KISU_v7_i1_COVER.indd

OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF NEPHROLOGY

VOLUME 7 | ISSUE 1 | JULY 2017

www.kisupplements.org

KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis,

Evaluation, Prevention, and Treatment of Chronic Kidney

Disease–Mineral and Bone Disorder (CKD-MBD)

KISU_v7_i1_COVER.indd 1KISU_v7_i1_COVER.indd 1 31-05-2017 13:23:0531-05-2017 13:23:05

KDIGO 2017 CLINICAL PRACTICE GUIDELINE UPDATE

FOR THE DIAGNOSIS, EVALUATION, PREVENTION, AND

TREATMENT OF CHRONIC KIDNEY DISEASE–MINERAL AND

BONE DISORDER (CKD-MBD)

Kidney International Supplements (2017) 7, 1–59 1

KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis,

Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral

and Bone Disorder (CKD-MBD)

3 Tables and supplementary material

6 KDIGO Executive Committee

7 Reference keys

8 CKