps of care

• Recommended observations and examinations

• Decisions to be considered

• Actions to be taken

A clinical algorithm diagrams a guideline into a step-by-step decision tree. Standardized symbols are 

used to display each step in the algorithm, and arrows connect the numbered boxes indicating the order 

in which the steps should be followed. [10] 

Rounded rectangles represent a clinical state or condition.

Hexagons represent a decision point in the guideline, formulated as a question 

that can be answered Yes or No. 

Rectangles represent an action in the process of care.

December 2014 Page 12 of 117
December 2014 Page 13 of 117
Recommendations 

# Recommendation Strength

Evaluation for Chronic Kidney Disease (CKD)

1. While there is insufficient evidence to associate exposure to depleted uranium and 

solvents such as hydrocarbons with CKD, we suggest that clinicians take a detailed 

occupational and non-occupational history.

Weak For

2. We suggest that periodic evaluation for CKD be considered in patients with the 

following:

a. Diabetes, hypertension, other end organ disease (e.g., chronic heart failure

[CHF]), or a personal or family history of kidney disease

b. Systemic illness (e.g., human immunodeficiency virus [HIV], systemic lupus

erythematosus, multiple myeloma)

c. History of acute kidney injury (AKI) (e.g., acute tubular necrosis, urinary tract

obstruction, interstitial nephritis)

d. Elderly patients

e. Races and ethnicities associated with increased risk (e.g., African Americans,

Hispanics, Native Americans)

(Carryover modified from the 2008 CPG)**

Weak For

Acute Kidney Injury Avoidance

Prevention of Contrast-induced Nephropathy (CIN) in Patients with CKD

3. We suggest that patients at increased risk for CIN receive volume expansion with 

intravenous (IV) isotonic crystalloid solutions (saline or sodium bicarbonate) prior to 

and following iodinated contrast administration.

Weak For

4. We suggest offering oral hydration to patients in which IV hydration is not feasible 

for CIN prophylaxis.

Weak For

5. Given inconsistent evidence, we do not recommend for or against the routine 

administration of N-acetylcysteine (NAC) for CIN prophylaxis.

Weak For

6. We recommend against the use of renal replacement therapy (RRT) for CIN 

prophylaxis.

Strong Against

7. We suggest not initiating statin therapy for the purpose of CIN prophylaxis in 

patients undergoing elective angiography.

Weak Against

8. We suggest not offering theophylline therapy for CIN prophylaxis for patients 

undergoing elective coronary angiography.

Weak Against

Management of Chronic Kidney Disease

Self-Management Strategies

9. We suggest the use of dietary sodium restriction as a self-management strategy to 

reduce proteinuria and improve blood pressure control in patients with CKD.

Weak For

10. In patients with stage 3 and 4 CKD, we suggest a protein diet of 0.6 to 0.8 g/kg/day 

as it may slow the decline in glomerular filtration rate (GFR) and progression to 

end-stage renal disease (ESRD). (Carryover modified from the 2008 CPG)

Weak For

11. There is insufficient evidence to recommend for or against weight loss in obese 

patients as an intervention to reduce proteinuria or to slow progression of CKD. 

However, we suggest weight loss interventions in obese patients as part of an 

overall health improvement strategy.

Weak For

December 2014 Page 14 of 117
# Recommendation Strength

12. There is insufficient evidence to recommend for or against exercise with or without 

lifestyle intervention to reduce ESRD, mortality, change in GFR, or change in urinary 

protein. However, we suggest regular exercise as part of an overall health 

improvement strategy.

Weak For

13. There is insufficient evidence to recommend for or against health education to 

reduce time to dialysis initiation or to reduce mortality. However, we suggest CKD 

health education because it supports the aim of maximizing patient-centered care. 

Weak For

14. There is insufficient evidence to recommend smoking cessation to halt progression 

of CKD, however, we suggest tobacco cessation for cardiovascular risk reduction in 

patients with CKD.

Weak For

Clinical Management Strategies

15. We suggest offering multidisciplinary care, if available, for patients with CKD to 

reduce non-fatal stroke, slow progression from micro- to macroalbuminuria, and 

reduce all-cause mortality.

Weak For

16. Although there is insufficient evidence to recommend for or against referral to a 

nephrology specialist for patients with stage 3 CKD for slowing CKD progression, we 

suggest consultation with a nephrologist to assist in the diagnosis and treatment of

patients with any of the following conditions: 

a. eGFR <30 mL/min/1.73 m2 to facilitate education and planning for renal

replacement therapy (dialysis or kidney transplant)

b. Kidney function that is rapidly worsening without obvious cause

c. Metabolic complications of CKD (e.g., anemia, secondary

hyperparathyroidism)

d. CKD of unclear etiology after initial work-up, or has a known or suspected

kidney condition requiring specialized care

e. Nephrotic range proteinuria

f. Nephrolithiasis

Weak For

17. We recommend that treatment with the following vaccinations be considered for

patients with CKD as a measure to prevent infections: 

a. Influenza vaccine*

b. Tdap vaccine

c. Pneumococcal polysaccharide vaccine (i.e., PCV 13 and PPSV23)

d. Hepatitis B vaccine

e. Zoster /shingles vaccine*

f. Varicella vaccine*

g. MMR vaccine*

(*Note: Live vaccines, including nasal influenza (LAIV), may be contraindicated in 

patients with CKD and severe immunodeficiency including treatment with 

immunosuppressive agents)

(Carryover modified from the 2008 CPG)

Strong For

18. We recommend that clinicians avoid or limit the use of nephrotoxic medications for

patients with CKD. (Carryover modified from the 2008 CPG)

Strong For

19. In patients with CKD, we suggest that medications should be reviewed and their 

dosing modified, where appropriate, according to the level of the patient’s kidney 

function. (Carryover modified from the 2008 CPG)

Weak For

December 2014 Page 15 of 117
# Recommendation Strength

20. We suggest the use of bicarbonate supplementation in CKD patients with metabolic 

acidosis to slow the progression of CKD.

Weak For

21. In adult patients with stages 1-4 CKD, we recommend that blood pressure targets 

should be less than 140/90 mmHg. (Carryover modified from the 2008 CPG)

Strong For

22. In patients with non-diabetic CKD, hypertension, and albuminuria, we recommend 

the use of an angiotensin-converting-enzyme inhibitor (ACEI) to prevent 

progression of CKD. Angiotensin II receptor blockers (ARBs) may be substituted for 

patients with an ACEI-induced cough. (Carryover modified from the 2008 CPG)

Strong For

23. In patients with diabetes, hypertension, and albuminuria, we recommend the use 

of an ACEI or ARB to slow the progression of CKD, unless there is documentation of 

intolerance. (Carryover modified from the 2008 CPG)

Strong For

24. We recommend against the use of combination renin-angiotensin-aldosterone 

system (RAAS) blockade (ACEI and ARB, or an ACEI or ARB with a direct renin 

inhibitor) in patients with CKD. 

Strong Against

25. We recommend that all patients with CKD who are not on dialysis and have no 

known history of coronary artery disease be assessed for 10-year CVD risk using a 

validated risk calculator for primary prevention. If at risk (as defined in the VA/DoD 

Management of Dyslipidemia guideline), we recommend use of at least a low dose 

statin.

Strong For 

26. We suggest against the use of statins prescribed with the intent of slowing eGFR 

decline or preserving kidney function.

Weak Against

27. We recommend against intensive glycemic control to patients with stage 3 or worse 

CKD due to the lack of benefit on renal or cardiovascular outcomes and potential 

for significant harm. (Carryover modified from the 2008 CPG)

Strong Against

28. We suggest initiation of oral iron therapy (in preference to parenteral) to support 

iron requirements in patients with CKD stages 3 and 4. 

Weak For

29. We recommend against offering erythropoiesis-stimulating agents (ESAs) to 

patients with CKD for the purpose of achieving a hemoglobin target above 11.5 

g/dL due to increased risk of stroke and hypertension.

Strong Against

30. We recommend against initiating ESAs at a hemoglobin level greater than 10 g/dL. Strong Against

31. We suggest offering supplemental vitamin D to correct vitamin D deficiency in 

patients with CKD stages 3 or 4.

Weak For

32. We suggest not offering active vitamin D analogs or calcitriol to patients with stage 

3 and 4 CKD with elevated parathyroid hormone (PTH) levels due to lack of 

evidence for kidney, bone, or cardiovascular benefit and increased potential of 

harm from hypercalcemia. (Any use of active vitamin D analogs should be managed 

by a nephrologist.)

Weak Against

33. We suggest not offering phosphate binders to patients with stage 3 and 4 CKD with 

normal serum phosphorous. (Carryover modified from the 2008 CPG)

Weak Against

34. We suggest not offering calcimimetics to patients with stage 3 and 4 CKD due to 

lack of evidence for kidney or cardiovascular benefit and increased risk of harm 

from hypocalcemia. 

Weak Against

**For additional information, please refer to Reconciling 2008 CPG Recommendations

December 2014 Page 16 of 117
Evaluation for Chronic Kidney Disease

Background 

Chronic kidney disease is common in the US, particularly among high risk groups. Factors that need to be 

considered prior to screening for an asymptomatic disease include if, a) a simple accurate test is 

available and b) there are treatments that improve patient outcomes. For CKD, there are currently no 

randomized controlled trials that demonstrate an improvement in patient outcomes associated with 

CKD screening. Given the lack of evidence for CKD screening, the Work Group does not encourage 

screening asymptomatic individuals for the presence of kidney disease. The Work Group recommends 

periodic evaluation of CKD in patients at high risk for CKD and further evaluation of CKD in those with 

elements of abnormal kidney tests such as those with albuminuria or abnormal imaging tests.

Military Occupational Risk of CKD

Military personnel have unique environmental and occupational exposures, some of which have been

thought to increase the risk for kidney disease. If confirmed, a change in CKD screening practices for the 

military/Veteran populations would be in order. We therefore undertook a review of the literature to 

summarize the evidence for increased risk of CKD following selected exposures. 

Recommendation

1. While there is insufficient evidence to associate exposure to depleted uranium and solvents such

as hydrocarbons with CKD, we suggest that clinicians take a detailed occupational and nonoccupational history. (Weak For)

Discussion

Two potentially nephrotoxic occupational or environmental exposures were considered in the evidence 

synthesis—depleted uranium and solvents, specifically hydrocarbons. The literature from 2007 forward 

did not provide sufficient evidence to associate hydrocarbon exposure with CKD. Therefore, patients 

exposed to these agents do not currently require routine screening for CKD. However, as the evidence 

base for hydrocarbon exposures may grow in the future, we suggest that providers screen patients 

newly diagnosed with CKD for hydrocarbon exposure and document its presence or absence. [11] The 

clinician should take a detailed occupational and non-occupation patient history, which includes but is 

not limited to: history of diabetes, hypertension, cardiovascular disease, lower urinary tract symptoms 

suggestive of urinary obstruction, hepatitis B or C, human immunodeficiency virus, kidney stones, 

urinary tract infections, symptoms suggestive of a systemic vasculitis (e.g., rash, arthritis, serositis) or 

chronic pain syndrome (raising suspicion for analgesic abuse), genitourinary malignancy, history of 

abdominal/pelvic surgery or radiation, occupational and other exposure to environmental toxins 

(including uranium, solvents and hydrocarbons). 

December 2014 Page 17 of 117
Periodic Evaluation

Recommendation

2. We suggest that periodic evaluation for CKD be considered in patients with the following:

a. Diabetes, hypertension, other end organ disease (e.g., chronic heart failure [CHF]), or a

personal or family history of kidney disease

b. Systemic illness (e.g., human immunodeficiency virus [HIV], systemic lupus erythematosus,

multiple myeloma)

c. History of acute kidney injury (AKI) (e.g., acute tubular necrosis, urinary tract obstruction,

interstitial nephritis)

d. Elderly patients

e. Races and ethnicities associated with increased risk (e.g., African Americans, Hispanics,

Native Americans)

(Carryover modified from the 2008 CPG) (Weak For)

Discussion

The guideline panel recommends assessing all patients for kidney disease risk factors. In patients with 

identified risk factors, further evaluation is performed. The goal of identification of high risk patients 

with CKD is to prevent further progression of disease, evaluate and treat comorbid conditions, aid in 

drug dosing and prevent exposure to potentially nephrotoxic medications.

For every newly discovered patient with kidney disease and those with acute worsening of CKD, the 

history, physical examination, and basic laboratory evaluation remain the cornerstone for establishing 

etiology and ruling out reversible causes. Clinical assessment will help identify the clinical markers that 

indicate kidney disease and outline basic diagnostic testing required in all patients. 

A targeted history to detect the presence and possible contribution of conditions present in a patient 

with new or established CKD includes:

• History of diabetes or kidney disease

• Hypertension

• Cardiovascular disease

• Significant end-organ disease (liver disease)

• Lower urinary tract symptoms suggestive of urinary obstruction

• Systemic illness (e.g., hepatitis B or C, HIV)

• Symptoms suggestive of a systemic vasculitis (e.g., rash, arthritis, serositis)

• Chronic pain syndrome (raising suspicion for analgesic abuse)

• Genito-urinary malignancy

• History of abdominal/pelvic surgery or radiation

• Exposure to environmental toxins or nephrotoxins

To assist in identifying elderly patients at increased risk for CKD, O’Hare et al. presents a mortality risk 

stratification based on age group for varying levels of Modification of Diet in Renal Disease (MDRD)

December 2014 Page 18 of 117
glomerular filtration rate (GFR). [12] 

In addition, medications should be reviewed to identify those that may be contributing to kidney

impairment including: non-steroidal anti-inflammatory drugs (NSAIDs), other analgesics, diuretics, 

lithium, cyclosporine, tacrolimus, antiviral agents, chemotherapeutic agents, antibiotics, allopurinol, and 

dietary and herbal supplements.

The guideline panel recommends screening for CKD with a serum creatinine measurement for use in 

GFR estimation and analysis of a random urine sample for albuminuria. Both measurements are needed 

to exclude the diagnosis of CKD because both conditions can exist independently.

Renal ultrasound helps establish the diagnosis and prognosis by documenting the size of the kidneys.

Normal size indicates kidney disease that may be amenable to medical treatment. Large kidneys (e.g., 

>13 cm) can be seen in diabetes, amyloid, infiltrative diseases and HIV-associated nephropathy (HIVAN). Small echogenic kidneys (<8 cm) suggest irreversible disease. Asymmetry in size suggests 

renovascular disease or ureteral obstruction and can also be due to a congenital abnormality.

December 2014 Page 19 of 117
Acute Kidney Injury Avoidance

Background

Acute kidney injury (AKI) is being increasingly recognized as a forerunner of CKD. Additionally, CKD is 

both a consequence of and a risk factor for AKI. Prevention of AKI may help reduce progression of CKD; 

thus, AKI avoidance should be a goal of care. Risk factors for AKI are increasingly described; however, 

the most well-described risk factor of AKI is the parenteral administration of iodinated radiocontrast 

agents. 

Prevention of Contrast-induced Nephropathy (CIN) in Patients with CKD 

AKI due to contrast-induced nephropathy (CIN) is an unfortunate complication of diagnostic and 

interventional procedures that require the intravenous (IV) administration of radiocontrast. There is no 

standard definition for CIN, however it is broadly described as acute kidney dysfunction following 

exposure to intravascular contrast media. [13] CIN is associated with unfavorable outcomes and 

prolonged hospitalizations. While numerous trials have suggested therapies that prevent the rise in 

creatinine associated with contrast nephropathy, no study has demonstrated an effect on patientoriented outcomes such as prevention of acute or chronic dialysis. Trials generally look at preventing a 

small change in creatinine (typically 25% or 0.25 mg/dL) and no trial has ever demonstrated a reduction 

in hospitalization, dialysis need, or mortality related to CIN prophylaxis. [14,15] Risk factors for 

developing CIN include:

• Preexisting CKD; serum creatinine >1.5 mg/dL or eGFR <60 mL/min

• Diabetes mellitus

• Heart failure

• Age >75 years

• Volume of contrast >100 mL

• Use of high-osmolality contrast

Patients who are going to receive radiocontrast agents should be made aware of the potential risk for 

developing CIN. Low-risk patients should maintain adequate hydration orally prior to contrast 

administration. High-risk patients should be given the standard therapy (defined below) and possibly 

one or more of the CIN prophylaxis measures discussed below. 

There are a variety of medications, techniques and IV fluids that have been examined for CIN 

prophylaxis. The current standard therapy for CIN prophylaxis is centered on:

• Obtaining a euvolemic state prior to radiocontrast administration through the use of IV and oral

fluids

• Avoiding or minimizing the amount of radiocontrast administered

• Using low or iso-osmolar non-ionic radiocontrast

We review below several strategies and interventions to prevent CIN in patients determined to be at 

high risk of CIN with imaging procedures that require contrast. 

December 2014 Page 20 of 117
Intravenous Isotonic Crystalloid Solutions 

Recommendation

3. We suggest that patients at increased risk for CIN receive volume expansion with intravenous (IV)

isotonic crystalloid solutions (saline or sodium bicarbonate) prior to and following iodinated

contrast administration. (Weak For)

Discussion

A systematic review of the literature identified nine studies of low to very low quality to address the 

efficacy of sodium bicarbonate volume administration for the prevention of CIN. Two studies evaluated 

sodium bicarbonate versus sodium chloride infusions in patients with moderate to severe CKD 

undergoing coronary angiography. There was no significant difference between groups regarding 

incidence of CIN (4.2% versus 2.7%, p=0.61, [N=145]; [16] and 13.4% versus 14.6%, p=0.82, [N=353];

[17]). One study infused fluids two hours before, during, and after contrast administration, with 

assessment of outcome via serum creatinine (SCr) at day one or two post-contrast. [16] In the other 

trial, sodium bicarbonate was administered peri- and post-procedural, while measuring outcomes via 

eGFR at day one through day four post contrast medium.

Two RCTs evaluated sodium bicarbonate and N-acetylcysteine (NAC) versus sodium chloride and NAC. 

These trials (n=454) found no significant differences between groups in incidence of CIN (4.5% versus

5.4%, p=.54). In one study by Lee et al. diabetic patients underwent coronary or endovascular 

intervention or angiography. [18] The other trial by Maoli et al. studied patients with CKD and creatinine 

clearance (CrCL) below 60 mL/min/1.73m2 in those undergoing planned angiography or intervention.

[19] Another trial by Briguori et al. looked at a similar intervention, and had a third arm with saline plus 

ascorbic acid and oral NAC. [20] Here, incidence of CIN was significantly lower than the saline group 

(p=0.019). 

Four additional RCTs looked at sodium bicarbonate bolus versus saline. Two of these studies found no 

significant differences between groups. [21,22] A study by Vasheghani-Farahani et al. found a significant 

difference between the single-bolus sodium bicarbonate plus saline versus saline solution (1.4% sodium 

bicarbonate, 12.5% saline, p=0.017) while another study found a significantly lower incidence of CIN in 

the sodium bicarbonate bolus group (3.3% sodium bicarbonate bolus, 27.5% sodium chloride bolus, risk 

ratio 0.12, 95% CI 0.016 to 0.91, p=0.01). [23,24] 

Due to different results from multiple trials, several meta-analyses and systematic reviews were 

performed. The results from the meta-analyses showed benefit, but heterogeneity and publication bias 

makes it difficult to make clear recommendations regarding the utility of sodium bicarbonate over the 

use of saline infusion. The 2008 CKD CPG commented that providing IV infusions of normal saline or 

sodium bicarbonate solutions during the peri-procedural period of contrast administration may reduce 

the incidence of contrast induced nephropathy. [25] Given the heterogeneity of the literature and 

evidence from our previous guideline, we suggest offering infusion of isotonic or sodium bicarbonate as 

standard therapy for CIN prophylaxis in patients at appropriate levels of high risk.

December 2014 Page 21 of 117
Oral versus IV Volume Expansion

Recommendation

4. We suggest offering oral hydration to patients in which IV hydration is not feasible for CIN

prophylaxis. (Weak For)

Discussion

Review of the literature for this update identified a single meta-analysis that included 513 patients 

within six trials who underwent percutaneous coronary intervention. [26] All but one of the trials used 

normal saline in the IV fluid arm (one used 0.45% saline). The oral fluid arm regimen varied markedly 

from trial to trial and included mineral water, oral sodium chloride with unrestricted fluid intake, 

unrestricted fluid intake alone and, finally, 1000 mL of fluid over 10 to 12 hours prior to contrast 

administration. The radiocontrast administered was predominately low-osmolality non-ionic and the 

average volume given was 101 mL to 201 mL. After 48-72 hour follow-up, there was no statistically 

significant difference in the incidence of CIN between the oral and IV groups.

Given the larger body of evidence demonstrating benefit of IV hydration, we suggest offering oral 

hydration to patients in which IV hydration is not feasible for CIN prophylaxis. While there is no 

universally accepted oral fluid regimen, patients should be counseled to consume at least 1000 mL of 

fluid over the 12 hours prior to contrast administration.

Emerging and Alternative Interventions 

Automated Induced Diuresis with Matched Hydration 

A systematic review of the literature conducted for the update of this guideline identified a single 

randomized controlled trial that included 170 patients undergoing coronary procedures. [27] One of two 

groups consisted of 87 patients who underwent furosemide-induced diuresis followed by matched 

hydration (FMH) prior to undergoing coronary procedures. Matched hydration was achieved using a 

device which delivers replacement fluid to a patient in an equal amount to the volume of urine the 

patient makes. The FMH received an initial 250 mL bolus of normal saline delivered over 30 minutes 

followed by an IV bolus of 0.5 mg/kg furosemide. Further IV hydration was automatically adjusted to 

precisely replace the patient’s urine output. When a urine output rate more than 300 mL/hour was 

obtained, patients underwent coronary procedures. Matched fluid replacement was maintained during 

the procedure and for four hours post procedure. A second (control) group of 83 patients received IV 

hydration with normal saline (1 mL/kg/hour) for at least 12 hours prior to and 12 hours after undergoing 

coronary procedures. All patients received non-ionic, low-osmolality radiocontrast. After a 72-hour 

follow-up, there was a statistically significant lower incidence of CIN in the FMH group (4.6% FMH, 18% 

saline; p=0.005. [27] This and other emerging evidence may lead to a suggestion for furosemide with 

matched hydration in patients with stage 3 or 4 CKD. 

Remote Ischemic Pre-conditioning (RIPC) 

Review of the literature for this update identified two randomized controlled trials by Igarashi et al. and 

Er et al. [28,29] The trials included a total of 160 patients that received standard therapy with normal 

December 2014 Page 22 of 117
saline and RIPC within two hours of undergoing elective angiography. The radiocontrast administered 

was low-osmolality and non-ionic. The RIPC regimen consisted of five minute inflation of a standard 

upper-arm blood pressure cuff to 200 mmHg or 50 mmHg above the patient’s systolic blood pressure. 

This was then followed by five minutes of deflation. The inflation and deflation cycle was repeated four 

times within two hours of the patient undergoing elective angiography. In one of the studies a third arm 

of patients received standard therapy with normal saline and sham RIPC which consisted of inflation of a 

standard upper-arm blood pressure cuff to the patient’s diastolic blood pressure minus 10 mmHg. After 

a 24-48 hour follow-up, there was a statistically significant lower incidence of CIN in the RIPC group 

(eight patients in the control group (26.9%) versus two patients in the RIPC group (7.7%), which could be 

clinically meaningful. Pending a stronger supporting evidence base, RIPC may be combined with 

standard therapy in the future for CIN prophylaxis in patients undergoing elective coronary angiography. 

Vitamin E 

Vitamin E is a fat-soluble antioxidant vitamin available over the counter. The recommended daily 

allowance of vitamin E as alpha tocopherol is 15 mg. Review of the literature for this update identified 

two randomized controlled trials that included a total of 325 patients. The larger RCT by Tasanarong et 

al. studied 305 patients with mild to moderate CKD, comparing α-tocopherol 350 mg/day, γ-tocopherol 

300 mg/day, and placebo. [14] All patients received standard therapy, which consisted of 0.9% saline 

infusion at a rate of 1 mL/kg/hr for 12 hours before and 12 hours after elective coronary procedures, 

and volume administered 1353 ±320 mL α-tocopherol, 1498 ±300 mL γ-tocopherol, 1520 ±370 mL 

placebo, depending on the group. Study participants were given their vitamin E or placebo daily for five 

days pre-procedure and two days post-procedure. The radiocontrast administered was low-osmolality 

and non-ionic. After 48 hours, there was a statistically significant lower incidence of CIN in the αtocopherol and γ-tocopherol groups versus placebo treated control group (4.9% and 5.9% versus 14.9%, 

respectively). 

The second RCT by Kitzler et al. [30] had three arms that included vitamin E plus 0.45% saline versus Nacetylcysteine plus 0.45% saline versus 0.45% saline alone. This RCT included only 30 patients, none of 

which developed CIN. The results indicate that neither vitamin E nor NAC in addition to saline provided 

additional benefit versus saline alone. 

The evidence suggests that there are some benefits to be gained from use of tocopheral. Oral vitamin E 

could be utilized as an adjunct to standard CIN prophylaxis therapy.

N-acetylcysteine (NAC)

Recommendation

5. Given inconsistent evidence, we do not recommend for or against the routine administration of Nacetylcysteine (NAC) for CIN prophylaxis. (Weak For)

Discussion

Over the past years, NAC has received substantial attention as an intervention to prevent contrastinduced AKI during various types of iodinated contrast administration. Multiple RCTs have shown 

December 2014 Page 23 of 117
conflicting results as to the efficacy of NAC. Meta-analyses have been performed to address this topic 

but have been inconclusive.

A review of the literature for this update identified one RCT that enrolled cardiac surgery patients 

receiving IV NAC versus placebo. There was no significant difference between the incidences of AKI in 

both groups (28% NAC versus 31% placebo). [31] 

The 2008 CKD CPG commented that the use of NAC may be effective in reducing the incidence of 

contrast nephropathy; however, the results were inconsistent. [32-47] Additionally, factors such as cost, 

history of drug shortages, and patient inconvenience should also be taken into consideration of NAC. At 

this time there is insufficient evidence to suggest for or against the routine administration of NAC for 

CIN prophylaxis. However, there is a large ongoing trial sponsored by the Department of Veterans Affairs 

that compares the effectiveness of IV isotonic sodium bicarbonate with IV isotonic sodium chloride and 

oral NAC with placebo for the prevention of serious adverse outcomes. This trial is slated to conclude in 

March 2016. [48] 

Renal Replacement Therapy

Recommendation

6. We recommend against the use of renal replacement therapy (RRT) for CIN prophylaxis. (Strong

Against)

Discussion

Review of the literature for this update identified a single meta-analysis that included 751 patients 

within six studies who received radiocontrast. Different types of radiocontrast were used, most of which 

were low-osmolality. RRT utilized included conventional hemodialysis and continuous renal replacement 

therapy (CRRT) initiated both before and after contrast administration. All patients appear to have 

received standard therapy to avoid CIN. After 48-72 hour follow-up, RRT did not significantly reduce the 

incidence of CIN. [49] RRT is not innocuous as it requires the placement of a large central venous 

catheter. Furthermore, while the therapy is generally safe, it can cause hemodynamic instability and 

cardiac arrhythmia. Thus, in the absence of demonstrable benefit, the risks of RRT prohibit its use as a 

rational strategy for CIN prophylaxis. 

Short-Term Statin Therapy

Recommendation

7. We suggest not initiating statin therapy for the purpose of CIN prophylaxis in patients undergoing

elective angiography. (Weak Against)

Discussion

Review of the literature since publication of the previous version of the VA/DoD CKD guideline identified 

three RCTs involving statin therapy for CIN prophylaxis that included a total of 3,458 patients undergoing 

coronary angiography. Patients were randomized to receive rosuvastatin 10 mg/day for two days before

and three days after procedure, or standard hydration therapy, which was administered at the 

December 2014 Page 24 of 117
physician’s discretion and included isotonic saline (0.9% sodium chloride, 1 ml/kg/hr) started 12 hours

before and continued for 24 hours after contrast medium administration. The radiocontrast 

administered was low-osmolality and non-ionic. After a 72-hour follow-up, there was a statistically 

significant lower incidence of CIN in the rosuvastatin group. The interpretation of this study is 

confounded because the rosuvastatin group did not receive standard hydration therapy. [15] 

Toso et al. [50] randomized 304 patients to receive high-dose atorvastatin (80 mg/day) in combination 

with standard hydration therapy or standard hydration therapy alone. The radiocontrast administered 

was low-osmolality and non-ionic; all patients were given NAC. There was no statistically significant 

difference in the incidence of CIN among the groups. [50] 

Liu et al. [51] randomized 156 patients to receive atorvastatin (40 mg/day) therapy alone, or 

atorvastatin (40 mg/day) therapy in combination with alprostadil (20 mcg/day) IV, for seven days 

starting at one day prior to coronary angiography. All patients received standard therapy. Some patients 

experienced hypotension and dizziness with alprostadil infusion. There was no statistically significant 

difference in the incidence of CIN among the groups. [51] 

Considered together, the aforementioned studies do not convincingly support the use of statins for the 

purpose of CIN prevention.

Theophylline Therapy

Recommendation

8. We suggest not offering theophylline therapy for CIN prophylaxis for patients undergoing elective

coronary angiography. (Weak Against)

Discussion

Review of the literature during the relevant time period for this update identified a single RCT that 

included a total of 217 patients. The authors compared the combination of NAC 600 mg twice daily plus

theophylline 200 mg twice daily both given the day preceding and the day of elective coronary

angiography plus standard therapy versus NAC plus standard therapy versus standard therapy only. The 

radiocontrast administered was low-osmolality and non-ionic. After 48 hour follow-up, there was a 

statistically significant lower incidence of CIN in the NAC plus theophylline plus standard therapy group. 

The authors stated that no arrhythmias were seen with theophylline administration during the study. 

[52] However, the significant adverse effect profile of theophylline including central nervous system 

excitement, headache, insomnia, irritability, restlessness, seizures, tachycardia and diarrhea, preclude 

support for its routine use as a CIN prophylactic measure. 

In addition to the literature found and assessed during the 2013 evidence review, the guideline panel 

recognized that there exists some newer literature to further support the weak recommendation against 

theophylline therapy. A recently published systematic review found that there is inconsistent evidence 

of efficacy for theophylline across eight clinical trials for contrast-induced AKI prevention. [53] 

December 2014 Page 25 of 117
Summary

In summary, AKI is a forerunner to CKD and may contribute to CKD progression. CIN is a potentially 

preventable form of AKI. Beyond standard therapy, additional emerging therapies to prevent CIN in 

patients at high risk could include vitamin E, RIPC, and automated diuresis.

December 2014 Page 26 of 117
Self-Management Strategies

Background

The role of the patient in management of CKD is being increasingly emphasized. We reviewed the 

literature for evidence of self-management strategies that might reduce CKD progression. Strategies 

identified include participation in multidisciplinary models of hypertension management, dietary sodium 

intake modification, dietary protein limitation, routine nutritional vitamin D supplementation, weight 

loss, exercise, health education, over-the-counter medication use, and smoking cessation. More broadly, 

evidence suggests that patient self-management plays an essential role in the management of any 

chronic disease. According to the Wagner model of chronic disease management, which has been 

adopted by many chronic care providers, patient self-management is a critical element. [54] 

Dietary Sodium Restriction

Recommendation

9. We suggest the use of dietary sodium restriction as a self-management strategy to reduce

proteinuria and improve blood pressure control in patients with CKD. (Weak For)

Discussion

The three RCTs that compared dietary sodium restriction to other interventions (diet or medication) 

were rated as fair quality for various reasons ranging from baseline imbalances in important patient 

characteristics to lack of an appropriate control group. [55-57] Blinding of dietary interventions was not 

feasible. 

De Brito-Ashurst et al. [55] compared blood pressure at a six-month follow-up for hypertensive patients

with CKD receiving a tailored low-salt diet to a control group receiving only advice on achieving a lowsalt diet. This study included 56 patients and reported that changes in eGFR from baseline to follow-up 

were similar for patients treated with low-salt dietary intervention and those given low-salt dietary 

advice (decrease of 3.0 ml/min/1.73m2

 [95% CI 0.1 to 6.0] and 3.4 ml/min/1.73m2, 95% CI 1.0 to 5.7 for 

intervention and control groups, respectively). The reduction in systolic blood pressure (primary 

endpoint) was significantly greater (by 8 mm Hg, p=0.0003) in those who received tailored low-salt 

dietary intervention compared to control group care. [55] 

McMahon et al. [56] evaluated the effects of sodium intake on blood pressure, proteinuria, and markers 

of cardiovascular and kidney disease progression in 25 patients with stage 3 or 4 CKD and hypertension. 

The study compared change in proteinuria levels between patients following a low-salt diet as compared 

to those following a high-sodium diet. Significantly lower proteinuria levels were observed for patients 

on a low-salt diet relative to high-salt diet (835 mg/24hr [95%CI, 185 to 1600] versus 493 mg/24hr 

[95%CI, 123 to 1300]—a difference of 342 mg/24hr [95%CI, 62 to 300], p<0.01). [56] 

Slagman et al. [57] examined the effects of dietary sodium restriction with mono or dual reninangiotensin aldosterone system (RAAS) inhibition in 52 non-diabetic CKD patients. All patients received a 

background treatment with ACEIs. The study examined proteinuria reduction with the use of either an 

December 2014 Page 27 of 117
ARB with a regular-sodium diet (target 200 mmol Na+

/day), a low-sodium diet (target 50 mmol Na+/day), 

or the combination of a low-sodium diet with an ARB. 

The addition of an ARB only (ARB/ACEI and a regular-sodium diet) did not significantly change creatinine 

clearance, but reduced proteinuria from 1.68 (95% CI, 1.31 to 2.14) g/day to 1.44 (95% CI, 1.07 to 1.93) 

g/day (p=0.003). A significantly larger (p<0.001) proteinuria reduction was seen with a low-sodium 

diet/ACEI therapy (-51%, 95% CI, -43% to -58%) than with the ARB/ACEI therapy (-21%, 95% CI, -8% to -

32%). Addition of a low-sodium diet only (low-sodium diet/ACEI) reduced proteinuria levels to 0.85 (95% 

CI 0.66 to 1.10) g/day. Additionally, utilizing the low-sodium diet/ACEI therapy decreased creatinine 

clearance (from 72 ml/min [62 to 84] to 66 ml/min [57 to 76], p=0.002). Finally, the combined therapy

(low-sodium diet + ARB/ACEI) decreased creatinine clearance (from 72 ml/min [62 to 84] to 61 mL/min 

[53 to 70], p<0.001) and produced the lowest level of proteinuria (0.61, 95% CI, 0.53 to 0.91) g/day, 

p<0.001). However, reduction of proteinuria by the combined therapy was not significantly larger than 

the reduction achieved with the low-sodium diet/ACEI therapy alone (-62%, 95% CI, -53% to -70%). [57] 

Dietary Protein Restriction

Recommendations

10. In patients with stage 3 and 4 CKD, we suggest a protein diet of 0.6 to 0.8 g/kg/day as it may slow

the decline in glomerular filtration rate (GFR) and progression to end-stage renal disease (ESRD).

(Carryover modified from the 2008 CPG) (Weak For)

Discussion

Several studies over the past 50 years have examined role of dietary protein restriction in reducing CKD 

progression. Most of these studies have compared low protein diets (LPD) with regular, standard or 

usual protein diets (RPD) in stages 3 and 4 CKD. Two meta-analyses and one systemic review have been 

published since 2008. Two reports examined patients with diabetic nephropathy, [58,59] and one report 

evaluated studies in non-diabetic kidney disease. [60] Most studies in the review by Robertson et al. 

were included in the recent meta-analysis by Nezu, et al. [58,59] 

Nezu, et al. examined 13 randomized controlled trials that included 209 type 1 and 555 type 2 CKD 

patients with diabetic nephropathy. [58] The LPD group (n=385) was prescribed 0.6-0.8 g/kg/day protein 

intake, while the RPD group (n=394) was instructed to ingest 1.0-1.6 g/kg protein daily. The study 

duration was from 4 to 60 months, while the individual studies contained 15 to 112 subjects. 

Importantly, the authors assessed the dietary compliance by estimating the protein intake in 10 studies 

using the Maroni’s formula [61,62] that uses 24 hour urinary urea nitrogen excretion. The compliance 

was calculated as actual protein intake ratio (APIR) using fraction of the estimated protein intake of the 

LPD to the RPD groups. The authors set a cutoff value of 0.9 APIR as optimal indicator of dietary 

compliance. The review found that the APIR ranged from 0.44 to 1.07, with nine studies showing values 

less than 0.9. [58] 

The primary outcome of the Nezu study was a change in GFR or creatinine clearance. [58] The secondary 

outcomes were changes in proteinuria, HbA1c and serum albumin values post-treatment. In 11 studies 

December 2014 Page 28 of 117
of 624 patients, the authors reported that the post-treatment GFR in the LPD group was significantly 

greater (5.82 ml/min/1.73m2

, p <0.001) than the RPD group. In a subgroup analysis, APIR had a 

significant effect on GFR. Thus, APIR <0.9, indicating fair compliance had better preservation of GFR than 

higher APIR values (p<0.006). In twelve studies that reported data in 634 patients, no difference was 

found in proteinuria. HbA1c in 11 studies showed modest improvement with the LPD. Serum albumin 

was reported by only four studies (179 patients), which showed significant heterogeneity and 

asymmetry. Due to small sample size and short intervention time noted in these studies, clinical 

significance of absence of any significant change in serum albumin is uncertain. [58] 

Robertson et al. reviewed the role of protein restriction in diabetic kidney disease. [59] Their review 

included nine RCTs and two before and after intervention studies. Their review showed that relative risk 

of ESRD or death was 0.23 (95% CI 0.07 to 0.72) in patients assigned to the LPD group. An effect of LPD 

on GFR was insignificant in both types 1 and 2 diabetes. However, the actual protein intake in the LPD 

group ranged from 0.7 to 1.0 g/kg daily, indicating potentially poor adherence to the prescribed diet.

[59] 

Fouque and Laville conducted a systemic review of the LPD in non-diabetic CKD stages 3 to 5 not 

receiving dialysis therapy. [60] The RDP group was prescribed 0.8 g/kg/day or greater protein intake. The 

LPD group was assigned 0.6 g/kg/day or a very low protein diet (0.3 g/kg/day) with essential amino acids 

or ketoacid supplements. They identified 10 RCT that included 1002 patients in the LPD group and 998 in 

the RPD group. The primary outcome was all-cause mortality or initiation of dialysis therapy. One 

hundred and thirteen primary outcome events were noted in the restricted protein group compared to 

168 in the RPD group (RR 0.68, 95% CI 0.55 to 0.84). The restricted protein diet resulted in a highly 

significant reduction in relative risk of the primary outcome (32%, p <0.002). The benefit of LPD was 

seen across the spectrum of causes of kidney disease. The difference in actual protein intake between 

the two groups was 0.2 to 0.35 g/kg/day. [60] 

In conclusion, the data shows that low protein diets, in the range of 0.6 to 0.8 g/kg/day exert a salutary 

effect in both diabetic and non-diabetic kidney diseases. The benefit was noted both in prevention of 

kidney failure and preservation of GFR. Two important caveats should be emphasized. First, low protein 

diets should be prescribed with optimal caloric intake to prevent muscle wasting and malnutrition. 

Second, careful monitoring of actual protein intake by 24 hour urinary urea nitrogen excretion should be 

carried out. Nutritional intervention should be a team approach that includes the primary care clinician, 

dietitian, patient and family members.

Weight Loss

Recommendation

11. There is insufficient evidence to recommend for or against weight loss in obese patients as an

intervention to reduce proteinuria or to slow progression of CKD. However, we suggest weight

loss interventions in obese patients as part of an overall health improvement strategy. (Weak For)

December 2014 Page 29 of 117
Discussion

The single relevant systematic review was rated as poor quality because the authors performed a metaanalysis of data to compare pre- and post-diet renal outcomes. [63] The lack of a concurrent control 

group creates a high potential for bias from confounding factors. The investigators analyzed five studies 

(two RCTs, three observational) that evaluated the potential benefits of weight loss due to hypocaloric 

diets in obese patients with non-dialysis dependent CKD. [63] Because the authors only analyzed the 

pre-post findings in the groups that received the diet, they essentially did an analysis of case series 

rather than studies with parallel control groups. The systematic review found no significant difference in 

change in GFR or creatinine clearance (weighted mean difference [WMD] 4.25 ml/min [95% CI -3.30 to 

11.81]); the 95% CI indicates very serious imprecision in the estimate of effect. The meta-analysis found 

significant difference in favoring weight loss in reduction in proteinuria (WMD -1.31 g/24h, 95% CI -2.11 

to -0.51, p=0.001); however, the test for heterogeneity in effect sizes indicated serious inconsistency 

among the individual study results in the meta-analysis. [63] 

In the opinion of the Work Group, the benefits of weight loss in obese subjects to reduce renal 

outcomes are uncertain. However, as overweight and obesity are associated with increased prevalence 

and worsening of several obesity-associated conditions, including type 2 diabetes, hypertension, 

dyslipidemia, metabolic syndrome, osteoarthritis, and obstructive sleep apnea, it is recommended that 

the VA/DoD Clinical Practice Guideline for the Management of Obesity and Overweight (OBE)1 be 

reviewed for additional information regarding overweight and obese patients.

Exercise

Recommendation

12. There is insufficient evidence to recommend for or against exercise with or without lifestyle

intervention to reduce ESRD, mortality, change in GFR, or change in urinary protein. However, we

suggest regular exercise as part of an overall health improvement strategy. (Weak For)

Discussion

Exercise versus no exercise

The only relevant systematic review comparing exercise to no exercise was rated as fair because the 

author reported that the single small RCT included therein had incomplete reporting of results. [64] This 

systematic review identified one RCT with 30 patients that compared the benefits of an exercise 

intervention to no exercise on renal endpoints in patients with CKD. The exercise intervention included 

at-home bicycle ergometer exercise, walking, running, and swimming, gradually increased in duration 

1 See the VA/DoD Clinical Practice Guideline for Management of Obesity and Overweight. Available at: 

http://www.healthquality.va.gov/guidelines/cd/obesity/index.asp 

December 2014 Page 30 of 117
(up to 30 minutes) and intensity over time. The results showed no significant difference between groups 

in ESRD, all-cause mortality, or median change in GFR. 

Exercise plus lifestyle intervention versus usual care

Two RCTs evaluated the combined effect on renal outcomes of a combination of exercise and lifestyle 

interventions in patients with CKD. [65,66] One study was primarily interested in the intervention effect 

on cardiovascular fitness and risk factors, but also reported on change in eGFR, serum creatinine, and 

albumin during the course of the study. In addition to exercise training, the patients received lifestyle 

guidance from a psychologist and dietitian as well as multidisciplinary care focused on cardiovascular 

risk management. There was no significant between-group difference in change in serum creatinine and 

serum albumin from baseline to 12 months follow-up. [65] Another trial investigated the combined 

effect of an exercise program and a nutrition program with counseling and group cooking classes 

compared with usual dietary counseling on cardiovascular risk factors and CKD-related outcomes 

(change in eGFR and urinary protein). This trial found no significant between-group difference in mean 

reduction in urinary protein from baseline to 12 months. Thus, neither investigator found that exercise 

plus lifestyle intervention significantly affected change in eGFR between treatment and control groups. 

[66] 

Although current evidence does not support the benefits of exercise in CKD patients, physical activity 

has the potential to provide health benefits and should be encouraged. 

Health Education

Recommendation

13. There is insufficient evidence to recommend for or against health education to reduce time to

dialysis initiation or to reduce mortality. However, we suggest CKD health education because it

supports the aim of maximizing patient-centered care. (Weak For)

Discussion 

Education versus usual care 

Two systematic reviews evaluated the impact of health education interventions versus usual care in 

patients with CKD. The systematic review by Clase et al. of three RCTs compared educational 

interventions to usual care or standard education to an enhanced education program in patients with 

CKD. [64] Clase et al. identified one RCT that measured the progression to ESRD and found significantly 

fewer patients progressed to ESRD in the education group (60%) versus the usual care group (72%, p 

<0.001). [64] The study reported the time to dialysis was significantly shorter in the education group (14 

months) than the usual care group (17 months, p <0.001). The study reported no significant betweengroup difference in reducing mortality prior to dialysis (education 13% versus usual care 7%, p=0.18). 

Clase et al. also identified one RCT that reported on long-term survival, finding longer median survival in 

the education group (7.84 years) compared to the usual care group (5.07 years), although the difference 

was not statistically significant (p=0.053). [64] The third RCT compared enhanced versus standard 

education and is discussed below.

December 2014 Page 31 of 117
The systematic review by Li et al. identified one RCT that compared an education program with usual 

care in patients with diabetic kidney disease. [67] This RCT reported change in self-efficacy at the end of 

an education intervention (five weeks) and at last follow-up (three months) in patients with diabetes 

and CKD. The study found a significant between-group difference in self-efficacy favoring the education 

intervention at the end of treatment, but no significant between-group difference in change from 

baseline to last follow-up. [67] 

An additional prospective controlled study by Choi and Lee [68] was identified that compared a face-toface self-management educational program to usual care in patients with CKD. Choi and Lee [68] 

reported no significant between-group difference in change in eGFR from baseline to eight weeks; the 

effect estimate had very serious imprecision due to the lack of between-group effect size and large 

variance around the reported change scores. The study also found no change in SCr in either group from 

baseline to eight weeks follow-up; although the variance was low, the estimate had serious imprecision 

because it came from a single small study. 

Enhanced versus Standard Education

In a systematic review, Clase et al. also identified one RCT that compared enhanced education (i.e., a 75-

minute slide presentation along with booklet of presentation contents) versus standard education 

interventions and found that the enhanced education group had a significantly longer average time 

before initiating dialysis (an additional 4.6 months) than the standard education group (p <0.05). [64] 

Although there was demonstrated benefit the effect estimate was methodologically limited. While there 

is insufficient evidence that renal outcomes are improved by using the self-management strategies of 

health education in adult CKD patients, the guideline panel emphasizes the importance of education for

each patient in order to enhance patient-driven care. Additional studies of longer duration are needed 

to better gauge the impact of educational interventions on outcomes in patients with CKD. 

Smoking Cessation

Recommendations

14. There is insufficient evidence to recommend smoking cessation to halt progression of CKD,

however, we suggest tobacco cessation for cardiovascular risk reduction in patients with CKD.

(Weak For)

Discussion

Smoking is highly prevalent in the general population. Numerous adverse effects of tobacco use have 

been described including illness and death. Tobacco use has been associated with over 435,000 deaths 

annually in the US. Smoking is a known cause of multiple cancers, heart disease, stroke, chronic 

obstructive pulmonary disease (COPD), and many other diseases (see the VA/DoD CPG for the 

December 2014 Page 32 of 117
Management of Tobacco Use2

). We were unable to identify any randomized controlled trials or 

systematic reviews of smoking and adverse renal outcomes. Numerous observational studies have 

suggested an increased risk of progression of kidney disease to ESRD [69,70] and cardiovascular 

mortality in patients with CKD. [71] While there is insufficient evidence to recommend smoking 

cessation for the specific improvement in kidney function, there is compelling evidence to recommend 

smoking cessation to improve other non-renal outcomes.

The benefits of tobacco cessation have been well documented over the last 30 years. VA/DoD EvidenceBased Clinical Practice Guidelines for Tobacco Use2

, Chronic Obstructive Pulmonary Disease3 and 

Chronic Heart Failure4 provide detailed information on these benefits in improving overall 

cardiovascular health. 

Summary

In summary, given that patient self-management is a critical element of care for CKD, the guideline 

panel suggests the use of dietary sodium restriction and dietary protein restriction as these 

interventions may slow CKD progression. The guideline panel also encourages weight loss, exercise, 

health education and smoking cessation interventions for patients with CKD as these are useful 

strategies to improve overall patient health.

2 See the VA/DoD Clinical Practice Guideline on the Management of Tobacco Use. Available at: 

http://www.healthquality.va.gov/guidelines/cd/mtu/index.asp 3 See the VA/DoD Clinical Practice Guideline on the Management of Chronic Obstructive Pulmonary Disease. 

Available at: http://www.healthquality.va.gov/guidelines/cd/copd/index.asp 4 See the VA/DoD Clinical Practice Guideline on the Management of Chronic Heart Failure. Available at: 

http://www.healthquality.va.gov/guidelines/cd/chf/index.asp 

December 2014 Page 33 of 117
Clinical Management Strategies

Background

Patients with CKD are at increased risk of progression of end-stage renal disease, AKI, and mortality due 

to cardiovascular disease and infection. Clinical management strategies that target these adverse 

outcomes are discussed below. Strategies to optimize CKD patient care include the implementation of 

various models of care, preventive immunizations, medication safety initiatives, proteinuria reduction,

pharmacologic management initiatives, correction of acidosis, treatment of dyslipidemia, hypertension, 

anemia, and bone and mineral disorders associated with CKD and appropriate nephrology referral. 

Model of Care

Recommendation 

15. We suggest offering multidisciplinary care, if available, for patients with CKD to reduce non-fatal

stroke, slow progression from micro- to macroalbuminuria, and reduce all-cause mortality.

(Weak For)

Discussion

The impact of including a multidisciplinary team in the delivery of nephrology care is not well 

established. A four-year cohort study and three-year prospective cohort study revealed that specific 

groups of CKD patients may also benefit from comprehensive multidisciplinary care (MDC). [72,73] 

Examples of multidisciplinary teams in these two studies consisted of a nephrologist, pharmacy 

specialist, diabetes educator, dietitian, social worker, and nephrology nurse, or a nephrologist, 

nephrology nurse educator, renal dietitian, social worker, pharmacy specialist, and surgeon (for vascular 

access placement, catheter implantation and transplantation). [72] Specific CKD guidelines were used to 

standardize interventions, with additional focus on lifestyle modification. [73] Multidisciplinary care 

facilitated within an integrated health care system may lead to a reduction in the decline of kidney

function, a postponement of dialysis, and improved health outcomes. [72,73] As compared with usual 

care, MDC for elderly patients with CKD in particular has been associated with improved survival. [74,75] 

Contemporary multidisciplinary teams may also include nurse practitioners, physician assistants, and 

other providers as appropriate.

Recommendation

16. Although there is insufficient evidence to recommend for or against referral to a nephrology

specialist for patients with stage 3 CKD for slowing CKD progression, we suggest consultation with

a nephrologist to assist in the diagnosis and treatment of patients with any of the following

conditions:

a. eGFR <30 mL/min/1.73 m2 to facilitate education and planning for renal replacement

therapy (dialysis or kidney transplantation)

b. Kidney function that is rapidly worsening without obvious cause

c. Metabolic complications of CKD (e.g., anemia, secondary hyperparathyroidism,

hyperkalemia)

December 2014 Page 34 of 117
d. CKD of unclear etiology after initial work-up, or has a known or suspected kidney condition

requiring specialized care

e. Nephrotic range proteinuria

f. Nephrolithiasis

(Weak For)

Discussion

There is insufficient evidence to recommend for or against routine referral to a nephrologist for stage 3 

CKD, however, nephrology referral is always appropriate when the primary care provider (PCP) is not 

comfortable managing a patient with CKD, or if there are specific indications as listed above. No 

randomized clinical trials were found during review of the literature in the specified timeframe for this 

update on nephrology referral or consultation to slow CKD progression or prevent ESRD. Four 

observational studies have evaluated the impact of nephrology referral on outcomes. While this 

evidence is limited, the findings suggest that nephrology referral may be associated with slower 

progression of kidney function decline, lower dialysis-free mortality or the composite outcome of CKD 

progression or death. Chen et al. reported a significantly lower kidney function decline in stage 3b (-5.5 

mL/min/year before versus -2.5 mL/min/year after referral, p<0.01), but not stage 3a (-3 mL/min/year 

before versus -2.3 mL/min/year after referral), one year after nephrology referral. [76] In a large study 

of Veterans Health Administration clinic users (n=39,031) with concomitant diabetes mellitus and stage 

3-4 CKD, Tseng et al. found a lower risk of dialysis-free mortality (in patients with stage 3 or 4 CKD and 

not receiving dialysis) among those who had a greater number of quarterly visits with a nephrologist. 

[77] The risk for ESRD was higher among those with a greater number of quarterly visits.

In a study of 1,533 Veterans at the Durham Veteran Affairs Medical Center, nephrology care was shown 

to be associated with decreased risk of the composite endpoint of death or CKD progression. [78] 

Nephrology care has also been shown to be associated with improved blood pressure control; however, 

this study did not report the impact of blood pressure control on CKD outcomes. [79] Patients receiving 

nephrology care are likely different than those who did not receive nephrology care and this may not be 

accounted for in these observational studies. For example, nephrology referral may be reserved for 

those patients considered to be the best candidates for dialysis or interventions to slow CKD 

progression, therefore overestimating the benefit of nephrology referral. Future research may be 

necessary to determine the impact of nephrology referral on slowing CKD progression. The use of tools 

to identify the stage 3 CKD patients at highest risk for progression to ESRD may help discriminate those 

patients who would most benefit from nephrology referral to improve outcomes. More research is

necessary to determine the utility of risk prediction tools in clinical decision making.

December 2014 Page 35 of 117
Immunization

Recommendation

17. We recommend that treatment with the following vaccinations be considered for patients with

CKD as a measure to prevent infections:

a. Influenza vaccine*

b. Tdap vaccine

c. Pneumococcal polysaccharide vaccine (i.e., PCV 13 and PPSV23)

d. Hepatitis B vaccine

e. Zoster /shingles vaccine*

f. Varicella vaccine*

g. MMR vaccine*

(*Note: Live vaccines, including nasal influenza (LAIV), may be contraindicated in patients with 

CKD and severe immunodeficiency including treatment with immunosuppressive agents) 

(Carryover modified from the 2008 CPG) (Strong For)

Discussion

The CDC recommends that the vaccines listed above are administered to patients with health conditions 

such as kidney disease. [80] Adults at increased risk include those who are generally immunocompetent 

but who have chronic cardiovascular diseases (e.g., congestive heart failure or cardiomyopathy), chronic 

pulmonary diseases (e.g., chronic obstructive pulmonary disease or emphysema), chronic liver diseases 

(e.g., cirrhosis), or diabetes mellitus. [81] Kidney transplant patients receiving immunosuppressive drugs 

should not be administered live viral vaccines, such as varicella, zoster, (nasal) influenza and MMR. 

These patients are at risk for developing disseminated viral infection due to immunosuppressive 

therapy. [82] 

Influenza immunization is recommend for adults less than age 50 with chronic illness (e.g., heart, lung or 

kidney disease; asthma; diabetes; anemia or other blood disorders; HIV/AIDS; patients with weakened 

immune systems) and all adults age 50 and older. It has been shown that an annual flu vaccine reduces 

the episodes of influenza in the high risk and elderly populations.

Tdap vaccination to protect against whooping cough and tetanus should be administered to all adult 

patients. Any adult 19 years of age and older who has not received a dose of Tdap should get one as 

soon as feasible. When feasible, Boostrix (GSK) should be used for adults 65 years and older; however, 

either vaccine product administered to a person 65 years or older provides protection and may be 

considered valid. [83] 

Pneumococcal immunization (PCV 13 and PPSV23) should be administered to all adults age 65 and older, 

and those less than age 65 with chronic illness that places them at the highest risk for serious 

pneumococcal infection (HIV/AIDS; sickle cell disease; immunosuppressive treatment with radiation, 

chemotherapy or long-term steroids; anatomic or functional asplenia; status post-organ or bone marrow 

transplant; nephrotic syndrome, or kidney failure). Additionally, diabetes mellitus is often associated 

December 2014 Page 36 of 117
with cardiovascular or kidney dysfunction, which increases the risk for severe pneumococcal illness. 

If not already administered, hepatitis B vaccine should be given to stage 4 CKD patients who are close to 

initiation of dialysis therapy (pre-dialysis). The CDC recommends testing pre-dialysis and

immunocompromised patients for hepatitis B exposure and offering vaccination to patients who are 

seronegative for hepatitis B infection. [84] These patients require a higher dose of the vaccine with an

additional dose at six months. A consultation with a nephrologist or infectious disease specialist may be 

obtained. In addition, the CDC also recommends hepatitis B vaccination for patients with type 1 or type 

2 diabetes mellitus who are aged 19 through 59 years. The hepatitis B vaccine may be given at the 

discretion of the providers in diabetics older than 60 years.

Adults age 60 years and older should be vaccinated with the zoster/shingles vaccine to reduce the 

occurrence of herpes zoster (shingles).Vaccination against shingles may help prevent the development 

of herpes zoster in patients over 60 years regardless of the medical condition. At this time, there is not 

enough information from the studies to determine the risks and benefits of the zoster/shingles vaccine 

in people younger than 60 years of age.

All adults without evidence of immunity to varicella should receive two doses of single-antigen varicella 

vaccine or a second dose if they have received only one dose. [85]

Generally, the CDC recommends that all patients 18 years of age or older who were born after 1956 

should get at least one dose of MMR vaccine, unless they can show that they have either been 

vaccinated or had all three diseases. Patients vaccinated before 1979 with either killed mumps vaccine 

or mumps vaccine of unknown type who are at high risk for mumps infection should be considered for 

revaccination with two doses of MMR vaccine. [80] 

For younger patients, the CDC also recommends the human papillomavirus (HPV) vaccine and the 

varicella vaccine. [80] The HPV should be administered to women up to age 26 and men up to age 21 to 

protect against HPV. The varicella/chickenpox vaccine should be administered to patients born in 1980 

or after and have not gotten two doses of this vaccine or have immunity to this disease.

Nephrotoxins and Adverse Drug Events Avoidance

Recommendations

18. We recommend that clinicians avoid or limit the use of nephrotoxic medications for patients with

CKD.

(Carryover modified from the 2008 CPG) (Strong For)

19. In patients with CKD, we suggest that medications should be reviewed and their dosing modified,

where appropriate, according to the level of the patient’s kidney function.

(Carryover modified from the 2008 CPG) (Weak For)

December 2014 Page 37 of 117
Discussion

Nephrotoxic medications

Many commonly used medications may be nephrotoxic to patients with CKD. These categories of 

medications include: 

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (non-specific and COX-2)

• Aminoglycosides

• Various chemotherapeutic agents (MTX, mitomycin, cisplatin)

• Lithium

• Some of the bisphosphonates (zoledronic acid)

• Calcineurin inhibitors (e.g., cyclosporine and tacrolimus)

NSAIDs (including cyclooxgenase-2 inhibitors) may cause kidney damage by causing reversible 

reductions in GFR, as well as idiosyncratic reactions such as acute kidney injury, interstitial nephritis, and 

nephrotic syndrome. The benefits of utilizing NSAIDs in patients with CKD must be weighed carefully 

against the possible adverse effects on kidney function. Currently, the appropriate threshold for the use 

of NSAIDs is not established. Topical NSAIDs such as diclofenac are generally considered to be safe in 

patients with mild CKD but should be used with caution in patients with advanced CKD.

Several other medications are not nephrotoxic, yet may cause adverse effects that can be harmful in 

patients with CKD. These effects include hyperkalemia (ACEI, ARB, potassium-sparing diuretics, 

trimethoprim, digoxin, and heparin) and lactic acidosis (metformin). Oftentimes, the manufacturer’s 

product information can be consulted to determine appropriate dosing based on the patient’s kidney 

function. 

One such medication that warrants caution in patients with CKD is metformin. The product information 

includes a warning of the risk for lactic acidosis. Although the risk is very low (reported as approximately 

0.03 cases/1000 patient-years), the fatality rate is reported to be approximately 50%. Metformin is 

primarily renally eliminated, and according to the product information, in patients with decreased 

kidney function (based on measured creatinine clearance), the half-life of metformin is prolonged and 

the renal clearance is decreased in proportion to the reduction in creatinine clearance (CrCL). As the risk 

of metformin accumulation and lactic acidosis increases with the degree of kidney dysfunction, it is 

therefore recommended that patients be treated with the lowest effective dose along with monitoring 

kidney function. According to the Food and Drug Administration (FDA) approved prescribing 

information, metformin is contraindicated in men with a SCr greater than 1.5 mg/dL and in women with 

a SCr greater than 1.4 mg/dL. To further evaluate the risk for lactic acidosis with metformin, pooled data 

from a systematic review reported no cases of lactic acidosis during 70,490 patient-years of metformin 

use. [86] It was also noted that nearly half of the trials allowed inclusion of patients with a SCr >1.5 

mg/dL. One trial in the review included patients with renal insufficiency (mean plasma creatinine 1.5 to 

2.5 mg/dL) and at least one contraindication to metformin, and reported no cases of lactic acidosis. [87] 

As the SCr alone may not accurately reflect kidney function (e.g., in older patients or those with reduced 

muscle mass), guidelines outside the US. have established recommendations for dosing metformin 

based on eGFR. [88] Additionally, temporary discontinuation of metformin at the time of or prior to 

December 2014 Page 38 of 117
intravascular iodinated radio contrast is encouraged and should be withheld for 48 hours after the 

procedure. Reinstitute only after renal function has been reevaluated and found to be normal. As there 

continues to be discussion regarding the recommended threshold and parameters for optimal safety of

dosing metformin in patients with kidney impairment, at this time, the most recent VA/DoD Clinical 

Practice Guideline on the Management of Diabetes Mellitus (2010) 5 refers to the current FDA approved 

prescribing information for the use and discontinuation of metformin based on SCr. 

Medication dose adjustments in CKD

Many commonly used medications require dose adjustment in patients with CKD. The extent of dose

reduction depends on the level of kidney function. Dose adjustments are most often based on the

patient’s calculated CrCL or SCr (as opposed to eGFR), according to recommendations established based

on these parameters per the manufacturer’s product information. In addition, some medications are 

potentially nephrotoxic and may precipitate acute kidney deterioration. Reduced kidney function may 

lead to drug accumulation with toxic effects specific to the drug. Thus, dosage adjustments based upon 

the level of the patient’s kidney function may be required. Table 2 includes a select list of the 

medications that may require dose adjustment based on kidney function. 

5 See the VA/DoD Clinical Practice Guideline on the Management of Diabetes Mellitus in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/cd/diabetes/index.asp 

December 2014 Page 39 of 117
Table 2. Select Medications Requiring Dose Adjustments or to be Used with Caution in Patients with 

CKD [89-91] 

Select Medications*

• Most antibiotics (macrolides,

clindamycin, and

metronidazole are

exceptions) and antiviral

agents

• Multiple anti-cancer

therapies (cytotoxic drugs,

targeted agents, biologics)

• Hypoglycemic agents

o Acarbose

o Miglitol

o Glyburide

o Chlorpropamide

o Insulin

o Metformin

o Exenatide

o Repaglinide

o Alogliptin

o Saxagliptin

o Sitagliptin

o Canagliflozin

o Dapagliflozin

o Empagliflozin

• Cardiovascular agents

o Atenolol

o Sotalol

o Digoxin

o Dofetilide

o Potassium-sparing

diuretics

• RAAS blockers

o ACEIs

o ARBs

o Aliskiren

o Eplerenone,

spironolactone

• Anticoagulants

o Apixaban

o Dabigatran

o Rivaroxaban

o Low molecular weight

heparins

• Opioid analgesics

o Codeine

o Fentanyl

o Hydrocodone

o Hydromorphone

o Meperidine

o Methadone

o Morphine

o Oxycodone

o Oxymorphone

o Tapentadol

o Tramadol

• NSAIDs

• Gabapentin

• Levetiracetam

• Lithium

• Memantine

• Risperidone, Paliperidone

• Antidepressants

o Bupropion

o Citalopram

o Desipramine

o Duloxetine

o Mirtazapine

o Paroxetine

o Venlafaxine

• Bisphosphonates

• Gout agents

o Allopurinol

o Colchicine

• H2-blockers

• PDE5 inhibitors

o Sildenafil

o Tadalafil

• Statins

o Fluvastatin

o Lovastatin

o Pitavastatin

o Pravastatin

o Rosuvastatin

o Simvastatin

• Fibric acid derivatives

o Gemfibrozil

o Fenofibrate

*Note this is not a comprehensive list; consult individual product information or alternate sources such

as the American Hospital Formulary Service (AHFS) Drug Information, Lexicomp Online, or UpToDate

for dosing information and/or precautions in patients with kidney function impairment.

When prescribing medications to patients with CKD, start at a lower dose and then gradually titrate the 

medication upward. When available, monitoring parameters (such as drug levels, blood sugar, and heart 

rate) should also be utilized. Certain patients with CKD and other comorbid diseases may also be at a 

higher risk than other patients for drug toxicity. For example, patients with: 

• Concurrent diabetes

• Advanced age

• Volume depletion (or states of effective volume depletion)

December 2014 Page 40 of 117
• Concomitant use of multiple nephrotoxic drugs or medications with the potential for drug

interactions

• Repeated and frequent use of higher doses of nephrotoxic drugs may increase risk of kidney

damage (however, specific data are lacking)

Currently, there are limited proven data that address measures to improve safety and reduce the risk of 

adverse drug events due to nephrotoxic or renally cleared medications (to include prescription drugs, 

over-the-counter medications, and nutritional or herbal supplements) for patients with CKD. Boussadi et 

al. noted that automated alert systems may assist pharmacists in monitoring for drug prescription safety 

in patients with CKD. [92] The utility of a pharmacovigilance system to reduce adverse drug events in 

CKD should be the subject of future research.

Correction of Acidosis

Recommendations

20. We suggest the use of bicarbonate supplementation in CKD patients with metabolic acidosis to

slow the progression of CKD. (Weak For)

Discussion

Susantitaphong et al. performed a systematic review of the effects of sodium bicarbonate 

supplementation on non-dialysis CKD patients. [93] They performed a meta-analysis of six studies with a 

total of 312 patients. All six trials prescribed sodium bicarbonate in the alkali-treated group. In the longterm studies, alkali therapy was associated with a net decrease in serum creatinine (-0.07 mg/dl, 95% CI 

-0.09, -0.05; p <0.001), a net improvement in GFR (3.2 ml/min/1.73 m2

, 95% CI 1.6, 4.7; p <0.001), and a 

lower incidence of dialysis initiation (RR 0.21, 95% CI 0.08, 0.54; p = 0.001). No benefit was observed on 

the serum creatinine or GFR in short-term studies. 

The RCT by de Brito-Ashurst et al. studied sodium bicarbonate supplementation in 134 patients with 

stage 4 or 5 CKD. [94] The results showed decline in CrCl was slower with bicarbonate supplementation 

versus the control group (1.88 versus 5.93 ml/min 1.73 m2; p <0.0001). Patients supplemented with 

bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; RR 0.15; 95% CI 

0.06 to 0.40; p <0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5 

versus 33%; RR 0.13; 95% CI 0.04 to 0.40; p <0.001). Taken together, these studies support the use of 

bicarbonate therapy.

Blood Pressure Targets

Recommendations

21. In adult patients with stages 1-4 CKD, we recommend that blood pressure targets should be less

than 140/90 mmHg. (Carryover modified from the 2008 CPG) (Strong For)

Discussion

Review of the literature for this update identified only one systematic review that addressed the 

December 2014 Page 41 of 117
question of targeting low versus usual blood pressure goals. This review included three trials that 

randomized adult CKD patients with or without proteinuria to two blood pressure targets (lower 

[125/75 mmHg to 130/80 mmHg] versus higher [<140/90 mmHg]). This systematic review included 

2,272 non-diabetic patients with CKD stage 3-4. The median follow-up varied from 1.6 years to 3.8 years. 

[95] The three trials included in the evidence review were the MDRD trial with 840 participants, AASK 

trial with 1094 participants and the REIN-2 trial with 338 participants. [95] The findings of these trials 

showed that low blood pressure target of less than 125/75 mmHg to 130/80 mmHg was not significantly 

associated with reduced kidney function decline compared to a blood pressure (BP) target of less than 

140/90 mmHg (p>0.05). This finding was consistent in the review but the authors noted that one study, 

the MDRD, reported a 23% reduction (95% CI, 18% to 43%) in the hazard for kidney failure in the group 

assigned to the low target during the long-term post trial follow-up. Regarding cardiovascular mortality,

a low BP target was not associated with a significant reduction in the risk of cardiovascular mortality 

compared to usual BP target ([AASK trial HR 0.98, 95% CI (0.48 to 2.01) p=0.96], REIN-2 trial 1% versus 

1%). None of the three trials found differences in all-cause mortality between the two levels of blood 

pressure. However, lower targets were associated with increased risk of adverse events such as the risk 

for increased pill burden, drug to drug interaction, difficulty with adherence, hypotension, increased risk 

of falling (particularly in the elderly), pre-renal azotemia and electrolyte disturbances. [95] In addition, 

there are resource burdens for the patient due to the need for more frequent visits and monitoring. 

Although two of the trials included in this systematic review signal for a beneficial effect of low blood 

pressure targets in the groups with proteinuria, these analyses were done as a post-hoc subgroup 

analyses. Also the cut points for proteinuria varied greatly across groups, ranging from “>320 mg per 

day” to “>1 mg per day” for the AASK and MDRD studies, respectively. [95] Hence, there remains an 

important gap in knowledge that needs to be addressed in future research regarding blood pressure 

targets in patients with proteinuria. 

In patients with diabetes and CKD, there is no conclusive evidence that treating to a lower target is 

beneficial, as there are no RCTs of patient with diabetes mellitus and CKD that randomized to two levels 

of blood pressure. At this time, the guideline panel suggests against lowering blood pressure to a target 

of less than 130/80 mmHg in patients with CKD stages 1-4 even in the presence of proteinuria due to 

increased risk of adverse outcomes. Refer to the VA/DoD Clinical Practice Guideline for Management of

Diabetes Mellitus in Primary Care6 and the VA/DoD Clinical Practice Guideline for the Management of 

Hypertension in Primary Care7 for further discussion of blood pressure targets in patients with diabetes. 

6 See the VA/DoD Clinical Practice Guideline for Management of Diabetes Mellitus in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/cd/diabetes/index.asp

7 See the VA/DoD Clinical Practice Guideline for the Management of Hypertension in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/cd/htn/index.asp 

December 2014 Page 42 of 117
Renin-Angiotensin Aldosterone System (RAAS) Blockade 

Recommendations 

22. In patients with non-diabetic CKD, hypertension, and albuminuria, we recommend the use of an

angiotensin-converting-enzyme inhibitor (ACEI) to prevent progression of CKD. Angiotensin II

receptor blockers (ARBs) may be substituted for patients with an ACEI-induced cough.

(Carryover modified from the 2008 CPG) (Strong For)

23. In patients with diabetes, hypertension, and albuminuria, we recommend the use of an ACEI or

ARB to slow the progression of CKD, unless there is documentation of intolerance.

(Carryover modified from the 2008 CPG) (Strong For)

24. We recommend against the use of combination renin-angiotensin-aldosterone system (RAAS)

blockade (ACEI and ARB, or an ACEI or ARB with a direct renin inhibitor) in patients with CKD.

(Strong Against)

Discussion

These recommendations are adapted from the previous VA/DoD 2008 CKD CPG with the supporting 

evidence dated before 2008. The recommendation of ACEIs or ARBs as the initial regimen is based 

primarily on their beneficial effects on kidney outcomes and significant benefit to slow CKD progression.

The data are limited regarding cardiovascular benefits of ACEIs or ARBs compared to other 

antihypertensive agents in patients with CKD. Two RCTs that support that ACEI therapy slows the 

progression of CKD in patients with proteinuria are the REIN-2 and the AASK trials. Both trials were 

reviewed as part of the evidence for blood pressure target recommendations. Results from Nakamura et 

al. [96] showed that ACEIs or ARBs are equally effective in controlling blood pressure in CKD. There is 

also good evidence that ARBs or ACEIs slow the progression of CKD in patients with CKD and diabetes, 

with micro- or macroalbuminuria. The supporting studies for this recommendation were reviewed in the 

previous CKD guideline. The direct renin inhibitors are not included in this review as there are no studies 

demonstrating their benefits on kidney or cardiovascular outcomes in patients with CKD. Table 3 

highlights the major updates in regard to controlling hypertension and medication selection from the 

previous 2008 CKD CPG. 

December 2014 Page 43 of 117
Table 3. Comparison of the Recommendations from VA/DoD 2008 CKD CPG for Controlling 

Hypertension in CKD with Current Recommendations

VA/DoD CPG for Management of CKD 

2008

VA/DoD CPG for Management of CKD 

2014

BP target • Antihypertensive therapy should be

adjusted to achieve blood pressure of

<130/80 mmHg

• If proteinuria is >1 g/day BP <125/75

mmHg

• Antihypertensive therapy should be

adjusted to achieve blood pressure

of <140/90 mmHg regardless of the

presence of proteinuria

Drug choice • ACEIs or ARBs are the preferred agent 

for patients with kidney disease and 

hypertension 

• ACEIs may be preferred based on cost;

ARBs may be substituted for patients 

with an ACEI induced cough

• ACEIs or ARBs are the preferred

agent for patients with kidney

disease and hypertension with

albuminuria

• ARBs may be substituted for

patients with an ACEI induced cough

Drug 

combination

• Combination ACEI and ARB are

supported in IgA nephropathy

• There is a strong recommendation

against the use of ACEI and ARB in

combination

Regarding the selection of second or third line agents for additional antihypertensive therapy in patients 

with CKD, there are limited data available to guide the clinician. Two recent small RCTs showed that a 

dihydropyridine calcium channel blocker (CCB) was as efficacious as an ACEI in controlling blood 

pressure [97], as was a loop diuretic compared to an antihypertensive control group. [98] In regard to 

reaching blood pressure control it seems that other recommended antihypertensive agents such as a 

thiazide or thiazide-type diuretic (or loop diuretic as indicated) and/or a dihydropyridine CCB are 

acceptable options. The decision for the use of these or other antihypertensive classes should be 

considered based on the potential for cardiovascular benefit and the patient’s comorbidities and 

preference. For more detailed information on the diagnosis and management of hypertension, refer to 

the VA/DoD Clinical Practice Guideline for Management of Hypertension in Primary Care8 for more 

complete information on the safety of all antihypertensive agents, and stepwise, sequential, and 

combination therapy. 

Use of ACEIs or ARBs will commonly increase serum creatinine and potassium. An increase up to 30% in 

SCr within the first two weeks after initiation is acceptable. If potassium becomes elevated, measures to 

reduce hyperkalemia (e.g., reduction in dose of ACEI or ARB, discontinuation of concomitant 

medications that may increase potassium, implementation of a low potassium diet, addition of a 

diuretic, as indicated) should be considered. If therapies to decrease potassium such as a low potassium 

8 See the VA/DoD Clinical Practice Guideline for the Management of Hypertension in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/cd/htn/index.asp 

December 2014 Page 44 of 117
diet and addition of diuretics are not effective, treatment should be discontinued. Although changes of 

smaller magnitude in these parameters may not require a dose adjustment, CKD patients on RAAS 

inhibition require monitoring of potassium and serum creatinine for safety reasons. Patients with cough 

due to ACEI should be switched to an ARB. It is unknown if an ARB can be safely used as an alternative in 

patients who have previously developed angioedema on an ACEI. A systematic review found the risk for 

angioedema to be 9.4% (95% CI 1.6 to 17%) of patients on an ARB who previously experienced 

angioedema on an ACEI; and 3.5% (95% CI 0 to 9.2%) of patients with previously confirmed angioedema 

on an ACEI. [99] Another review estimated the risk of cross-reactivity of angioedema with an ARB in 

patients who previously experienced this adverse event with an ACEI to be from less than 7% up to 17%.

[100] Therefore, an ARB should be used with caution in patients who have previously experienced 

angioedema with an ACEI. 

Combination RAAS blockade versus RAAS blockade monotherapy

Although studies evaluating combination therapy with two agents that block the renin-angiotensinaldosterone system have reported a greater benefit on surrogate endpoints (e.g., decrease in urinary 

albumin-to-creatinine ratio, reduction in albuminuria) in patients with CKD (trials also included patients 

with diabetes mellitus) compared to those receiving monotherapy, [101-106] additional information was 

needed to determine whether combination therapy provided long-term outcome benefit on slowing the 

progression to ESRD or a reduction in mortality, without an increase in adverse outcomes. More 

recently, clinical trials have been conducted to determine the long-term outcome benefit and safety of 

combination RAAS blockade in patients with CKD. [107-109] Results of recent trials are discussed in the 

text below and displayed in Table 4. 

Table 4. Summary of Evidence for Dual RAAS Blockades

Trial Name Therapy* Results

VA NEPHRON-D

Fried et al. 2013

[108]

ACEI + ARB

versus 

ARB alone 

(n = 1,448)

Trial terminated due to a greater 

number of observed acute kidney injury 

events (HR 1.7 95% CI 1.3 to 2.2; 

p<0.001) and hyperkalemia (HR 2.8 95% 

CI 1.8 to 4.3; p<0.001) in the group 

receiving combination therapy, without 

a significant difference in the primary 

endpoint of first occurrence of a decline 

in eGFR, ESRD, or death between 

treatment groups (HR 0.88 95% CI 0.70 

to 1.12; p=0.30).

PRONEDI

Fernandez Juarez et al. 2013

[107] 

ACEI + ARB

versus 

ACEI or ARB alone

(n = 133)

Found no difference in the primary 

composite endpoint of >50% decrease 

in SCr, ESRD, or death between an ACEI 

and combination therapy (HR 0.96 95% 

CI 0.44 to 2.05; p=0.90) or ARB 

compared to combination therapy (HR 

0.90 95% CI 0.39 to 2.02; p=0.80).

December 2014 Page 45 of 117
Trial Name Therapy* Results

Systematic review

Susantitaphong et al. 2013

[110] 

ACEI+ARB; ACEI or ARB+ARA;

ACEI+ARB+DRI; ACEI+ARB+ARA

versus 

ACEI or ARB alone

( n = 4,975; across 59 studies)

Combined RAAS blockade was 

associated with a 3.4% higher rate of 

hyperkalemia (95% CI, 1.7 to 5.1, p 

<0.001, I2=29.2; 35 study arms) and a 

4.6% higher rate of hypotension (4.6%, 

95% CI, 2.3 to 6.8, p <0.001, I2=33.1; 24 

study arms).

AHRQ Comparative 

Effectiveness Review

Fink et al. 2012

[111] 

ACEI + ARB 

versus 

ACEI alone

(n = 7,233; across 6 studies)

ACEI + ARB 

versus 

ARB alone

(n =~4,300; across 3 studies)

ACEI + ARB 

versus 

ACEI or ARB 

(n = 8,933; across 1 study)

ACEI + ARB 

versus 

ACEI + ARA

(n = 54; across 1 study)

ACEI-ARB combination therapy 

produced no significant reduction in the 

risk of doubling creatinine (n=1 study) 

relative to ACEI monotherapy (HR 0.07, 

95%CI, 0.0–1.13);

One study reported more serious 

adverse events for the combination 

therapy group (9.3%) versus the ARBonly group (2.3%) and another study 

reported a higher incidence of cough

for combination therapy (4.3 versus 

0%);

Adverse events were more common for 

the combination therapy group (need 

for acute dialysis , hyperkalemia (RR 

1.65, 95% CI, 1.10 to 1.25), hypotension 

(RR 1.65, 95% CI, 1.4 to 1.95), cough

(RR 1.72, 95% CI, 1.34 to 2.20), and 

syncope (RR 2.44, 95% CI, 0.75 to 8.0);

Reported no significant difference in allcause mortality or doubling SCr in 53 

patients receiving an ACEI who were 

randomized to either an ARB (losartan) 

or ARA (spironolactone) for 48 weeks.

Randomized controlled trial

Wang et al. 2013

[112] 

ACEI +/or ARB + ARA

versus

ACEI +/or ARB alone

(n = 221)

ARA(spironolactone) group had 

significantly reduced urine protein 

levels relative to pre-treatment 

measures and relative to the control 

(ACEI plus ARB only) group (both p 

<0.05). The control group showed no 

significant reduction in urine protein 

relative to pretreatment measures. No 

significant differences in serum 

creatinine or eGFR.

December 2014 Page 46 of 117
Trial Name Therapy* Results

Chronic Renal Impairment 

in Birmingham II study 

(sub-analysis)

Edwards et al. 2012

[113]

ARA or placebo +

ACEI +/or ARB

(n = 117)

Difference in eGFR between the

ARA (spironolactone) and placebo 

group at week 40 approached 

significance (46.1 versus 52.3 

ml/min/1.72 m2, p=0.09).

Systematic review

Navaneethan et al. 2009

[114] 

ARA + ACEI +/or ARB

versus 

ACEI +/or ARB + placebo

(n = 845; across 10 studies)

ARA (spironolactone) plus ACEI and/or 

ARB significantly reduced 24 hour 

proteinuria by the end of treatment 

relative to ACEI and/or ARB alone 

(mean difference (MD) = -0.80 g/24 

hours, 95% CI, -1.27 to -0.33). 

Combination therapy with ARA plus 

ACEI or ARB did not significantly affect 

end of treatment eGFR (MD = 0.70 

ml/min, 95% CI, -4.73 to 3.34).

Randomized controlled trial

Guney et al. 2009

[115] 

ARA + ACEI +/or ARB 

versus

ACEI +/or ARB alone

(n = 30)

Urinary protein/creatinine was 

significantly reduced relative to 

baseline in the spironolactone group 

(from 2.43 ± 4.85 to 1.76 ± 3.39 

mg/mgCr), respectively, p=0.028) after 

3 months and further reduced after 6 

months (1.66 ± 3.51mg/mgCr, p=0.003).

Randomized controlled trial

Furumatsu et al. 2008

[116] 

ARA + ACEI + ARB 

versus

ACEI + ARB + diuretic

(n = 38)

Proteinuria was significantly decreased 

at 12 weeks and 1 year follow-ups for 

the triple-blockade (spironolactone) 

group (p <0.05 versus baseline at 0 

weeks). Estimated GFR did not change 

throughout the treatment period for 

either group.

Randomized controlled trial

Ohsawa et al. 2013

[117] 

ACEI or DRI + ARB

(n = 37)

Baseline measures of urinary 

albumin/creatinine ratio (UACR) or 

eGFR were not significantly different 

between groups. UACR of the aliskiren 

group, but not the benazepril group, 

was significantly reduced at 24 weeks. 

Group eGFR measures were not 

significantly different.

ALTITUDE

Parving et al. 2012

[109] 

DRI or placebo + ACEI or ARB

(n = 8,606)

Difference between groups was 

statistically non-significant (HR 1.08, 

95% CI, 0.98 to 1.20; p=0.12) for the 

composite primary outcome.

*Abbreviations: ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; ARA:

Aldosterone receptor antagonist; DRI: Direct renin inhibitor

December 2014 Page 47 of 117
Combination RAAS blockade with an ACEI and ARB, or an ACEI or ARB with a direct renin inhibitor,

versus ACEI or ARB monotherapy

When evaluating the individual components of the primary endpoint, there was no significant difference 

between treatment with combination ACEI and ARB versus ACEI or ARB monotherapy on progression to 

ESRD, [107,108,111] death, [107,108,110,111] or eGFR decline (as defined in Fried et al. 2013 [108]), 

>50% increase in SCr [107] or doubling SCr. [110,111] Despite the reduction in proteinuria with 

combination RAAS blockade compared to monotherapy, there was no significant long-term benefit on 

reducing kidney disease progression with combination therapy. [108,110] In addition, given the level of 

evidence that treatment with combination therapy increased the risk for hyperkalemia, [108,110,111] 

acute kidney injury, [108,111] as well as low level evidence for the risk of hypotension [110,111]

compared to monotherapy, the Work Group members felt the harms outweighed the benefit and 

therefore made a strong recommendation against the use of combination RAAS blockade in patients 

with CKD.

Results from the VA Cooperative Study, Combination Angiotensin Receptor Blocker and AngiotensinConverting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D), support the 

recommendation against the use of combination therapy with an ACEI and ARB in patients with CKD. 

[108] In this trial, 724 patients were randomized to treatment with combination of an ARB (losartan) and 

ACEI (lisinopril) and 724 patients to an ARB plus placebo. The trial was terminated at a median follow-up 

of 2.2 years due to a greater number of observed acute kidney injury events and hyperkalemia in the 

group receiving combination therapy, without a significant difference in the primary endpoint of first 

occurrence of a decline in eGFR, ESRD, or death between treatment groups. There was a greater decline 

in the urinary albumin-to-creatinine ratio (tertiary endpoint) with combination therapy compared to 

monotherapy (p<0.001). [108] 

Another trial, PRONEDI, with a median follow-up of 32 months, randomized 133 patients with diabetic 

nephropathy to an ACEI (lisinopril), an ARB (irbesartan), or the combination, and found no difference in 

the primary composite endpoint of >50% decrease in SCr, ESRD, or death between an ACEI and 

combination therapy or an ARB compared to combination therapy. There was no significant difference 

in the decrease in proteinuria (secondary endpoint) between treatment groups. There was a significant 

increase in serum potassium in all treatment groups, which was reported not to be statistically 

significantly different between the treatment groups. [107] 

This strong recommendation against use of combination RAAS blockade also includes combination with 

a direct renin inhibitor and an ACEI or ARB. Evidence for this recommendation includes data from the 

Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) that evaluated patients with 

type 2 diabetes mellitus and CKD, cardiovascular disease, or both treated with combination of a direct 

renin inhibitor (aliskiren) and an ACEI or ARB versus monotherapy with an ACEI or ARB. This trial was 

terminated early with a median follow-up of 32.9 months. [109] There was no significant difference 

between combination and monotherapy for the primary composite outcome (time to cardiovascular 

death or first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal 

stroke; unplanned hospitalization for heart failure; ESRD, death attributable to kidney failure, or the 

December 2014 Page 48 of 117
need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling 

of the baseline SCr level). There was a significant increase in discontinuations due to an adverse event 

(13.2% versus 10.2%; p<0.001), rates of hyperkalemia (39.1% versus 29.0%; p<0.001) and hypotension 

(12.1% versus 8.3%; p<0.001) in patients treated with combination therapy versus monotherapy,

respectively. [109] A significantly increased risk (3.4%) for hyperkalemia with combination therapy 

compared to monotherapy was also found in several studies (95% CI, 1.7 to 5.1, p <0.001, 35 study 

arms) included in one systematic review. [110] 

Mineralocorticoid receptor antagonist in combination with RAAS blockade versus RAAS blockade 

monotherapy

Data was not available to adequately determine the impact on long-term outcomes such as progression 

to ESRD or death with a mineralocorticoid receptor antagonist in combination with additional RAAS 

blockade compared to monotherapy in patients with CKD. The suggestion against use of combination 

with a mineralocorticoid receptor antagonist and additional RAAS blockade is based on the following 

data: one trial [118] included in one systematic review [111] reported no significant difference in allcause mortality or doubling SCr in 53 patients receiving an ACEI who were randomized to either an ARB 

(losartan) or aldosterone antagonist (spironolactone) for 48 weeks; and results from one systematic 

review, [114] one 16-week trial of 221 patients, [112] and a one-year study of 32 patients (comparing 

triple RAAS blockade including a mineralocorticoid receptor antagonist versus dual RAAS blockade with 

an ACEI and ARB), [116] that reported additional RAAS blockade with a mineralocorticoid receptor 

antagonist further reduced proteinuria versus the comparator group. 

One systematic review evaluating the addition of a mineralocorticoid receptor antagonist to RAAS 

blockade reported an increased risk for hyperkalemia in patients receiving a mineralocorticoid receptor

antagonist plus an ACEI and/or ARB compared to an ACEI and/or ARB alone (RR 2.23; 05% CI 1.19 to 

41.0; p=0.01). [114] In a trial of 115 patients, serum potassium levels were significantly higher (p<0.05) 

in patients treated with a mineralocorticoid receptor antagonist (spironolactone) in addition to an ACEI 

and/or ARB (1% of patients on ACEI plus ARB) compared to placebo plus an ACEI and/or ARB (2% of

patients on ACEI plus ARB), with two patients in each group experiencing an increase in serum 

potassium >5.5 mEq/L. There was also an increased risk for developing hyperkalemia if the baseline 

potassium was >5.0 mEq/L (p<0.01) or baseline eGFR <45 mL/min/1.73 m2 (p=0.04). [113] Two of 15 

patients treated with a mineralocorticoid receptor antagonist (spironolactone) in addition to an ACEI 

and ARB experienced an increase in serum potassium (>5.0 mEq/L) requiring intervention with a 

potassium binder. [116] In another trial of 221 patients, no significant difference in potassium levels was 

found between treatment with a mineralocorticoid receptor antagonist (spironolactone) in addition to 

an ACEI and/or ARB compared to patients continuing treatment on an ACEI and/or ARB. [112] 

The mineralocorticoid receptor antagonists, ACEIs, ARBs, and direct renin inhibitors have all been 

associated with an increase in serum potassium and/or risk for hyperkalemia. As noted above, when

multiple RAAS blockades are used, the risk for hyperkalemia is further increased. [108,110,111,114] 

Most trials evaluating combination RAAS blockade in patients with CKD excluded patients with a serum 

potassium >5.0 mEq/L [109,112,116] or >5.5 mEq/L. [107,108,111,113] Patients with CKD receiving RAAS 

December 2014 Page 49 of 117
blockers require close monitoring of serum potassium, as well as kidney function. Although combination 

RAAS blockade is not recommended in patients with CKD in general, if the combination is used (e.g., use 

of an ACEI or ARB in combination with a mineralocorticoid receptor antagonist in patients with heart 

failure), increased diligence is recommended to monitor for hyperkalemia (i.e., within three days and at 

one week after initiation of a mineralocorticoid receptor antagonist and at least monthly for the first 

three months, and every three months thereafter) [119] as well as for acute kidney injury. Clinical trials 

evaluating combination RAAS compared to monotherapy in patients with CKD varied in their protocols 

for follow-up, with the most conservative monitoring at one and two weeks after initiation of therapy 

[113] or at 10 to 14 days after initiation or increase in dose, [108] then monthly (e.g., for the study 

duration of 16 weeks [112]) to every three months. [108] Frequency of monitoring should take into 

account additional factors including baseline serum potassium or SCr, medications that may increase the 

risk for hyperkalemia, or conditions that may contribute to volume depletion. [119,120] (See Appendix 

B: Pharmacotherapy with ACEIs or ARBs.) 

Given the minimal data on the benefit of combining a mineralocorticoid receptor antagonist with an 

additional RAAS blockade, the limited data suggesting an increased incidence of hyperkalemia, and the 

harms demonstrated for combinations with other drugs using this mechanism of action (renin blockers 

and combination RAAS blockers), the Work Group suggests against the use of a mineralocorticoid 

receptor antagonist with additional RAAS blockade. Furthermore, the Work Group identified that 

additional studies are needed to determine the impact on long-term clinical outcomes and safety of 

RAAS blockade in combination with a mineralocorticoid receptor antagonist in patients with CKD. 

Statins for Cardiovascular Risk Reduction 

Recommendations

25. We recommend that all patients with CKD who are not on dialysis and have no known history of

coronary artery disease be assessed for 10-year CVD risk using a validated risk calculator for

primary prevention. If at risk (as defined in the VA/DoD Management of Dyslipidemia guideline),

we recommend use of at least a low dose statin. (Strong For)

26. We suggest against the use of statins prescribed with the intent of slowing eGFR decline or

preserving kidney function. (Weak Against)

Discussion

Risk calculators

Population-based observational studies provide the basis to calculate the estimated 10-year risk for 

CVD, using demographic (age, sex, race) and clinical (total cholesterol [TC], high-density lipoprotein 

cholesterol [HDL-C], blood pressure [BP]) variables. Several calculators exist and are based on different 

(though sometimes overlapping) populations and a different combination of variables. Below are some 

examples of calculators that clinicians may want to consider using to calculate the 10-year risk, 

depending on the characteristics (e.g., age) of their patient population:

• Framingham (cohort age range 40-74): http://cvdrisk.nhlbi.nih.gov/

• ASCVD Pooled Risk Calculator from the 2013 American College of Cardiology (ACC)/American

December 2014 Page 50 of 117
Heart Association (AHA) Lipid Guideline (cohort age range 40-79): 

http://clincalc.com/Cardiology/ASCVD/PooledCohort.aspx

• Cardiovascular Risk/Benefit Calculator (combines Framingham and ACC/AHA cohorts):

http://bestsciencemedicine.com/chd/calc2.html

• Mayo Statin Decision Aid: http://statindecisionaid.mayoclinic.org/index.php/site/index

While the Framingham risk calculator was developed based on a primarily white population, some 

observational studies have shown that it performs fairly well in other populations, including those with 

CKD. The more recently developed ACC/AHA calculator is based on a more diverse population that 

include a large enough number of African American subjects to calculate separately risk for white and 

for African American patients. Additionally, the ACC/AHA calculator includes ischemic stroke as an 

outcome. The Cardiovascular Risk/Benefit Calculator uses the same prediction models as the previous 

two calculators, but displays the results in an interactive visual format that facilitates shared decision 

making with patients and can illustrate the potential effect of medications. The Mayo Statin Decision Aid 

also provides a patient-friendly illustration of risk.

All of these risk calculators have limitations and their use has not been rigorously shown to improve 

outcomes. However, their wide acceptance may render such studies difficult to perform. Risk calculators 

have been criticized for overestimating the risk. One of the reasons may be that they are based on data 

that were collected before the recent significant improvement in clinical care and prevention for CVD, 

when the overall population was at higher risk of events or death from CVD causes.

Another limitation of risk calculators is that they provide an average risk or probability and cannot 

precisely predict whether an individual patient will develop a CVD event or benefit from medications. 

They can, however, be useful to discuss CVD risks and potentials for harm or benefit from medications in 

the process of shared decision making. Based on these calculations, patients at low 10-year risk for CVD 

events are unlikely to benefit from medications in the near future, but could experience some of the 

side effects. On the other hand, patients at high risk may benefit from a significantly decreased risk of an 

acute event in the following 10 years. Therefore, the use of risk calculators to aide in medication 

decision making is currently recommended by most medical societies. 

Once the 10-year risk has been calculated, shared decision making is recommended to decide whether 

the potential benefits of medications outweigh the potential harms. For high-risk patients with a 10-year 

risk of 12% or more, it is estimated that risk of cardiovascular events can be decreased by 20-30% with 

use of medication for five years. The rationale for a threshold of 12% may appear arbitrary, but it 

reflects a threshold that most closely resembles the populations in the clinical trials for which the 

benefits clearly outweighed the risks, including the SHARP trial whose mean 10-year risk exceeded 15%. 

A similar rationale is used for the threshold of 6%. There are no clinical trials that specifically address 

this <6% ten-year risk category. The mean 10-year risk of the few primary preventions trials that 

included patients in what is considered an intermediate risk group (6-12%) was approximately 8%. 

However, these trials are few in number and had idiosyncratic inclusion criteria (e.g., Jupiter, MEGA). 

Also, 6% has been used by the ACC/AHA as a conventional threshold for defining the transition from low 

December 2014 Page 51 of 117
to intermediate risk. Admittedly, these are arbitrary thresholds, but they also represent thresholds that 

rationally define inflection points of increasing risk and increasing congruency with the populations 

included in clinical trials that showed benefit from statin therapy. Additional information regarding risk 

calculation can be found in the VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia.9

Statins to reduce cardiovascular events 

Literature prior to 2007 suggests benefit from use of statins as a means of secondary prevention of 

cardiovascular events in patients with CKD. [121,122] A review of the literature since 2007 identified 

four RCTs which expand the examined scope of statin therapy in non-dialysis CKD patients to reduce 

renal outcomes or primary or secondary prevention of cardiovascular endpoints. [123-126] One trial 

examined the role of statins to reduce renal endpoints. [123] Two of the RCTs [124,125] were large trials 

initially constructed to assess prevention of secondary or primary prevention of non-renal end points 

with secondary analyses of statin efficacy to reduce lipid levels. The fourth RCT was a secondary analysis 

of patients with stage 2-4 CKD enrolled in a primary prevention study evaluating statin efficacy 

compared to placebo to reduce cardiovascular events or mortality. [126] In addition, the SHARP trial 

examined the efficacy and safety of the combination of simvastatin plus ezetimibe in patients with 

moderate-to-severe kidney disease in the primary prevention of atherosclerotic events and mortality. 

[127] 

One secondary and one post-hoc analysis of moderate quality RCTs support the recommendation for 

use of statins to reduce cardiovascular events in patients with stage 3 or 4 CKD. [125,126] In the 

secondary analysis, Ridker et al. studied 3,267 patients with CKD who were on rosuvastatin (20 mg/d) or 

placebo (the JUPITER trial). [126] Cardiovascular events, including composite myocardial infarction (MI), 

stroke or confirmed cardiovascular death, were reduced by 41% in those patients receiving the statin, 

regardless of Framingham risk score of > or ≤10% . All-cause mortality was also reduced in those treated 

with statin (HR 0.56; 95% CI 0.37-0.85). In the post-hoc analysis, Kendrick et al. studied 304 patients with 

stage 3 CKD receiving either lovastatin (20 mg/d) or placebo. [125] Lovastatin was associated with 

reduced rates of fatal and nonfatal cardiovascular events (adjusted RR, 0.39; 95% CI of 0.16 to 0.93, 

p=0.03), fatal and nonfatal coronary events (adjusted RR, 0.35; 95% CI 0.13-0.93), and coronary 

revascularizations (adjusted RR 0.23; 95% CI 0.07-0.77), and while not associated with a significant 

decrease in cardiovascular or coronary heart disease mortality, the study had a low frequency of these 

endpoints and was not powered to detect treatment differences in this frequency range. [126] 

The SHARP trial, conducted by Baigent et al., included 9,270 patients and evaluated the efficacy 

simvastatin in combination with ezetimibe to reduce atherosclerotic events and mortality. [127] 

Although the trial examined statin therapy in combination with ezetimibe, it offered support for the 

9 See the VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia. Available at:

http://www.healthquality.va.gov/guidelines/cd/lipids/index.asp 

December 2014 Page 52 of 117
reduction of the incidence of major atherosclerotic events in patients with advanced CKD. Compared to 

the placebo group, the simvastatin plus ezetimibe group experienced a 17% proportional reduction in 

major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe versus 619 [13.4%] placebo; RR 

0.83, 95% CI 0.74-0.94, p=0.0021) over a range of kidney function and degree of proteinuria. [127] 

Taken together, the three studies that examined the effect of statin therapy on the primary prevention 

of cardiovascular outcomes, all demonstrate benefit in their cohorts of patients with CKD, and while 

each of these cohorts was free of manifest CVD, each population had a predisposing CV risk factor to 

qualify them for treatment (e.g., dyslipidemia, elevated C-reactive protein [CRP], or diabetes, 

respectively). [123,125,126] In the opinion of the working group, the comprehensive risk for 

arteriosclerotic cardiovascular disease in those with CKD should be considered. Those with CKD may not 

have diabetes and may not have a low-density lipoprotein (LDL) high enough to indicate statin 

treatment, but they may still benefit from use of statin therapy to modify the independent increased 

risk of cardiovascular disease in CKD. A risk prediction equation has been validated for use in the CKD 

population and may be useful in guiding decisions about initiation of statin therapy. [128] 

While patients with CKD may be at increased risk of drug-induced myopathy, [129] none of the studies 

included in the evidence base found a statistically significant difference in adverse events for any of the 

statins investigated. However, providers are nonetheless encouraged to engage in shared decision 

making discussions with patients so that the risks and benefits are adequately communicated, and are in

line with patient values and preferences. Providers should also consider the individual patient, to 

include presence of comorbidities and cardiovascular disease risk, life expectancy and the time needed 

to treat with a statin to see benefits in morbidity and mortality, and the individual risk for adverse 

events related to statin therapy (e.g., rhabdomyolysis). Providers are also encouraged to consult the 

VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia.10

Statins to slow CKD progression

The literature was also reviewed for reports concerning the impact of statins on decline of kidney 

function. The decline in kidney function is defined by change in mean eGFR. Ridker et al. reported a 

marginal improvement in eGFR at 12 months between those assigned to rosuvastatin versus placebo 

(66.8 versus 66.6 m/min/1.73m2

, p = 0.02). [126] In the study by Huskey et al., [124] kidney function loss 

(defined as a ≥ 25% decrease in eGFR from baseline) was significantly decreased in the simvastatin 

group versus placebo (adjusted OR: 0.21, 95% CI 0.05 to 0.94, p = 0.04). However, using the same 

definition of kidney function loss, Kendrick et al. [125] found no difference between lovastatin versus 

placebo. Fassett el al. [123] used the rate of Modification of Diet in Renal Disease (MDRD) equation to 

estimate GFR from creatinine. The results of the study found no statistically significant different in eGFR 

10 See the VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia. Available at:

http://www.healthquality.va.gov/guidelines/cd/lipids/index.asp 

December 2014 Page 53 of 117
between atorvastatin and placebo but was underpowered to detect a meaningful difference. Due to the 

inconsistencies in study findings, the Work Group suggests against use of statins to slow CKD 

progression until further evidence is available. 

Glycemic Control

Recommendations

27. We recommend against intensive glycemic control to patients with stage 3 or worse CKD due to

the lack of benefit on renal or cardiovascular outcomes and potential for significant harm.

(Carryover modified from the 2008 CPG) (Strong Against)

Discussion

Recommendations regarding the treatment of diabetes were also discussed in the 2008 CKD CPG. The 

Work Group noted the importance of the recommendation and decided to modify the recommendation 

in this update to be consistent with the VA/DoD CPG for Management of Diabetes Mellitus.11 We 

suggest patients with CKD and diabetes be targeted to an HbA1c consistent with that recommended for 

the general diabetes population as outlined in the VA/DoD Clinical Practice Guideline for Management 

of Diabetes Mellitus.11 Generally, the target range for glycemic control should be individualized based on 

the provider’s appraisal of the risk-benefit ratio and discussion of the target with the patient. Table 5 

summarizes the target glycemic control in the current VA/DoD Clinical Practice Guideline for 

Management of Diabetes Mellitus.11

11 See the VA/DoD Clinical Practice Guideline for Management of Diabetes Mellitus in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/cd/diabetes/index.asp 

December 2014 Page 54 of 117
Table 5. Determination of Target HbA1c Level (1) (2)

Major Comorbidity (d) or 

Physiologic Age

Microvascular Complications

Absent or Mild (a) Moderate (b) Advanced (c)

Absent

>10 years of life expectancy

<7% <8% 8-9% *

Present (e)

5 to 10 years of life expectancy

<8 % <8% 8-9% *

Marked (f)

<5 years of life expectancy

8-9% * 8-9% * 8-9% *

(1) Based upon the Diabetes Control and Complications trial referent standard. Clinicians need to evaluate the 

methodology used at their site. 

(2) Reflects a “goal” over time. Intensification of therapy should be undertaken based upon individual clinical 

circumstances and treatment option. 

(a) Mild microvascular disease is defined by early background retinopathy, and/or microalbuminuria, and/or mild 

neuropathy. 

(b) Moderate microvascular disease is defined by pre-proliferative (without severe hemorrhage, intra-retinal 

microvascular anomalies [IRMA], or venous bleeding) retinopathy or persistent, fixed proteinuria 

(macroalbuminuria) and/or demonstrable peripheral neuropathy (sensory loss). 

(c) Advanced microvascular disease is defined by severe non-proliferative (with severe hemorrhage, IRMA, or 

venous bleeding), or proliferative retinopathy and/or renal insufficiency (serum creatinine level >2.0 mg/dL), 

and/or insensate extremities or autonomic neuropathy (e.g., gastroparesis, impaired sweating, or orthostatic 

hypotension). 

(d) Major comorbidity includes, but is not limited to, any or several of the following active conditions: significant 

cardiovascular disease, severe chronic kidney disease, severe chronic obstructive pulmonary disease, severe 

chronic liver disease, recent stroke, and life-threatening malignancy. 

(e) Major comorbidity is present, but is not end-stage and management achievable. 

(f) Major comorbidity is present and is either end-stage or management is significantly challenging. 

* Further reductions may be appropriate, balancing safety and tolerability of therapy.

Intensive versus conventional glycemic control therapy

Diabetes mellitus is the leading cause of ESRD in the United States. [130] We identified two randomized 

controlled studies comparing intensive to conventional glycemic control in our target population of 

patients with CKD. [131,132] The first study included 70 patients with microalbuminuria who were 

randomized to intensive glycemic management (≤7.5%) versus conventional control (no defined control 

level, but insulin was adjusted based only on symptoms). At six months post randomization those in the 

intensive group achieved a glycosylated hemoglobin concentration of 8.9% versus 10.3% in the control 

group. This difference became smaller over time and was abolished after 36 months. Progression to 

clinical albuminuria was the same in both groups. [131] The larger VA Cooperative Study by Duckworth 

et al. comparing intensive versus conventional glycemic control involved 1791 patients not selected on 

the basis of kidney function. [132] Patients were randomized to intensive therapy (defined as an 

absolute reduction in glycosylated hemoglobin of 1.5%) versus standard therapy (achieved glycosylated

hemoglobin at six months 6.9% versus 8.4%, intensive versus control, respectively). The study duration 

was 5.6 years. In the overall population, there was no difference in any component of the primary 

outcomes (major cardiovascular event, a composite of myocardial infarction, stroke, death from 

cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary 

disease, and amputation for ischemic gangrene), death, or microvascular complications with the 

December 2014 Page 55 of 117
exception of albuminuria. Among the subgroup of patients with microalbuminuria at baseline there was 

no difference in the incidence of macroalbuminuria (p=0.10). [132] But patients in the more intensive 

therapy group had a greater incidence of hypoglycemia (24.1%) compared to the conventional therapy 

group (17.6%).

A meta-analysis of these two studies by Fink et al. [111] showed that intensive glycemic control 

therapies resulted in a non-significant 3.1% decrease in the risk of progression from micro- to 

macroalbuminuria (8.7% versus 12.8% for intensive and conventional therapies, respectively, risk ratio 

0.69 [95% CI, 0.42 to 1.12], n=561 patients). [111] 

Thus the current evidence does not support intensive glycemic control for the purpose of reducing 

adverse renal or cardiovascular outcomes in patients with CKD.

Iron Therapy

Recommendation

28. We suggest initiation of oral iron therapy (in preference to parenteral) to support iron

requirements in patients with CKD stages 3 and 4. (Weak For)

Discussion

Use of iron therapy for treatment of iron deficient anemia has been a mainstay of management in 

patients with CKD. Iron deficiency is common in patients with CKD due to reasons such as non-renal 

factors (i.e., menstrual bleeding) and iron depletion as a result of gastrointestinal (GI) loss or surgical 

blood loss. In patients with CKD, medications and drug interactions such as gastric acid reducers or 

phosphate binders may cause poor intestinal absorption of iron. Also, patients with CKD not on dialysis 

are at an increased risk of inflammation with elevated C-reactive protein (CRP) and hepcidin levels, 

which causes poor iron absorption. [133] 

Based upon current evidence, route of administration of iron therapy in patients with CKD did not make 

a significant difference in the ability to reduce the dose of or discontinue erythropoietin-stimulating 

agents (ESAs). Albaramki, et al. performed a comprehensive systematic review on IV iron therapy versus 

oral iron therapy. [134] For the purpose of this guideline, nine studies that evaluated outcomes in adult 

non-dialysis patients were reviewed. This systematic review reported that IV iron therapy was 

associated with a small but significant increase in hemoglobin, ferritin and transferrin saturation levels 

compared to oral iron therapy. Use of ESAs was varied. Adverse effects were reported in 50% of 

included studies. The most common side effects reported for oral iron therapy were GI-related; for IV 

iron therapy hypotensive and allergic reaction were the most common side effects. There was limited 

data on mortality, cardiovascular mortality and quality of life. One study reported patient-centered 

outcomes; however there was no significant difference between IV iron therapy and oral iron therapy. 

[134] 

There is limited evidence to support recommendation for specific ferritin and transferrin saturation 

levels to start iron therapy, or as targets. The 2008 CKD CPG suggested ferritin levels be maintained 

December 2014 Page 56 of 117
above 100 ng/mL and transferrin saturation more than 20% in patients with CKD not on dialysis. The 

Work Group concurred with these parameters, recognizing these are largely based on expert opinion.

The Work Group also assessed other potential burdens of IV iron therapy and oral iron therapy for the 

patient and provider. Some of the burdens for patients prescribed oral iron therapy would be potential 

GI side effects, pill burden, possible drug-drug interactions, and drug-diet interactions. For patients 

receiving IV iron therapy, some of the burdens would be increased costs; inconvenience of travel and 

time to an infusion center or clinic for treatment; risks associated with any IV therapy, such as venous 

infiltration; and potential serious adverse effects, such as anaphylaxis. Resource implications present 

challenges for IV iron therapy, such as need for IV iron infusion centers, additional cost of IV iron, and 

increased nursing time. Burdens to the provider are increased provider time to monitor response, order 

surveillance laboratory tests and availability to respond to potential severe adverse drug events.

It is the expert opinion of the Work Group that oral iron therapy is as effective as IV iron therapy in most 

cases. Patient preferences due to side effects, added patient costs and burdens and response to 

treatment should take priority in the treatment decision. If IV iron therapy is required, the Work Group 

suggests referral to nephrology, if not already done, for management of therapy. Future research is 

needed to explore oral iron therapy options in CKD patients, maximize the most effective dose regimens 

and assess long-term clinical benefits or adverse events associated with chronic use. 

Safety and Efficacy of Erythropoiesis-Stimulating Agents

Recommendation

29. We recommend against offering erythropoietin-stimulating agents (ESAs) to patients with CKD for

the purpose of achieving a hemoglobin target above 11.5 g/dL due to increased risk of stroke and

hypertension. (Strong Against)

30. We recommend against initiating ESAs at a hemoglobin level greater than 10 g/dL. (Strong

Against)

Discussion

Anemia is a common complication that develops in patients with CKD, usually most prevalent when 

eGFR is consistently below 30 mL/min. Common factors for anemia in CKD include lack of effective 

erythropoietin (EPO) production by diseased kidneys, shortened life of red blood cells in uremic state, 

and the chronic inflammatory state seen in uremia. While its incidence and prevalence tends to increase 

as CKD progresses, anemia can occur at any CKD stage. Anemia with patients with CKD is normochromic 

and normocytic and has been associated with adverse effects on cardiac function, mental and cognitive 

decline, fatigue and dyspnea. 

The 2008 CKD CPG recommended the use of hemoglobin to define anemia and to start an anemia workup when hemoglobin falls below 13.0 g/dL in males and below 12.0 g/dL in females. Due to wide 

variability, the usage of hematocrit to define anemia is not recommended. There are other complete 

blood count (CBC) indices that are used in the differential diagnosis of anemia and to assess adequacy of 

bone marrow function. Evaluation of anemia in CKD should screen for all causes of anemia except for

December 2014 Page 57 of 117
EPO deficiency. Serum EPO levels in persons with CKD are usually inappropriately low and generally not 

helpful in establishing the differential diagnosis of anemia. The regular surveillance of hemoglobin for 

CKD patients is recommended. The frequency of monitoring should be influenced by the level of 

hemoglobin and the rate of decline.

Recognizing there are multiple etiologies for anemia, the objective of the evaluation is to determine the 

cause and to assess the potential reversibility of anemia with treatment. For the primary care provider, 

early awareness of anemia in patients with CKD, prompt diagnosis, and referral to nephrology are the 

cornerstones of clinical management. 

Safety and efficacy of ESAs in CKD

The literature search included five systematic reviews, 13 RCTs and one case study which evaluated the 

safety and/or efficacy of ESA treatment in CKD patients with anemia. Outcomes of interest were allcause mortality, cardiovascular mortality, stroke, myocardial infarction, worsening hypertension, 

progression to ESRD, mean decrease in GFR, and quality of life. 

In the evidence reviewed, the ESA treatment was effective in raising the mean hemoglobin. Recent data 

suggest that an ESA (darbepoetin alfa) effectively reduces the need for blood transfusions in patients

with stage 3 to 5 CKD. [135-138] However, there was insufficient evidence to recommend specific 

thresholds for starting treatment or for maintaining hemoglobin within a certain target range to 

decrease the need for blood transfusions.

Treatment with ESAs is associated with risks and benefits and these should be discussed by a 

nephrologist or anemia management clinic with the patient. In weighing the potential harms versus 

benefits of ESA treatment, there was moderate evidence that treatment to higher hemoglobin targets 

was associated with increased risk of hypertension and cerebral vascular accident compared to lower 

hemoglobin targets. [138,139] There were no significant differences in all-cause mortality, [140,141] 

cardiovascular mortality or reducing progression to ESRD. [137,142] The TREAT study [138] was a large 

trial looking at the use of ESAs in patients with CKD, type 2 diabetes, and anemia that randomized 

patients to an ESA to achieve a hemoglobin of 13 g/dL or rescue ESA when the hemoglobin was less than 

9 g/dL. The primary end-points were the composite outcomes of death or a cardiovascular event 

(nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial 

ischemia) and of death or ESRD. The use of an ESA did not reduce the risk of either of the two primary 

composite outcomes (either death or a cardiovascular event, or death or a renal event) and was 

associated with an increased risk of stroke. In patients with history of malignancy, ESA use was 

associated with increased adverse events, including increased mortality from cancer, tumor progression 

and thrombotic events. [138,143,144] In the 2008 VA/DoD CKD Clinical Practice Guideline review of 

other controlled trials on ESA treatment in patients with CKD and anemia (CHOIR and CREATE trials 

[145,146]), patients experienced greater risks for death, serious adverse cardiovascular reactions, and 

stroke when administered ESAs to target a hemoglobin level of greater than 11.5 g/dL.

The FDA released its guidance on the usage of ESAs in 2011. [147] The Agency stated that the providers 

should individualize the dosing to use the lowest dose of ESA sufficient to reduce the need for red blood 

December 2014 Page 58 of 117
cell transfusions and to adjust the dose as indicated. The FDA did not recommend a specific target range 

but did advise to initiate ESA treatment when the hemoglobin level falls below 10 g/dL. Other situations 

to consider use of ESA include the rate of decline suggesting the need for red blood cell transfusion; and 

the reduction of risks of alloimmunization and/or other risks related to red blood cell transfusion. If the 

hemoglobin level rises above 10 g/dL in patients with CKD not on dialysis, the FDA recommended 

lowering or stopping the ESA. 

ESA use should be individualized based upon the rate of hemoglobin decline, prior response to iron 

therapy, and weighing the risks related to blood transfusion versus ESA therapy with the benefits of 

alleviation of symptoms. It advised not to start ESAs when hemoglobin is above 10 g/dL or to maintain 

hemoglobin above 11.5 g/dL. The harms outweigh the benefits of normalization of hemoglobin above 13 

g/dL in patients with CKD. Recognizing there may be patients who may need higher hemoglobin due to 

symptom alleviation, other comorbidities, such as heart failure or pulmonary disease, and geography, 

such as living in high altitude. Providers need to discuss with the patient the risks of ESA use versus the 

benefits for these special circumstances. 

Quality of life

There was incomplete reporting of full domains for assessment of quality of life, which did not support 

consistent data interpretation across all domains. The mean difference in the quality of life among those 

with the higher hemoglobin level was not statistically significant. [137-139] Similarly, in the 2014 

Cochrane review, use of darbepoetin had little or no effect on quality of life. [139] 

Comparisons of ESA products

None of the drug-specific studies included in the recent literature search were relevant, due to the drugs 

not being available on the U.S. market. Therefore, the Work Group was not able to compare specific ESA 

drugs against each other or different dosing strategies based on the recent literature review.

The Work Group considered other burdens associated with ESA use for patients with CKD not on 

dialysis, such as the cost of the drug, frequency of clinic visits for ESA injections and need for laboratory

monitoring. There are also burdens to the provider for ESA management which include increase in 

resource allocations for the provider, laboratory, clinic staff and pharmacy. Additional burdens would 

include monthly laboratory monitoring, on-going surveillance of patient condition changes and prompt 

identification of critical findings requiring cessation of ESA treatment. Due to the ability to promptly 

identify risks associated with ESA use for patients with CKD and follow resource burdens, the Work 

Group encourages referral to a nephrology clinic or specialized clinic for ESA management.

Correction of Vitamin D Deficiency

Recommendations

31. We suggest offering supplemental vitamin D to correct vitamin D deficiency in patients with CKD

stages 3 or 4. (Weak For)

December 2014 Page 59 of 117
Discussion

As noted in the previous VA/DOD CKD guideline (2008), vitamin D deficiency is common in the general 

population and may be even more common in patients with CKD. The Institute of Medicine (IOM) 

recommends a Recommended Dietary Allowance (RDA) of 600 IU/day (800 IU/day in those >70 years of 

age) vitamin D for bone health. In addition, the IOM concluded that intake of vitamin D above 4,000 

IU/day increases the risk for harm. [148] It has been suggested that doses of 800 IU to 1000 IU per day 

are necessary for those individuals with inadequate sun exposure, and daily supplementation of 400 IU 

to 2,000 IU of cholecalciferol for the prevention of vitamin D deficiency in those at high risk. [149] 

Three studies identified for this review examined the effects of oral cholecalciferol supplementation on 

biochemical parameters in CKD patients. [150-152] The average baseline serum calcidiol levels in two 

studies were indicative of vitamin D deficiency, [150,151] while the third study included patients with 

normal serum levels. [152] All three studies, varying in duration (one to six months) and dose 

(normalized monthly dose ranging from 200,000-300,000 IU), reported a significant improvement in 

serum calcidiol levels. Serum parathyroid hormone (PTH) levels improved significantly in one study,

[151] tended to decline in another [150]and did not change in the third. [152] No changes were 

observed in serum calcium or phosphate levels. No incidence of hypercalcemia or hyperphosphatemia 

was reported in these studies. None of the three studies reported mortality or morbidity outcomes. 

Although none of these studies reported convincing changes in biochemical parameters or other 

outcomes, the Work Group suggests that supplemental vitamin D (cholecalciferol or ergocalciferol) to 

correct vitamin D deficiency may be offered to CKD patients as recommended for the general population 

after six months of treatment.

Active Vitamin D Use 

Recommendation

32. We suggest not offering active vitamin D analogs or calcitriol to patients with stage 3 and 4 CKD

with elevated parathyroid hormone (PTH) levels due to lack of evidence for kidney, bone, or

cardiovascular benefit and increased potential of harm from hypercalcemia. (Any use of active

vitamin D analogs should be managed by a nephrologist.) (Weak Against)

Discussion

In CKD patients, the updated literature review identified studies with two orally active vitamin D 

compounds, paricalcitol [153-155] and doxercalciferol, [156] both compared with placebo. Kovesdy et 

al. [157] compared paricalcitol to ergocalciferol. All studies demonstrated a significant decline in PTH 

levels during 8 to 48 weeks of study duration. Thadhani et al. also noted a significant decline in bonespecific serum alkaline phosphatase levels. [154] Whereas Kovesdy et al. reported a significant increase 

in serum calcidiol levels in both paricalcitol and ergocalciferol groups, de Boer et al. found a significant 

decline in serum calcidiol levels with paricalcitol compared to placebo. The study also reported a 

significant elevation in serum fibroblast growth factor 23 (FGF23) levels in the paricalcitol treated group 

versus placebo. [153,157] 

December 2014 Page 60 of 117
The study by Thadhani et al. [154] was designed to examine changes in left ventricular mass index by 

cardiac magnetic resonance imaging (MRI) and echocardiography in patients with left ventricular 

hypertrophy during paricalcitol therapy in a randomized, placebo controlled trial. They did not report a 

significant improvement in left ventricular mass index or left ventricular end-diastolic volume index after 

48 weeks of therapy. The hospitalization rates from all causes did not differ between the two groups, 

although hospital admissions due to congestive heart failure were greater in the placebo group. [154] 

Fishbane et al. [155] evaluated the effects of paricalcitol on proteinuria and eGFR in a randomized, 

placebo-controlled trial. Although a significant decrease in proteinuria was observed by these authors, 

the eGFR did not significantly change. [155] 

The effects of active vitamin D compounds on changes in serum calcium and phosphate levels were 

variable. Thadhani et al. and de Boer et al. reported a significant increase in serum calcium levels and 

incidences of hypercalcemia with paricalcitol therapy. [153,154] The Thadhani et al. study also reported 

significantly higher serum phosphate levels in the treatment group compared to placebo. Fishbane et 

al., Patel et al. and Kovesdy et al. noted no differences in serum calcium or phosphate values. These 

disparate findings may be explained by varying sample size, dose and duration of treatment apparent in 

these clinical trials. [154-157] 

Of note, Thadhani et al. found that the paricalcitol group experienced significantly higher serum 

creatinine levels and lower creatinine-based eGFR values when compared to placebo. This difference in 

eGFR was not observed with cystatin-C based eGFR measurements. The authors attributed the 

discrepancy in eGFR outcomes by serum creatinine and cystatin-C to reported increase in creatinine 

production by active vitamin D drugs. [154] 

In a systemic review, Palmer et al. reported on studies that described bone histomorphomatric changes, 

bone density and fractures in CKD patients treated with active vitamin D compounds. [158] In one study, 

no significant differences were found in bone mineral density at femoral neck or lumber spine after 12

months of oral calcitriol therapy in 25 patients. In the same analysis, studies reporting changes in bone 

histomorphometry included small number of patients. These studies suggested that oral calcitriol may 

slightly improve osteitis fibrosa, but may increase the risk of developing osteomalacia. In another study 

reported in the same systemic review, calcitriol did not improve fracture rates with oral calcitriol in 38

patients.

In summary, in the absence of consistent evidence pointing toward kidney, bone or cardiovascular 

benefit (other than parathyroid hormone reduction) and because of the potential for harm of causing 

hypercalcemia, the Work Group suggests not offering active vitamin D analogs or calcitriol to patients 

with stage 3 and 4 CKD.

December 2014 Page 61 of 117
Phosphate Binders

Recommendation

33. We suggest not offering phosphate binders to patients with stage 3 and 4 CKD with normal serum

phosphorous. (Carryover modified from the 2008 CPG) (Weak Against)

Discussion

In CKD patients, hyperphosphatemia occurs when GFR is reduced to less than 30-35 mL/min/1.73m2

. 

Serum phosphate levels are dependent on dietary phosphorus intake, intestinal absorption and renal 

excretion. The hormonal regulation by parathyroid hormone, vitamin D and FGF23 play a crucial role in 

the physiology of phosphorus homeostasis. Hyperphosphatemia in stage 4 CKD patients occurs due to 

ingestion of phosphorus containing foods, including additives and preservatives. The common metabolic 

consequences of hyperphosphatemia include changes in serum calcium and phosphorus levels, 

secondary hyperparathyroidism and vascular calcification. Changes in phosphaturic hormones, such as 

FGF23 and serum fetuin-A, an inhibitor of vascular calcification, are also reported.

The initial approach to manage hyperphosphatemia is dietary restriction of phosphorus-containing 

foods. Phosphate binders are currently approved by the FDA for the control of serum phosphate levels 

in end-stage renal disease patients receiving renal replacement therapy.

Oral phosphate binders are classified as calcium based (calcium carbonate or acetate) or non-calcium 

based (sevelamer, lanthanum salts, or iron-based, magnesium-based, or aluminum-based binders). Use 

of these agents in CKD patients have been evaluated in placebo-controlled and comparator clinical 

studies.

Five RCTs identified in patients with CKD not on dialysis were placebo-controlled studies, four of the five 

RCTs used a single agent, calcium acetate, [159] sevelamer [160] or lanthanum. [161,162] One study 

compared three drugs with placebo. [163] Two studies reported comparison of sevelamer with calcium 

carbonate [164] or calcium acetate. [165] Also of note, three of the seven studies were conducted in 

patients who had normal serum phosphorus levels, with a mean baseline < 4.6 mg/dL. [160,161,163] 

The outcome parameters included changes in serum calcium, phosphate and parathyroid hormone

(PTH) levels. Some studies measured serum calcitriol levels. [160,162,163] Few authors reported 

measurements of bone mineral density [160,161,163] or vascular calcification. [161,163] Only one study 

reported mortality data. [164] 

Changes in serum PTH levels showed conflicting results. Using lanthanum carbonate versus placebo, 

Seifert et al. found no significant change in serum PTH or serum phosphate levels at 12 months in 

patients with normal baseline serum phosphorus (mean < 3.5 mg/dL), while Sprague et al. reported a 

significant decline in serum PTH and serum phosphate values after eight weeks of the same drug 

therapy. [161,162] Chue et al. examined sevelamer therapy with a placebo control in patients with 

normal serum phosphorus levels (mean baseline approximately 3.2 mg/dL) for 40 weeks. [160] They 

reported no significant differences in serum phosphorus, PTH, calcitriol or calcidiol levels or bone 

December 2014 Page 62 of 117
mineral density between the two groups. Qunibi et al. evaluated calcium acetate versus placebo in 

nondialysis CKD patients with hyperphosphatemia (baseline phosphorous 5.1 mg/dL) and reported 

greater than 50% reduction in serum PTH levels associated with a significant decline in serum phosphate 

levels. [159] However, the drug therapy resulted in significant incidence of hypercalcemia. In a 

preliminary study, Block et al. conducted a 1:1:1 RCT using calcium acetate, sevelamer and lanthanum 

versus placebo in 148 patients with stage 3 and 4 CKD and normal serum phosphorus (mean baseline 4.2 

mg/dL). [163] The authors reported no significant change in serum PTH levels with active therapy, while 

the placebo group showed 21% increase in serum PTH. Serum phosphate was significantly lower in the 

lanthanum group. The calcium acetate group showed improvement in annualized bone density. In a 

subgroup of patients, active phosphate binder therapy showed significant increase in calcification of 

coronary arteries and abdominal aorta. Using Hokanson criterion, 38% of patients in the phosphatebinder group had progression of coronary calcification compared with 17% in the placebo group (p = 

0.03). Caglar et al. confirmed salutary effects of sevelamer and calcium acetate on serum phosphorus 

levels in stage 4 CKD patients with hyperphosphatemia (mean baseline 7.8 mg/dL). [165] However, both 

groups exhibited a significant increase in serum PTH levels at the end of eight weeks.

The evidence reviewed yielded conflicting and inconsistent results. Based on inadequate data and 

possible increased risk of vascular calcification, we do not recommend use of phosphate binders in 

patients with normal serum phosphorous levels. However, oral phosphate binders may be considered in 

patients with stage 3 or 4 CKD with elevated serum phosphorous levels that do not normalize with 

dietary interventions alone. 

Calcimimetics 

Recommendation

34. We suggest not offering calcimimetics to patients with stage 3 and 4 CKD due to lack of evidence

for kidney or cardiovascular benefit and increased risk of harm from hypocalcemia. (Weak Against)

Discussion

Calcimimetic agents are approved for the control of secondary hyperparathyroidism in end-stage renal 

disease patients. Rated as a fair quality study, Chonchol et al. examined the effects of cinacalcet versus 

placebo in a 32 week study of patients with CKD stages 3 and 4. [166] The cinacalcet group showed a 

significant decline in serum parathyroid hormone levels, and a greater proportion of patients on therapy 

showed more than 30% fall in serum PTH values compared with the placebo group. However, 

approximately two thirds of patients treated with cinacalcet developed hypocalcemia. Importantly, 

cinacalcet therapy led to a 20% increase in serum phosphorus levels at the end of the study. The clinical 

significance of these biochemical changes in PTH is uncertain. No studies have documented any 

bone/mineral or cardiovascular benefit of calcimimetic treatment in CKD population. Due to substantial 

risk of developing hypocalcemia and a moderate possibility of developing hyperphosphatemia with 

cinacalcet therapy, we do not recommend this class of drugs to manage hyperparathyroidism in stage 3 

and 4 CKD patients. 

December 2014 Page 63 of 117
Summary

Complementing patient self-management strategies, there are numerous effective clinical management 

strategies that may be employed to reduce the adverse outcomes of CKD. Blood pressure control, 

appropriately tailored to patient tolerance, and preferential use of ACEI/ARBs in patients with 

hypertension and CKD with albuminuria are essential to limit progression of CKD to ESRD. Monitored 

dietary interventions including sodium and protein restriction in patients with CKD, and bicarbonate 

supplementation in patients with metabolic acidosis may also be useful in limiting progression to kidney 

failure. For patients with diabetes and CKD, the risks and benefits of intensive glycemic control need to 

be discussed with the patient and balanced to achieve patient-centered goals of care. 

Prevention of cardiovascular disease and infection is paramount in this at-risk population, thus the 

directed use of statins and administration of prophylactic immunizations should be built into the routine 

care of patients with CKD. 

In light of the increased possibility for adverse drug events in patients with CKD, vigilance is required to 

appropriately dose-adjust all medications for the patient’s level of kidney function, avoid potentially 

hazardous combinations of medications, and limit the patient’s exposure to potentially nephrotoxic 

agents. 

Patient safety must also be considered and prudence applied when using medications to treat the 

complications of progressive kidney disease (e.g., ESAs to treat anemia, and oral phosphate binders, 

vitamin D analogs, and calcimimetics in the management of CKD bone and mineral disorders). 

Lastly, the use of a multidisciplinary model of care and timely engagement of nephrology specialty care 

is suggested to more effectively meet the myriad needs of patients with CKD.

December 2014 Page 64 of 117
Knowledge Gaps and Recommended Research 

The availability of high quality CKD research is limited due to the stipulation of CKD as a common

exclusion criterion in non-kidney related trials. This has resulted in frequent reliance on either 

observational studies of CKD populations or secondary cohort analyses of RCTs involving non-CKD 

subjects rather than on primary CKD population health studies for insight into effective health care 

strategies in kidney disease. During the course of the literature review for this guideline, the Work

Group identified a need for additional research to close the knowledge gap in the optimal primary and 

secondary prevention and treatment of patients with CKD. 

The need for clinical trials and comparative effectiveness research was identified in key areas. First, 

there is a need for studies evaluating patient activation strategies such as patient education, in order to 

quantify the impact that patient education and self-management may have on clinical outcomes, and to 

determine the relative efficacy of tools and methodologies employed in the education process. 

Second, the impact of alternative health care models and practitioners on clinical outcomes in CKD 

deserves attention. Particularly, with the VA/DoD investment in virtual care, there is a growing need to 

define the role and health care value of electronically facilitated access to care as compared to the 

traditional face-to-face model, especially in patients with complex disease such as CKD. There is also a 

need to better understand the optimal deployment of non-nephrologists and of primary care versus 

patient-aligned care teams to meet the needs of patients with CKD. 

Third, the sparseness of literature on the effective dissemination and implementation of evidence-based 

CKD management strategies warrants further research. Literature investigating tools to translate 

evidence for optimal CKD care into clinical practice (e.g., virtual care models, smartphone apps, 

checklists, etc.) should be conducted. 

An important gap in knowledge remains for the target blood pressure and the best antihypertensive 

choice for the older patient with CKD, where a careful balance of risks and benefits needs to be taken 

into consideration. Another gap in knowledge remains regarding the appropriate blood pressure target

in patients with proteinuria. Additionally, future studies need to address the use of self-monitoring of 

blood pressure using the VA/DoD created tools, such as MyhealthyVET, health promotion mobile apps, 

and home telehealth.

Other recommendations for research include studies to gain an improved understanding of predictors of 

CKD progression to enable high risk population management. Confirming a benefit of targeted reduction 

of proteinuria on CKD outcomes is overdue. Also, strategies and tools to reduce the harm of treatments 

used in the CKD population need to be developed.

Newer forms of clinical trial design such as point of care/pragmatic research may be particularly cost 

effective and valuable in studying the care of CKD patients where there is clinical equipoise between 

competing management strategies. 

A dearth of new literature exists about optimal nutrition prescriptions, but additional research 

December 2014 Page 65 of 117
examining phosphate and micronutrients balance is necessary. Other recommended research includes

mortality in CKD and CKD progression in high risk population management. 

Further epidemiologic study of the impact of military occupational exposures on the development and 

progression of CKD is also warranted.

Finally, because of the substantial data assets of the VA health care system, including one of the world’s 

largest genetic data bases, and its comprehensive, national, and longitudinal EHR, the VA is uniquely 

poised to offer insights into the drivers of health disparities in kidney disease and into the kidney health 

of the Veteran population. 

December 2014 Page 66 of 117
Appendix A: Evidence Review Methodology

The Clinical Practice Guideline (CPG) Champions were tasked with identifying key evidence questions to 

guide the systematic review of the literature on Chronic Kidney Disease (CKD). These questions, which 

were developed in consultation with the Lewin team, addressed clinical topics of the highest priority for 

the Veterans Affairs (VA) and Department of Defense (DoD) populations. The key questions follow the 

population, intervention, comparison, outcome, timing and setting (PICOTS) framework for evidence 

questions, as established by the Agency for Healthcare Research and Quality (AHRQ). Table A-1 provides

a brief overview of the PICOTS typology.

Table A-1. PICOTS [167]

P

Patients, 

Population 

or Problem

A description of the patients of interest. It includes the condition(s), populations 

or sub-populations, disease severity or stage, comorbidities, and other patient 

characteristics or demographics.

I Intervention 

or Exposure

Refers to the specific treatments or approaches used with the patient or 

population. It includes doses, frequency, methods of administering treatments, 

etc.

C Comparison

Describes the interventions or care that is being compared with the 

intervention(s) of interest described above. It includes alternatives such as 

placebo, drugs, surgery, lifestyle changes, standard of care, etc.

O Outcome

Describes the specific results of interest. Outcomes can include short, 

intermediate, and long-term outcomes, or specific results such as quality of life, 

complications, mortality, morbidity, etc.

(T) Timing, if 

applicable

Describes the duration of time that is of interest for the particular patient 

intervention and outcome, benefit, or harm to occur (or not occur).

(S) Setting, of 

applicable

Describes the setting or context of interest. Setting can be a location (such as 

primary, specialty, or inpatient care).

The Champions and evidence review team carried out several iterations of this process, each time 

narrowing the scope of the CPG and the literature review by prioritizing the topics of interest. Table A-2 

contains the final set of key questions used to guide the systematic review for this CPG. 

Population(s)

The key questions are specific to adults 18 years or older with CKD In this review, CKD is defined as

abnormalities of kidney structure or function, present for >3 months, with implications for health 

outcomes. [3] Patients with CKD stage 5 (end-stage renal disease), patients who have received a kidney 

transplant, and pediatric patients with CKD are not covered in this guideline. 

Interventions

The therapeutic interventions considered under Key Question 1 and 2 of the review were the measures 

designed to prevent acute kidney injury. The reviews also addressed the association of occupational/

December 2014 Page 67 of 117
environmental exposure and acute kidney injury or CKD.

Treatments covered in Key Questions 3 through 7 of the review include the following: pharmacologic 

treatments such as renin-angiotensin blockade (ACEIs and ARBs), mineralocorticoid antagonists, direct 

renin inhibitors (e.g., aliskiren), statin therapy, diuretics, and erythropoiesis-stimulating agents (ESAs). 

Management approaches considered in Key Questions 7 through 9, 11 and 12 included integrated 

models of patient care, consulting referral for nephrologist, impact of glycemic control and measures 

designed to improve safety and reduce risk of adverse drug events. 

Self-management approaches considered in Key Question 10, which included strategies such as exercise, 

smoking cessation, nutrition, weight loss, health education, and lowering blood pressure. 

Outcomes

For some Key Questions the outcomes of interest were measures of disease progression, including rate 

of progress to ESRD, increase in serum creatinine, proteinuria, and development of cardiovascular 

disease. For other key questions the outcomes of interest were patient-oriented clinical outcomes, 

including disease-related morbidity (e.g., stroke), treatment-related adverse events, hospitalization, 

quality of life and mortality. For Key Question 1 the outcome of interest was development of acute 

kidney injury. For Key Question 2 (occupational exposures), the outcome of interest was the degree of 

association with acute kidney disease or CKD. For Key Question 5 the outcomes of interest include 

change in blood markers such as vitamin D level, parathyroid hormone levels, and phosphate levels; 

DEXA scans; decrease in bone fractures; and mortality. 

Conducting the Systematic Review

The methods guiding this systematic review are described below. In part, these methods follow the 

guidelines for conducting a systematic review set forth by the Agency for Healthcare Research and 

Quality (AHRQ) in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews. [168] The 

methods also follow the guidance set forth by the VA/DoD in the Guideline for Guidelines document. [7] 

Extensive literature searches identified 7,172 citations potentially addressing the key questions of 

interest to this evidence review. Of those, 2,857 were excluded upon title review for clearly not meeting 

inclusion criteria (e.g., not pertinent to the topic, not published in English, published prior to study 

inclusion publication date, or not a full-length article). Overall, 4,315 abstracts were reviewed with 3,050 

of those being excluded for the following reasons: not a systematic review or clinical study, did not 

address a Key Question of interest to this review, did not enroll population of interest, or published prior 

to January 2007. A total of 1,265 full-length articles were reviewed. Of those, 884 were excluded at a 

first pass review for the following: not addressing a key question of interest (42%), not enrolling the 

population of interest (26%), not meeting the inclusion criteria for clinical study or systematic review

(21%), or being a duplicate (11%). A total of 381 full-length articles were thought to address one or more 

key questions and were further reviewed. Of these, 262 were ultimately excluded. Reasons for their 

exclusion are presented in Figure A-1 below. 

December 2014 Page 68 of 117
Overall, 115 studies addressed one or more of the Key Questions and were considered as evidence in 

this review. Table A-2 indicates the number of studies that addressed each of the questions. 

Figure A-1. PRISMA Diagram of Literature Search Results

, 

 262 Citations Excluded at 2nd Pass Full Article 

Level

110 Does not address KQ or enroll population of 

interest

68 Includes too many patients outside of 

population of interest

28 SR superseded by more comprehensive 

review, study covered in an included SR, or 

duplicate publication

62 Other 

2,857 Citations Excluded at the Title Level

Citations excluded at this level were off-topic, not 

published in English, or published prior to

inclusion date

7,172 Citations Identified by Searches

4,315 Abstracts 

Reviewed

3,050 Citations Excluded at the Abstract Level

Citations excluded at this level were not SR or 

CS, clearly did not address a KQ, did not report 

on an outcome of interest, or were outside cutoff 

publication dates

381 Articles 

Reviewed

115 Included Studies

 884 Citations Excluded at 1st Pass Full Article 

Level

Articles excluded at this level did not: address a 

key question of interest, enroll the population of 

interest, meet inclusion criteria for clinical study or 

systematic review, or were a duplicate.

1,265 Full-length Articles Reviewed

December 2014 Page 69 of 117
Table A-2. Evidence Base for Key Questions 

Number of 

Question

Question Number of Studies and 

Type of Studies

Screening/Prevention/Risk Factors

1 In adult patients with CKD, what are the causes of and effective 

measures to prevent acute kidney injury?

2 systematic reviews, 19 

randomized controlled 

trials (RCTs) and 1 nonrandomized controlled 

study

2 In Veterans and military Service Members, what occupational 

exposures are nephrotoxic or increase the risk of CKD and 

therefore should prompt screening for CKD?

3 systematic reviews, 6 

observational cohort 

studies and 1 crosssectional study

Pharmacologic Treatments

3 In adult patients with chronic kidney disease (CKD), is 

combined renin-angiotensin aldosterone (RAAS) blockade 

(ACEIs and ARBs), or spironolactone or eplerenone, or direct 

renin inhibitors in conjunction with RAAS inhibitor, safe and 

effective for slowing progress to end-stage renal disease 

(ESRD), slowing increase in serum creatinine (SCr), and 

decreasing proteinuria?

3 systematic reviews and 

8 RCTs

4 In adult non-diabetic patients with CKD and dyslipidemia (LDLC>100), what is the evidence that pharmacologic therapy is 

safe and effective as an adjunct to lifestyle changes in 

improving morbidity (such as decreased CVD, stroke) and 

mortality?

3 secondary analyses of 

RCTs and 1 primary RCT

5 In adult patients with CKD 3 and 4, what therapies are effective 

for treatment of CKD-mineral and bone disorder (MBD)?

2 systematic reviews and 

10 RCTs

6 In adult patients with CKD and anemia, are ESAs safe and 

effective in increasing hemoglobin, improving QoL and slowing 

the progression of CKD and if so, how should iron be 

supplemented to optimize ESA effectiveness?

6 systematic reviews, 13 

RCTs, and 1 case-control 

study

7 In adult hypertensive patients with CKD with and without 

proteinuria, what medication (ACEI, ARB, diuretics) should be 

used for controlling blood pressure? In adult patients with CKD, 

what is the evidence for a blood pressure target and what is 

the evidence that outcomes are differentially improved based 

on targets? Do those targets vary by age?

3 systematic reviews and 

11 RCTs

December 2014 Page 70 of 117
Number of 

Question

Question Number of Studies and 

Type of Studies 

Management Strategies

8 In patients with CKD and diabetes, what is the impact of 

glycemic control on slowing progression to ESRD, proteinuria, 

SCr, and decreased hospitalization? What is the optimal range 

of glycemic control to achieve the measures above and 

decrease morbidity?

1 systematic review, 2 

RCTs and 2 retrospective 

cohort studies

9 In adult patients with stage 3 CKD, with and without diabetes, 

is consultation with a nephrology specialist associated with 

slowing progress to ESRD, slowing increase in serum creatinine, 

decreasing proteinuria, reducing development of 

cardiovascular disease (CVD), preparing and transitioning to 

renal replacement therapy and addressing advanced care 

planning?

4 observational study 

designs

10 In adults with CKD, what is the evidence that outcomes are 

improved by self- management strategies addressing:

8 systematic reviews and 

4 individual studies (see 

below for breakdown 

according to specific selfmanagement category)

a. Blood pressure interventions 1 RCT

b. Nutrition (protein restriction, micronutrients) 5 systematic reviews

c. Weight loss management, maintenance of healthy body

weight

1 systematic review 

d. Exercise 1 systematic review and 

2 RCTs

e. Smoking cessation No studies identified

f. Health education 2 systematic reviews and 

1 prospective nonrandomized controlled 

study

11 In adult patients with CKD, what measures (e.g., dose 

adjustment for eGFR, periodic laboratory monitoring, clinical 

reminders, informed consent, clinical pharmacist surveillance, 

education) have been proven to improve safety and reduce the 

risk of adverse drug events due to nephrotoxic or renallycleared medications, including prescription drugs, OTCs, and 

nutritional supplements?

1 diagnostic performance 

study

December 2014 Page 71 of 117
Number of 

Question

Question Number of Studies and 

Type of Studies 

12 In adult patients with CKD, what integrated models of CKD 

patient care have been shown to improve outcomes? 

(Outcomes: proteinuria, SCr, slow progression to ESRD, 

decreased hospitalization, functional status, quality of life)

1 systematic review, 2 

RCTs, and 5 nonrandomized controlled 

studies

Total Evidence Base 115 studies 

Criteria for Study Inclusion/Exclusion

General Criteria

• Clinical studies or systematic reviews published on or after January 1, 2007 (eliminated via filtered

search)

• Studies must have been published in English (eliminated via filtered search)

• Publication must have been a full clinical study or systematic review; abstracts alone were not

included. Similarly, letters, editorials, and other publications that are not full-length, clinical

studies were not accepted as evidence (partially eliminated via filtered search)

• Studies must have enrolled a patient population in which at least 85% of patients had CKD (stage

1, 2, 3, or 4) or associated condition or symptoms

• Studies enrolled adults 18 years or older; in studies that mixed adults and children, at least 85% of

the enrolled patients had to be 18 years or older

Prevention, Pharmacologic Treatment, and Management Strategies 

• Studies must have evaluated a treatment or management strategy for CKD

• Studies must have been a randomized controlled trial (RCT), prospective controlled clinical trial

(CCT) or a systematic review of RCTs and/or CCTs. If no studies meet this criterion for all or part of

a given key question, large observational studies (n ≥500 patients) will be considered for inclusion

• Crossover trials were considered only if data from the first treatment period were reported

separately

• Studies must have enrolled ≥ 10 patients per treatment arm

• Studies must report data on at least one of the included outcomes

• Studies must have followed patients for at least 4 weeks; the exception is studies addressing Key

Questions with acute kidney injury as an outcome (Key Question 1 and 2), which have no

minimum follow-up time requirement

• All subjective outcomes (e.g., quality of life) must be measured using validated instruments

CKD Risk Factor Awareness Studies (Key Question 2)

• Studies must have been a case controlled or a comparative cohort study that assesses presence

versus absence of occupational exposure (e.g., development of CKD in occupational exposure

cohort versus cohort without exposure, or history of occupational exposure in patients with CKD

versus comparison group without CKD)

• Studies must have investigated occupational exposures that may increase the risk of CKD. Expert

December 2014 Page 72 of 117
opinion papers were not considered as evidence addressing this question

Literature Search Strategy

Name Date Limits Platform/Provider

Agency for Healthcare Research and 

Quality (AHRQ) 

2007 through December 12, 2013 U.S. Department of Health & Human 

Services

Cochrane Library 2007 through December 4, 2013 John Wiley and Sons, Ltd.

EMBASE 2007 through December 2, 2013 OVID Technologies, Inc.

MEDLINE 2007 through December 2, 2013 OVID Technologies, Inc.

National Institute of Health and Care 

Excellence (NICE)

2007 through December 4, 2013 National Institute for Health and 

Care Excellence

PubMed (In-process, Publisher, and 

PubMedNotMedline records)

2007 through December 4, 2013 National Library of Medicine (NLM)

EMBASE and Medline

The strategies below are presented in OVID syntax; the searches were simultaneously conducted across 

EMBASE and Medline. 

OVID Conventions:

$ or * = truncation character (wildcard)

ADJn = search terms within a specified number (n) of words from each other in any order

exp = “explodes” controlled vocabulary term (e.g., expands search to all more specific related 

terms in the vocabulary’s hierarchy)

.de. = limit controlled vocabulary heading

.mp. = combined search fields (default if no fields are specified)

.pt. = publication type 

.ti. = limit to title 

.tw. = limit to title and abstract fields 

Key Question 1

Concepts Search Statement

1 Acute kidney injury prevention *acute kidney injury/et,pc

2 Acute kidney injury *acute kidney injury/ or AKI.ti. or (acute adj (renal or kidney$) adj (injur$

or insufficienc$ or fail$)).ti.

3 Prevention and etiology *primary prevention/ or *accident prevention/ or *biomarkers,

pharmaceutical/ or (prevent$ or protect$ or caus$ or etiolog$).ti,ab.

4 Combine 1 or (2 and 3)

5 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

6 Combine 4 and 5

December 2014 Page 73 of 117
Concepts Search Statement

7 Limit by study type 6 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

8 Limit by study type 6 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

9 Combine 7 or 8

10 Limit 9 to “all adult (19 plus years)” and English language and humans and yr=

11 Deduplicate Remove duplicates from 10

Key Question 2

Concepts Search Statement

1 Chronic kidney disease exp renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) adj 

(failure or disease)).ti,ab.

2 Acute kidney injury exp acute kidney injury/ci or exp kidney diseases/ci

3 Nephrotoxicity nephrotox$.mp.

4 Combine 1 or 2 or 3

5 Service Members exp veterans/ or exp veterans health/ or exp military personnel/ or 

(veteran$ or military or army or navy or naval or marine$ or soldier$ or 

armed force$ or air force or coast guard$).mp.

6 Occupational exposures exp occupational exposure/ or (OSHA or environment$ or work$ or 

vocation$ or occupation$).mp. 

7 Combine 4 and 5 and 6

8 Deduplicate remove duplicates from 7

9 Limit 8 to English and yr="2007 -Current"

Key Question 3

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

December 2014 Page 74 of 117
Concepts Search Statement

2 Combined renin-angiotensin 

blockade (ACEIs and ARBs)

(exp *angiotensin-converting enzyme inhibitors/ or ACE inhibitor$.ti,ab. 

or ACE-I.ti,ab. or ACEI.ti,ab. or ACE-inhibitor$.ti,ab. OR (angiotensin ADJ3 

inhibitor$).ti,ab.) and (exp *angiotensin receptor antagonists/ or 

ARB.ti,ab. or ARBs.ti,ab. or ((angiotensin or angiotensin-receptor) ADJ3 

(block$ or antagonist$)).ti,ab.) OR renin-angiotensin blockade.ti,ab. or 

RAS blockade.ti,ab. or renin-angiotensin inhibitor.ti,ab. or RAS 

inhibitor.ti,ab.

3 Spironolactone spironolactone/ or spironolactone.ti,ab.

4 Direct renin inhibitor DRI.ti,ab. or (direct adj renin adj inhibitor$).ti,ab.

5 Combine 2 or 3 or 4

6 Treatment outcome "outcome assessment (health care)"/ or treatment outcome/ or 

outcome$.ti,ab. or disease progression/ or progress$.ti,ab. or 

efficac$.ti,ab. or effective$.ti,ab.

7 Combine 1 and 5 and 6

8 Limit by study type 7 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

9 Limit by study type 7 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

10 Combine 8 or 9

11 Limit 10 to English language and humans and "all adult (19 plus years)" and 

yr="2007 -Current"

12 Deduplicate Remove duplicates from 11

Key Question 4

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Dyslipidemia dyslipidemias/ or (dyslipid$ or dyslipoproteinemia$).ti,ab.

3 Pharmacologic therapy drug therapy/ or (drug$ or medicat$ or pharma$).ti,ab.

4 Lifestyle changes life style/ or health behavior/ or diet/ or exercise/ or weight loss/ or 

(lifestyle$ or life style$ or life-style$ or diet$ or exercis$ or nutrit$ or 

weigh$ or health$ or cessation$ or smok$).ti,ab.

December 2014 Page 75 of 117
Concepts Search Statement

5 Combine 1 and 2 and 3 and 4

6 Limit 5 to "all adult (19 plus years)" and humans and English language and 

yr="2007 -Current"

7 Deduplicate Remove duplicates from 6

Key Question 5

Concepts Search Statement

1 Chronic kidney disease exp renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ 

(failure or disease)).ti,ab.

2 Mineral and bone disorders exp hyperparathyroidism, secondary/ or exp osteomalacia/ or exp bone 

diseases, metabolic/ or exp renal osteodystrophy/ or (hyperparathyroid$ 

or osteomalac$ or adynamic bone or (bone adj2 disease$) or mixed bone 

disease$ or renal osteodystroph$ or renal ricket$).ti,ab. 

3 Mineral and bone disorder ((mineral$ ADJ3 bone$ ADJ3 disorder$) or MBD OR CKD-MBD or MBDCKD or CKD-mineral bone disorder OR chronic kidney disease-mineral 

bone disorder).ti,ab. 

4 Combine (1 and 2) or 3

5 Stages 3 and 4 ((advanced adj stage) or (stage adj (three or III or "3" or four or IV or "4" 

or 3?4))).ti,ab.

6 Combine 4 and 5

7 Limit 6 to "all adult (19 plus years)"

8 Limit 7 to English and yr="2007 -Current"

9 Deduplicate remove duplicates from 8

Key Question 6

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Anemia *anemia/ or anemi$.ti,ab.

3 Erythropoiesis-stimulating 

agents (ESAs)

*erythropoietin/ or (erythropoie$ or ESA OR ESAs).ti,ab.

4 Combine 1 and 2 and 3 

December 2014 Page 76 of 117
Concepts Search Statement

5 Limit by study type 4 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

6 Limit by study type 4 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

7 Combine 5 or 6

8 Limit 7 to "all adult (19 plus years)" and English and human and yr="2007 -

Current"

9 Deduplicate Remove duplicates from 8

Key Question 7

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Hypertension *hypertension/ or hypertens$.ti,ab. or (blood ADJ pressure).ti,ab.

3 Antihypertensive agents *antihypertensive agents/ or *diuretics/ or *angiotensin-converting

enzyme inhibitors/ or *angiotensin receptor antagonists/ or (antihypertensive$ or antihypertensive$ or anti hypertensive$ or diuretic$ or 

ACE inhibitor$ or ACE-I or ACEI or ACE-inhibitor$ or ARB or ARBs).ti. or 

(angiotensin adj2 inhibitor$).ti. or ((angiotensin or angiotensin-receptor) 

adj2 (block$ or antagonist$)).ti.

4 Combine 1 and 2 and 3 

5 Limit by study type 4 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

December 2014 Page 77 of 117
Concepts Search Statement

6 Limit by study type 4 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

7 Combine 5 or 6 

8 Limit 7 to English and human and yr="2007 -Current" and "all adult (19 plus 

years)"

9 Deduplicate remove duplicates from 8

Key Question 8

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Diabetes diabetes mellitus/ or diabet$.ti,ab.

3 Glucose blood glucose/ or (glucose or glycemi$ or sugar$).ti,ab.

4 Control (control$ or regulat$ or monitor$ or self-monitor$).ti,ab.

5 Blood glucose self-monitoring blood glucose self-monitoring/ 

6 Combine (3 and 4) or 5

7 Combine 1 and 2 and 6

8 Limit by study type 7 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

9 Limit by study type 7 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

10 Combine 8 or 9

11 Limit Limit 10 to English language and humans and "all adult (19 plus years)" 

and yr="2007 -Current"

12 Deduplicate Remove duplicates from 11

December 2014 Page 78 of 117
Key Question 9

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Stage 3 (stage adj (three or III or "3")).ti,ab.

3 Nephrology specialist nephrology/ OR nephrolog$.ti,ab. or specialization/ or special$.ti,ab. or 

consult$.ti,ab. or refer$.ti,ab.

4 Combine 1 and 2 and 3 

5 Limit by study type 4 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

6 Limit by study type 4 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

7 Combine 5 or 6

8 Limit 7 to English and humans and"all adult (19 plus years)" and yr="2007 -

Current"

9 Deduplicate remove duplicates from 8

Key Question 10

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Self-care *self care/ or *risk reduction behavior/ or *health behavior/ or selfcare.ti,ab. or self-management.ti,ab. or (behave$ and (risk$ or 

health$)).ti,ab. or (self ADJ (care$ or caring or manag$)).ti,ab.

3 Combine 1 and 2

December 2014 Page 79 of 117
Concepts Search Statement

4 Limit by study type 3 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

5 Limit by study type 3 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

6 Combine 4 or 5

7 Limit 6 to "all adult (19 plus years)" and English language and humans and 

yr="2007 -Current"

8 Deduplicate remove duplicates from 7

Key Question 11

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Safety/risk reduction patient safety/ or biomarkers, pharmacological/ or risk reduction 

behavior/ or (safe$ or risk$).ti,ab.

3 Nephrotoxins kidney/de or kidney/me or nephrotox$.ti,ab.

4 Renally cleared medication (clear$ adj2 (renal or kidney)).ti,ab.

5 Combine 3 or 4

6 Combine 1 and 2 and 5

7 Limit by study type 6 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

December 2014 Page 80 of 117
Concepts Search Statement

8 Limit by study type 6 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

9 Combine 7 or 8

10 Limit 9 to "all adult (19 plus years)" and English language and humans and 

yr="2007 -Current"

11 Deduplicate remove duplicates from 10

Key Question 12

Concepts Search Statement

1 Chronic kidney disease *renal insufficiency, chronic/ or CKD.ti,ab. or ((kidney OR renal) ADJ

(failure or disease)).ti,ab.

2 Integrated health care delivery of health care, integrated/ or (integrated adj (health or care or 

medicine$ or deliver$ or system$ or treatment$ or therap$ or 

model$)).ti,ab.

3 Integrative medicine integrative medicine/ or complementary therapies/ or ((integrative or 

complementary or alternative) adj (health or care or medicine$ or 

medicat$ or drug$ or deliver$ or system$ or treatment$ or therap$ or 

model$)).ti,ab. 

4 Combine 2 or 3

5 Combine 1 and 4 

6 Limit by study type 5 and (randomized controlled trial/ or random allocation/ or double-blind 

method/ or single-blind method/ or placebos/ or cross-over studies/ or 

crossover procedure/ or cross over studies/ or double blind procedure/ or 

single blind procedure/ or placebo/ or latin square design/ or crossover 

design/ or double-blind studies/ or single-blind studies/ or triple-blind 

studies/ or random assignment/ or exp controlled study/ or exp clinical 

trial/ or exp comparative study/ or cohort analysis or follow-up studies/ 

or intermethod comparison/ or parallel design/ or control group/ or 

prospective study/ or retrospective study/ or case control study/ or major 

clinical study/ or evaluation studies/ or follow-up studies/ or 

random$.hw. or random$.ti. or placebo$.mp.)

7 Limit by study type 5 and (research synthesis or pooled or systematic review/ or meta 

analysis/ or meta-analysis/ or ((evidence base$ or methodol$ or 

systematic or quantitative$ or studies or search$).mp. and (review/ or 

review.pt.)))

8 Combine 6 or 7

9 Limit 8 to "all adult (19 plus years)" and English and yr="2007 -Current"

10 Deduplicate remove duplicates from 9

PubMed

The strategies below are presented in MeSH syntax; the searches were conducted in PubMed.

December 2014 Page 81 of 117
* = truncation character (wildcard)

[tiab] = limit to title or abstract

Key Question 1

Concepts Search Statement

1 Acute kidney injury AKI OR (acute AND (renal OR kidney*) AND (injur* OR insufficienc*))

2 Prevention caus* OR etiolog* OR prevent* OR protect*

3 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

4 Combine 1 AND 2 AND 3

5 Combine 4 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

6 Limit 5 to yr="2007 -Current"

Key Question 2

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Acute kidney injury acute kidney injur*

3 Nephrotoxicity Nephrotox*

4 Combine 1 OR 2 OR 3

5 Service Members Veteran* OR military OR army OR navy OR naval OR marine* OR soldier* 

OR armed force* OR air force OR coast guard

6 Occupational exposures OSHA OR environment* OR work* OR vocation* OR occupation*

7 Combine 4 AND 5 AND 6

8 Limit 7 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

9 Limit 8 to yr="2007 -Current"

Key Question 3

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure or disease))

2 Combined renin-angiotensin 

blockade (ACEIs and ARBs)

((renin-angiotensin blockade* OR RAS blockade* OR renin-angiotensin 

inhibitor* OR RAS inhibitor*)) OR (((ACE inhibitor* OR ACE-I OR ACEI OR 

ACE-inhibitor* OR (angiotensin AND inhibitor*))) AND (ARB OR ARBs OR 

((angiotensin OR angiotensin-receptor*) AND (block* OR antagonist*))))

3 Spironolactone spironolactone

4 Direct renin inhibitor DRI OR (direct AND renin AND inhibitor*)

5 Combine 2 OR 3 OR 4

6 Treatment outcome Outcome* OR progress* OR efficac* OR effective*

7 Combine 1 and 5 and 6

8 Limit by publication type 7 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

9 Limit 8 to yr="2007 -Current"

December 2014 Page 82 of 117
Key Question 4

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Dyslipidemia Dyslipid* OR dyslipoproteinemia*

3 Pharmacologic therapy Drug* OR medicat* OR pharma*

4 Lifestyle changes Lifestyle* OR life style* OR life-style* OR diet* OR exercis* OR 

nutrit* OR weigh* OR health* OR cessation* OR smok*

5 Combine 1 AND 2 AND 3 AND 4

6 Limit 5 AND ("inprocess"[sb] OR publisher[sb] OR 

pubmednotmedline[sb])

7 Limit 6 to yr="2007 -Current"

Key Question 5

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Mineral and bone disorders Hyperparathyroid* OR osteomalac* OR adynamic bone OR (bone AND 

disease*) OR osteodystroph* OR renal ricket* 

3 Mineral and bone disorder MBD OR CKD-MBD OR MBD-CKD OR CKD-mineral bone disorder* OR 

chronic kidney disease-mineral bone disorder* 

4 Combine (1 AND 2) OR 3

5 Stages 3 and 4 (advanced AND stage) OR (stage AND (three OR III OR "3" OR four OR IV 

OR "4" OR 3?4))

6 Combine 4 AND 5

7 Limit 6 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

8 Limit 7 to yr="2007 -Current"

Key Question 6

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Anemia Anemi*

3 Erythropoiesis-stimulating 

agents (ESAs)

Erythropoie* OR ESA OR ESAs

4 Combine 1 AND 2 AND 3 

5 Limit 4 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

6 Limit 5 to yr="2007 -Current"

Key Question 7

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Hypertension Hypertens* OR (blood AND pressure)

December 2014 Page 83 of 117
Concepts Search Statement

3 Antihypertensive agents anti-hypertensive* OR antihypertensive* OR anti hypertensive* OR 

diuretic* OR ACE inhibitor* OR ACE-I OR ACEI OR ACE-inhibitor* OR ARB 

OR ARBs OR (angiotensin AND inhibitor*) OR ((angiotensin OR 

angiotensin-receptor) AND (block* OR antagonist*))

4 Combine 1 AND 2 AND 3 

5 Limit 4 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

6 Limit 5 to yr="2007 -Current" 

Key Question 8

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure or disease))

2 Diabetes diabet*

3 Glucose glucose OR glycemic* OR sugar*

4 Control control* OR regulat* OR monitor* OR self-monitor*

5 Combine 1 AND 2 AND 3 AND 4

6 Limit 5 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

7 Limit 6 to yr="2007 -Current"

Key Question 9

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure or disease))

2 Stage 3 stage AND (three OR III OR "3")

3 Nephrology specialist Nephrolog* OR special* OR consult* OR refer*

4 Combine 1 AND 2 AND 3 

5 Limit 4 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

6 Limit 5 to yr="2007 -Current"

Key Question 10

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Self-care self-care* OR self-management OR (behave* AND (risk* OR health*)) OR 

(self AND (care* OR caring OR manag*))

3 Combine 1 AND 2

4 Limit 3 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

5 Limit 4 to yr="2007 -Current"

Key Question 11

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

December 2014 Page 84 of 117
Concepts Search Statement

2 Safety/risk reduction safe* OR risk*

3 Nephrotoxins nephrotox*

4 Renally cleared medication clear* AND (renal OR kidney*)

5 Combine 3 OR 4

6 Combine 1 AND 2 AND 5

7 Limit 6 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

8 Limit 7 to yr="2007 -Current"

Key Question 12

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Integrated health care integrated AND (health OR care OR medicine* OR deliver* OR system* OR 

treatment* OR therap* OR model*)

3 Integrative medicine (integrative OR complementary OR alternative) AND (health OR care OR 

medicine* OR medicat* OR drug* OR deliver* OR system* OR treatment* 

OR therap* OR model*)

4 Combine 2 OR 3

5 Combine 1 AND 4

6 Combine 5 AND ("inprocess"[sb] OR publisher[sb] OR pubmednotmedline[sb])

7 Limit 6 to yr="2007 -Current"

Cochrane

The strategies below were conducted in Cochrane.

* = truncation character (wildcard)

Key Question 1

Concepts Search Statement

1 Acute kidney injury AKI OR (acute AND (renal OR kidney*) AND (injur* OR insufficienc* OR 

fail*))

2 Prevention prevent* OR protect* OR caus* OR etiol*

3 Combine 1 AND 2

4 Limit by publication dates 3 from 2007 to 2013

Key Question 2

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Acute kidney injury acute kidney injury

3 Nephrotoxicity nephrotox*

December 2014 Page 85 of 117
Concepts Search Statement

4 Combine 1 OR 2 OR 3

5 Service Members Veteran* OR military OR army OR navy OR naval OR marine* OR soldier* 

OR armed force* OR air force OR coast guard*

6 Occupational exposures OSHA OR environment* OR work* OR vocation* OR occupation*

7 Combine 4 AND 5 AND 6

8 Limit by publication dates 7 from 2007 to 2013

Key Question 3

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure or 

disease))

2 Combined renin-angiotensin 

blockade

((angiotensin-converting enzyme inhibitor* OR ACE inhibitor* OR 

angiotensin inhibitor* OR ACEI OR ACE-I) AND (angiotensin receptor 

antagonist* OR angiotensin blocker* OR ARB OR ARBs)) OR reninangiotensin blockade* OR RAS blockade* OR renin-angiotensin inhibitor* 

OR RAS inhibitor*

3 Spironolactone spironolactone

4 Direct renin inhibitor DRI OR (direct AND renin AND inhibitor*)

5 Combine 2 OR 3 OR 4

6 Treatment outcome outcome* OR progress* OR efficac* OR effective*

7 Combine 1 AND 5 AND 6

8 Limit by publication dates 7 from 2007 to 2013

Key Question 4

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Dyslipidemia dyslipid* OR dyslipoproteinemia*

3 Pharmacologic therapy drug* OR medicat* OR pharma*

4 Lifestyle changes lifestyle* OR life style* OR life-style* OR diet* OR exercise* OR nutrit* OR 

weigh* OR health* OR cessation* OR smok*

5 Combine 1 AND 2 AND 3 AND 4

6 Limit by publication dates 5 from 2007 to 2013

Key Question 5

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Mineral and bone disorders hyperparathyroid* OR osteomalac* OR renal osteodystroph* OR 

adynamic bone* OR bone disease* OR renal ricket* 

December 2014 Page 86 of 117
Concepts Search Statement

3 Mineral and bone disorder MBD OR CKD-MBD OR MBD-CKD OR (mineral AND bone AND disorder*) 

4 Combine (1 AND 2) OR 3

5 Stages 3 and 4 advanced stage* OR (stage AND (three OR III OR 3 OR four OR IV OR 4 OR 

3-4 OR 3&4))

6 Combine 4 AND 5

7 Limit by publication dates 6 from 2007 to 2013

Key Question 6

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Anemia anemi*

3 Erythropoiesis-stimulating 

agents (ESAs)

erythropoie* OR ESA OR ESAs

4 Combine 1 AND 2 AND 3 

5 Limit by publication dates 4 from 2007 to 2013

Key Question 7

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Hypertension hypertens* OR (blood AND pressure)

3 Antihypertensive agents anti-hypertensive* OR antihypertensive* OR anti hypertensive* OR 

diuretic* OR ACE inhibitor* OR ACE-I or ACEI OR ACE-inhibitor* OR ARB 

OR ARBs OR ((angiotensin OR angiotensin-receptor) AND (block* OR 

antagonist*))

4 Combine 1 AND 2 AND 3 

5 Limit by publication dates 4 from 2007 to 2013

Key Question 8

Concepts Search Statement

1 Chronic kidney disease CKD OR ((kidney OR renal) AND (failure OR disease))

2 Diabetes diabet*

3 Glucose glucose OR glycemic* OR sugar*

4 Control control* OR regulat* OR monitor* OR self-monitor*

5 Combine 1 AND 2 AND 3 AND 4

6 Limit by publication dates 5 from 2007 to 2013

December 2014 Page 87 of 117
Key Question 9

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Stage 3 stage AND (three OR III OR 3)

3 Nephrology specialist nephrolog* OR special* OR consult* OR refer*

4 Combine 1 AND 2 AND 3 

5 Limit by publication dates 4 from 2007 to 2013

Key Question 10

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Self-care (behave* AND (risk* OR health*)) OR (self AND (care* OR caring OR 

manag*))

3 Combine 1 AND 2

4 Limit by publication dates 3 from 2007 to 2013

Key Question 11

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Safety/risk reduction safe* OR risk*

3 Nephrotoxins nephrotox*

4 Renally cleared medication (clear* AND (renal* OR kidney*))

5 Combine 3 OR 4

6 Combine 1 AND 2 AND 5

7 Limit by publication dates 6 from 2007 to 2013

Key Question 12

Concepts Search Statement

1 Chronic kidney disease CKD OR “chronic kidney disease” OR ((kidney OR renal) AND (failure OR 

disease))

2 Integrated health care integrated AND (health OR care OR medicine* OR deliver* OR system* 

OR treatment* OR therap* OR model*)

3 Integrative medicine (integrative OR complementary OR alternative) AND (health OR care OR 

medicine* OR medicat* OR drug* OR deliver* OR system* OR treatment* 

OR therap* OR model*)

4 Combine 2 OR 3

5 Combine AND 

6 Limit by publication dates 5 from 2007 to 2013

December 2014 Page 88 of 117
Convening the Face-to-Face Meeting

In consultation with the Contracting Officer Representative (COR), the Champions, and the Work Group, 

the Lewin Team convened a three and a half day face-to-face meeting of the CPG Champions and Work 

Group members on March 17-20, 2014. These experts were gathered to develop and draft the clinical 

recommendations for an update to the 2008 CKD CPG. Lewin presented findings from the evidence 

review of the key questions in order to facilitate and inform the process. 

Under the direction of the Champions, the Work Group members were charged with interpreting the 

results of the evidence review, and asked to retain, revise, or reject each recommendation from the 

2008 CKD CPG. The members also developed new clinical practice recommendations, not presented in 

the 2008 CKD CPG, based on the 2014 evidence review. The subject matter experts were divided into 

two smaller subgroups at this meeting. 

Following the drafting of clinical practice recommendations, the Work Group assigned a grade for each 

recommendation based on a modified GRADE and US Preventative Service Task Force (USPSTF) 

methodology. Each recommendation was graded by assessing the quality of the overall evidence base, 

the associated benefits and harms, the variation in values and preferences, and other implications of the 

recommendation. 

Grading Recommendations

This CPG uses the GRADE methodology to assess the quality of the evidence base and assign a grade for 

the strength for each recommendation. The GRADE system uses the following four domains to assess 

the strength of each recommendation: [169] 

• Balance of desirable and undesirable outcomes

• Confidence in the quality of the evidence

• Values and preferences

• Other implications, as appropriate, e.g.,:

o Resource Use

o Equity

o Acceptability

o Feasibility

o Subgroup considerations

The following sections further describe each domain. 

Balance of desirable and undesirable outcomes refers to the size of anticipated benefits (e.g., increased 

longevity, reduction in morbid event, resolution of symptoms, improved quality of life (QoL), decreased 

resource use) and harms (e.g., decreased longevity, immediate serious complications, adverse event, 

impaired quality of life, increased resource use, inconvenience/hassle) relative to each other. This 

domain is based on the understanding that the majority of clinicians will offer patients therapeutic or 

preventive measures as long as the advantages of the intervention exceed the risks and adverse effects. 

December 2014 Page 89 of 117
The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the 

strength of the recommendation.

Some of the discussion questions that fall under this domain include:

• Given the best estimate of typical values and preferences, are you confident that the benefits

outweigh the harms and burden or vice versa?

• Are the desirable anticipated effects large?

• Are the undesirable anticipated effects small?

• Are the desirable effects large relative to undesirable effects?

Confidence in the quality of the evidence reflects the quality of the evidence base and the certainty in 

that evidence. This second domain reflects the methodological quality of the studies for each outcome 

variable. In general, the strength of recommendation follows the level of evidence, but not always, as 

other domains may increase or decrease the strength. The evidence review used for the development of 

recommendations for CKD, conducted by ECRI, assessed the confidence in the quality of the evidence 

base and assigned a rate of “High”, “Moderate”, “Low” or “Very Low”. 

The elements that go into the confidence in the quality of the evidence include: 

• Is there high or moderate quality evidence that answers this question?

• What is the overall certainty of this evidence?

Values and preferences is an overarching term that includes patients’ perspectives, beliefs, 

expectations, and goals for health and life. More precisely, it refers to the processes that individuals use 

in considering the potential benefits, harms, costs, limitations, and inconvenience of the therapeutic or 

preventive measures in relation to one another. For some, the term “values” has the closest 

connotation to these processes. For others, the connotation of “preferences” best captures the notion 

of choice. In general, values and preferences increase the strength of the recommendation when there 

is high concordance and decrease it when there is great variability. In a situation in which the balance of 

benefits and risks are uncertain, eliciting the values and preferences of patients and empowering them 

and their surrogates to make decisions consistent with their goals of care becomes even more 

important. A recommendation can be described as having “similar values”, “some variation”, or “large 

variation” in typical values and preferences between patients and the larger populations of interest.

Some of the discussion questions that fall under the purview of values and preferences include:

• Are you confident about the typical values and preferences and are they similar across the

target population?

• What are the patient’s values and preferences?

• Are the assumed or identified relative values similar across the target population?

Other implications consider the practicality of the recommendation, including resources use, equity, 

acceptability, feasibility and subgroup considerations. Resource use is related to the uncertainty around 

the cost-effectiveness of a therapeutic or preventive measure. For example statin use in the frail elderly 

December 2014 Page 90 of 117
and others with multiple comorbidities may not be effective and depending on the societal benchmark 

for willingness to pay, may not be a good use of resources. Equity, acceptability, feasibility and subgroup 

considerations require similar judgments around the practically of the recommendation.

The framework below was used by the Work Group to guide discussions on each domain.

Table A-3. Evidence to Recommendation Framework

Decision Domain Judgment

Balance of desirable and undesirable outcomes

Given the best estimate of typical values and preferences, 

are you confident that the benefits outweigh the harms and 

burden or vice versa?

Are the desirable anticipated effects large?

Are the undesirable anticipated effects small?

Are the desirable effects large relative to undesirable 

effects?

Benefits outweigh harms/burden

Benefits slightly outweigh harms/burden

Benefits and harms/burden are balanced

Harms/burden slightly outweigh benefits

Harms/burden outweigh benefits

Confidence in the quality of the evidence

Is there high or moderate quality evidence that answers this 

question?

What is the overall certainty of this evidence?

High

Moderate

Low

Very low

Values and preferences

Are you confident about the typical values and preferences 

and are they similar across the target population?

What are the patient’s values and preferences? 

Are the assumed or identified relative values similar across 

the target population?

Similar values

Some variation

Large variation

Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations)

Are the resources worth the expected net benefit from the 

recommendation?

What are the costs per resource unit?

Is this intervention generally available?

Is this intervention and its effects worth withdrawing or not 

allocating resources from other interventions

Is there lots of variability in resource requirements across 

settings?

Various considerations

The strength of a recommendation is defined as the extent to which one can be confident that the 

desirable effects of an intervention outweigh its undesirable effects and is based on the framework 

above, which combines the four domains. [169] GRADE methodology does not allow for 

recommendations to be made based on expert opinion alone. While strong recommendations are 

usually based on high or moderate confidence in the estimates of effect (quality of the evidence) there 

may be instances where strong recommendations are warranted even when the quality of evidence is 

December 2014 Page 91 of 117
low. [170] In these types of instances where the balance of desirable and undesirable outcomes and 

values and preferences played large roles in determining the strength of a recommendation, this is 

explained in the discussion section for the recommendation.

The GRADE of a recommendation is based on the following elements:

• Four decision domains used to determine the strength and direction (described above)

• Relative strength (Strong or Weak)

• Direction (For or Against)

The relative strength of the recommendation is based on a binary scale, “Strong” or “Weak.” A strong 

recommendation indicates that the Work Group is highly confident that desirable outcomes outweigh 

undesirable outcomes. If the Work Group is less confident of the balance between desirable and 

undesirable outcomes, they present a weak recommendation.

Similarly, a recommendation for a therapy or preventive measure indicates that the desirable 

consequences outweigh the undesirable consequences. A recommendation against a therapy or 

preventive measure indicates that the undesirable consequences outweigh the desirable consequences.

Using these elements, the grade of each recommendation is presented as part of a continuum:

• Strong For (or “We recommend offering this option ...”)

• Weak For (or “We suggest offering this option ...”)

• Weak Against (or “We suggest not offering this option ...”)

• Strong Against (or “We recommend against offering this option ...”)

Note that weak (For or Against) recommendations may also be termed “Conditional,” “Discretionary,” or 

“Qualified”. Recommendations may be conditional based upon patient values and preferences, the 

resources available, or the setting in which the intervention will be implemented. Recommendations 

may be at the discretion of the patient and clinician or they may be qualified with an explanation about 

the issues that would lead decisions to vary.

Drafting and Submitting the Final CPG

Following the face-to-face meeting, the Champions and Work Group members were given writing 

assignments for the update of specific sections of the 2008 CKD CPG that would form the narrative text 

for the 2014 CKD CPG. During this time, the Champions also revised the 2008 algorithms and identified 

the content for the guideline summary and pocket card, as part of the provider toolkits that will be 

developed by the Evidence-Based Practice Working Group (EBPWG) following the publication of the 

2014 CPG. The algorithms will be included as part of this CPG so as to provide a clear description of the 

flow of patient care. The final 2014 CKD CPG was submitted to the EBPWG in December 2014.

December 2014 Page 92 of 117
Appendix B: Pharmacotherapy with ACEIs or ARBs

Table B-1. Dosing Recommendations for ACEIs and ARBs in Patients with CKDa,b 

DRUG USUAL DOSE RANGE COMMENTS/CAUTIONS

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Benazepril 10 – 40 mg divided once or 

twice daily

o Start with lower or less frequent doses in patients with

CKD (except fosinopril as partial compensation by

hepatobiliary elimination) or in patients currently

being treated with a diuretic.

o Use with caution in patients with renal artery stenosis.

o Monitor potassium and kidney function (e.g., one-totwo weeks after initiation or dose adjustment)

o Concomitant therapy with potassium-sparing diuretics,

potassium supplements, and/or additional RAAS

blockers may result in hyperkalemia.

o Boxed Warning: due to the potential risk for fetal

morbidity and mortality in patients taking an ACEI

during pregnancy, it is recommended that therapy be

discontinued as soon as a woman becomes pregnant;

alternate therapy should be considered.

o Contraindicated in patients with a history of

angioedema on an ACEI.

Captoprilc 25 – 150 mg divided two to 

three times daily

Enalapril 5 – 40 mg divided once or 

twice daily

Fosinopril 10 – 40 mg once daily

Lisinopril 10 – 40 mg once daily 

Moexiprilc 7.5 – 30 mg divided once or 

twice daily

Perindopril 4 – 8 mg divided once or twice 

daily

Quinapril 10 – 40 mg divided once or 

twice daily

Ramipril 2.5 – 20 mg divided once or 

twice daily

Trandolapril 1 – 4 mg once daily

Angiotensin II Receptor Blockers (ARBs)

Azilsartan 80 mg once daily o Consider lower doses in patients with intravascular

volume depletion (e.g., patients currently being

treated with a diuretic).

o Use with caution in patients with renal artery stenosis.

o Monitor potassium and renal function after initiation.

o Concomitant therapy with potassium-sparing diuretics,

potassium supplements, and/or additional RAAS

blockers may result in hyperkalemia.

o Boxed Warning: due to the potential risk for fetal

morbidity and mortality in patients taking an ARB

during pregnancy, it is recommended that therapy be

discontinued as soon as a woman becomes pregnant;

alternate therapy should be considered.

o Use with caution in patients with a history of

angioedema on an ACEI.

o An ARB may be considered in patients unable to

tolerate an ACEI due to cough.

Candesartan 8 – 32 mg once daily

Eprosartan 400 – 800 mg divided once or 

twice daily

Irbesartan 150 – 300 mg once daily

Losartan 25 – 100 mg divided once or 

twice daily

Olmesartan 20 – 40 mg once daily

Telimisartan 20 – 80 mg once daily

Valsartan 80 – 320 mg once daily

Refer to www.pbm.va.gov or https://vaww.cmopnational.va.gov/cmop/PBM/default.aspx for a current list of medications on the VA 

National Formulary 

a Adapted from VA/DoD Clinical practice guideline for management of chronic kidney disease in primary care. Washington DC: 

Department of Veteran Affairs and Department of Defense; Version 2.0 - 2007. b Facts & Comparisons® eAnswers http://efactsonline.com/ Accessed 2014 Apr 25. c One hour before meals, on an empty stomach.

December 2014 Page 93 of 117
Appendix C: Evidence Table

2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

Evaluation for Chronic Kidney Disease

1. While there is insufficient evidence to associate exposure to depleted uranium

and solvents such as hydrocarbons with CKD, we suggest that clinicians take a

detailed occupational and non-occupational history.

- Very Low Weak For

2. We suggest that periodic evaluation for CKD be considered in patients with the

following:

a. Diabetes, hypertension, other end organ disease (e.g., chronic heart failure

[CHF]), or a personal or family history of kidney disease

b. Systemic illness (e.g., human immunodeficiency virus [HIV], systemic lupus

erythematosus, multiple myeloma)

c. History of acute kidney injury (AKI) (e.g., acute tubular necrosis, urinary

tract obstruction, interstitial nephritis)

d. Elderly patients

e. Races and ethnicities associated with increased risk (e.g., African Americans,

C Weak For

12 The 2008 VA/DoD CKD CPG used the U.S. Preventive Services Task Force (USPSTF) evidence grading system. http://www.uspreventiveservicestaskforce.org. 13 The evidence column indicates studies that support each recommendation. For new recommendations, developed by the 2014 guideline Work Group, the 

literature cited corresponds directly to the 2013 evidence review. For recommendations that have been carried over from the 2008 VA/DoD CKD CPG, slight 

modifications were made to the language in order to better reflect the current evidence and/or the change in grading system used for assigning the strength of 

each recommendation (USPSTF to GRADE). For these “modified” recommendations, the evidence column indicates “additional evidence,” which can refer to 

either 1) studies that support the recommendation and which were identified through the 2014 evidence review, or 2) relevant studies that support the 

recommendation, but which were not systematically identified through a literature review. 14 The strength of evidence is only one of four domains in the GRADE system that factor into the strength of recommendation. See the Grading 

Recommendations section for more information. 15 Refer to the Grading Recommendations section for more information on how the strength of the recommendation was determined using GRADE 

methodology. 

December 2014 Page 94 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

Hispanics, Native Americans)

Acute Kidney Injury Avoidance

3. We suggest that patients at increased risk for CIN receive volume expansion with

intravenous (IV) isotonic crystalloid solutions (saline or sodium bicarbonate) prior

to and following iodinated contrast administration.

- [16]

[17] 

[18] 

[19] 

[20] 

[21] 

[22] 

[23] 

[24]

Very Low Weak For

4. We suggest offering oral hydration to patients in which IV hydration is not

feasible for CIN prophylaxis.

- [26] Low Weak For

5. Given inconsistent evidence, we do not recommend for or against the routine

administration of N-acetylcysteine (NAC) for CIN prophylaxis.

- [31] Low Weak For

6. We recommend against the use of renal replacement therapy (RRT) for CIN

prophylaxis.

- [49] Very Low Strong Against

7. We suggest not initiating statin therapy for the purpose of CIN prophylaxis in

patients undergoing elective angiography.

- [15]

[50] 

[51]

Moderate Weak Against

8. We suggest not offering theophylline therapy for CIN prophylaxis for patients

undergoing elective coronary angiography.

- [52]

[53]

Low Weak Against

Management of Chronic Kidney Disease

Self-Management Strategies

9. We suggest the use of dietary sodium restriction as a self-management strategy

to reduce proteinuria and improve blood pressure control in patients with CKD.

- [55]

[171] 

[57]

Low Weak For

10. In patients with stage 3 and 4 CKD, we suggest a protein diet of 0.6 to 0.8

g/kg/day as it may slow the decline in glomerular filtration rate (GFR) and

B

Additional 

Evidence:

Low

Weak For

December 2014 Page 95 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

progression to end-stage renal disease (ESRD). [58]

[59] 

[60]

11. There is insufficient evidence to recommend for or against weight loss in obese

patients as an intervention to reduce proteinuria or to slow progression of CKD.

However, we suggest weight loss interventions in obese patients as part of an

overall health improvement strategy.

- [63] Very Low Weak For

12. There is insufficient evidence to recommend for or against exercise with or

without lifestyle intervention to reduce ESRD, mortality, change in GFR, or

change in urinary protein. However, we suggest regular exercise as part of an

overall health improvement strategy.

- [64]

[65] 

[66] 

Very Low Weak For

13. There is insufficient evidence to recommend for or against health education to

reduce time to dialysis initiation or to reduce mortality. However, we suggest

CKD health education because it supports the aim of maximizing patientcentered care.

- [64]

[67] 

[68] 

Very Low Weak For

14. There is insufficient evidence to recommend smoking cessation to halt

progression of CKD, however, we suggest tobacco cessation for cardiovascular

risk reduction in patients with CKD.

- Very Low Weak For

Clinical Management Strategies

15. We suggest offering multidisciplinary care, if available, for patients with CKD to

reduce non-fatal stroke, slow progression from micro- to macroalbuminuria, and

reduce all-cause mortality.

- [72]

[73] 

[64] 

[74] 

[75]

Low Weak For

16. Although there is insufficient evidence to recommend for or against referral to a

nephrology specialist for patients with stage 3 CKD for slowing CKD progression,

we suggest consultation with a nephrologist to assist in the diagnosis and

treatment of patients with any of the following conditions:

a. eGFR <30 mL/min/1.73 m2 to facilitate education and planning for renal

- [76]

[77] 

[78] 

[79] 

Low Weak For

December 2014 Page 96 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

replacement therapy (dialysis or kidney transplant) 

b. Kidney function that is rapidly worsening without obvious cause

c. Metabolic complications of CKD (e.g., anemia, secondary

hyperparathyroidism)

d. CKD of unclear etiology after initial work-up, or has a known or suspected

kidney condition requiring specialized care

e. Nephrotic range proteinuria

f. Nephrolithiasis

17. We recommend that treatment with the following vaccinations be considered for

patients with CKD as a measure to prevent infections:

a. Influenza vaccine*

b. Tdap vaccine

c. Pneumococcal polysaccharide vaccine (i.e., PCV 13 and PPSV23)

d. Hepatitis B vaccine

e. Zoster /shingles vaccine*

f. Varicella vaccine*

g. MMR vaccine*

(*Note: Live vaccines, including nasal influenza (LAIV), may be contraindicated in 

those patients with CKD and severe immunodeficiency including treatment with 

immunosuppressive agents)

A-C

Additional 

Evidence:

[80] 

[82] 

[83] 

[84] 

[85]

Strong For

18. We recommend that clinicians avoid or limit the use of nephrotoxic medications

for patients with CKD.

D

Additional 

Evidence:

[86] 

[87] 

[88]

Strong For

19. In patients with CKD, we suggest that medications should be reviewed and their

dosing modified, where appropriate, according to the level of the patient’s

kidney function.

C

Additional 

Evidence:

[90] 

[89]

Weak For

December 2014 Page 97 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

[91]

20. We suggest the use of bicarbonate supplementation in CKD patients with

metabolic acidosis to slow the progression of CKD.

- [93]

[94] 

Very Low Weak For

21. In adult patients with stages 1-4 CKD, we recommend that blood pressure targets

should be less than 140/90 mmHg.

C

Additional 

Evidence:

[95]

Low

Strong For

22. In patients with non-diabetic CKD, hypertension, and albuminuria, we

recommend the use of an angiotensin-converting-enzyme inhibitor (ACEI) to

prevent progression of CKD. Angiotensin II receptor blockers (ARBs) may be

substituted for patients with an ACEI-induced cough.

A

Additional 

Evidence:

[96] 

Moderate

Strong For

23. In patients with diabetes, hypertension, and albuminuria, we recommend the

use of an ACEI or ARB to slow the progression of CKD, unless there is

documentation of intolerance.

A

Additional 

Evidence:

[96]

Moderate

Strong For

24. We recommend against the use of combination renin-angiotensin-aldosterone

system (RAAS) blockade (ACEI and ARB, or an ACEI or ARB with a direct renin

inhibitor) in patients with CKD.

- [108]

[107] 

[110] 

[111] 

[109] 

[112] 

[113] 

[114] 

[115] 

[116] 

[117]

Moderate Strong Against

25. We recommend that all patients with CKD who are not on dialysis and have no

known history of coronary artery disease be assessed for 10-year CVD risk using a

validated risk calculator for primary prevention. If at risk (as defined in the

- [121]

[122] 

[123] 

[124]

Low Strong For

December 2014 Page 98 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

VA/DoD Management of Dyslipidemia guideline), we recommend use of at least 

a low dose statin. 

[125]

[126] 

[127]

26. We suggest against the use of statins prescribed with the intent of slowing eGFR

decline or preserving kidney function.

- [123]

[124] 

[125] 

[126]

Low Weak Against

27. We recommend against intensive glycemic control to patients with stage 3 or

worse CKD due to the lack of benefit on renal or cardiovascular outcomes and

potential for significant harm.

N/A

Additional 

Evidence:

[131] 

[132]

Strong Against

28. We suggest initiation of oral iron therapy (in preference to parenteral) to support

iron requirements in patients with CKD stages 3 and 4.

- [134] Moderate Weak For

29. We recommend against offering erythropoietin-stimulating agents (ESAs) to

patients with CKD for the purpose of achieving a hemoglobin target above 11.5

g/dL due to increased risk of stroke and hypertension.

- [135]

[136] 

[137] 

[138] 

[139] 

[141] 

[140] 

[142] 

[143] 

[144] 

[145] 

[146]

Moderate Strong Against

30. We recommend against initiating ESAs at a hemoglobin level greater than 10

g/dL.

- [135]

[136] 

[137] 

[138] 

[139]

Moderate Strong Against

December 2014 Page 99 of 117
2008 2014

Recommendation Grade12 Evidence13 Strength of 

Evidence14

Strength of 

Recommendation15

[141]

[140] 

[142] 

[143] 

[144] 

[145] 

[146]

31. We suggest offering supplemental vitamin D to correct vitamin D deficiency in

patients with CKD stages 3 or 4.

- [150]

[151] 

[152]

Low Weak For

32. We suggest not offering active vitamin D analogs or calcitriol to patients with

stage 3 and 4 CKD with elevated parathyroid hormone (PTH) levels due to lack of

evidence for kidney, bone, or cardiovascular benefit and increased potential of

harm from hypercalcemia. (Any use of active vitamin D analogs should be

managed by a nephrologist.)

- [153]

[154] 

[155] 

[156] 

[157] 

[158]

Moderate Weak Against

33. We suggest not offering phosphate binders to patients with stage 3 and 4 CKD

with normal serum phosphorous.

N/A

Additional 

Evidence:

[159] 

[160] 

[161] 

[162] 

[163] 

[164] 

[165]

Low

Weak Against

34. We suggest not offering calcimimetics to patients with stage 3 and 4 CKD due to

lack of evidence for kidney or cardiovascular benefit and increased risk of harm

from hypocalcemia.

- [166] Low Weak Against

December 2014 Page 100 of 117
Appendix D: Participant List

LT Col. Eric Barnes, DO, FASN (Co-Chair)

Nephrology Consultant to the Air Force Surgeon 

General

Chief, Section of Nephrology

Wright-Patterson Medical Center

Dayton, OH

C. Barrett Bowling, MD, MSPH

Geriatrician

Atlanta VA Medical Center

Atlanta, GA

Sarah Campoy, DNP

Renal Nurse Practitioner

VA Eastern Colorado Health Care System

Denver, CO

Nicole Cheran, RD

Registered Dietician

Pittsburgh VA Medical Center

Pittsburgh, PA

Lt Col. Heidi L Clark MS, RD

Faculty, Graduate Program in Nutrition

Registered Dietitian 

Army Medical Department Center and School

San Antonio, TX

Susan T. Crowley, MD, FASN (Co-Chair)

Chief, Renal Section, 

VA Connecticut Healthcare Systems

VHA National Program Director for Kidney Disease 

and Dialysis

West Haven, CT

Ernest Degenhardt, COL USA (Ret.),MSN, RN, 

ANP,FNP

Chief, Office of Evidence Based Practice

Clinical Performance Directorate

US Army Medical Command

Ft. Sam Houston, TX

Corinne K.B. Devlin MSN, RN, FNP-BC

Family Nurse Practitioner

Chronic Disease Clinical Practice Guideline 

Coordinator US Army Medical Command Quality 

Management Division, Office of Evidence Based 

Practice

Elaine Furmaga, PharmD

National PBM Clinical Pharmacy Program 

Manager-Formulary Management

VHA Pharmacy Benefits Management Services

Hines, Illinois

Adriana Hung, MD

Nephrologist

Tennessee Valley Health Care System

Nashville, TN

Areef Ishani, MD, MS

Chief, Section of Nephrology

Minneapolis VA Medical Center

Minneapolis, MN

Michelle Kasefang, RN

Boise VA Medical Center

Boise, IA

MAJ Khayanga Namasaka, MD

Primary Care Physician

Andrews Air Force Base Hospital

Joint Base Andrews, MD 

Annie T. Nguyen, PharmD

Clinical Pharmacy Specialist

Nephrology/Organ Transplant Clinic

Walter Reed National Military Medical Center 

Bethesda, MD

D. Nick Patterson, PharmD, BCPS

Clinical Pharmacist

Blanchfield Army Community Hospital

Fort Campbell, KY

M. Eric Rodgers, PhD, FNP, BC

Acting Director

VA/DoD Evidence-Based CPG Program

Office of Quality, Safety and Value

Department of Veterans Affairs

Washington, DC

Robert Selvester, MD

Family Practice

Naval Air Station Corpus Christi

Corpus Christi, TX

Gaurang Shah, MD, FACP, FASN

Chief, Nephrology Section

Long Beach VA Healthcare System

Long Beach, CA

December 2014 Page 101 of 117
Douglas Slotkoff, MD

Primary Care Physician

Orlando VA Medical Center

Orlando, FL

Suzanne Watnick, MD (Co-Chair)

Medical Director, PVAMC Dialysis

Training Program Director, Nephrology

Portland VA Medical Center

Portland, OR

Janette Williams-Smith, LCSW

Social Worker

Little Rock VA Medical Center

Little Rock, AR

December 2014 Page 102 of 117
Appendix E: Acronyms List

Abbreviation Definition

ACC American College of Cardiology

ACEI angiotensin-converting enzyme inhibitor

AER albumin excretion rate

AHA American Heart Association

AHRQ Agency for Healthcare Research and Quality

AKI acute kidney injury

APIR actual protein intake ratio

ARA aldosterone receptor antagonist 

ARB angiotensin II receptor blockers

BP blood pressure

CBC complete blood count

CBOC community-based outreach clinics

CCB calcium channel blocker 

CCT controlled clinical trial

CDC Centers for Disease Control and Prevention

CHF chronic heart failure

CI confidence interval

CIN contrast-induced nephropathy

CKD chronic kidney disease

COPD chronic obstructive pulmonary disease

COR Contracting Officer Representative

CPG clinical practice guideline

CrCL creatinine clearance

CRP C-reactive protein

CRRT continuous renal replacement therapy

CV cardiovascular

CVD cardiovascular disease

DM diabetes mellitus

DoD Department of Defense

DRI direct renin inhibitor

EBPWG Evidence-Based Practice Working Group

eGFR estimated glomerular filtration rate

EPO erythropoietin

ESA erythropoietin-stimulating agents

ESRD end-stage renal disease

FDA Food and Drug Administration

FGF23 fibroblast growth factor 23

FMH furosemide with matched hydration

GFR glomerular filtration rate

GI gastrointestinal

HDL-C high density lipoprotein cholesterol

HIV human immunodeficiency virus

HPV human papillomavirus

December 2014 Page 103 of 117
Abbreviation Definition

HR hazard ratio

HTN hypertension

IV intravenous

LPD low protein diets

MBD mineral and bone disorder

MDC multidisciplinary care

MDRD modification of diet in renal disease

MI myocardial infarction

MRI magnetic resonance imaging

NAC N-acetylcysteine

NSAID non-steroidal anti-inflammatory drug

PCP primary care provider

PTH parathyroid hormone

RAAS renin-angiotensin-aldosterone system

RCT randomized controlled trial

RIPC remote ischemic pre-conditioning

RPD regular protein diets

RR relative risk

RRT renal replacement therapy

SCr serum creatinine

TC total cholesterol

UAER urinary albumin excretion rate

USPSTF US Preventative Service Task Force

VA Department of Veteran Affairs

VHA Veterans Health Administration

WMD weighted mean difference

December 2014 Page 104 of 117
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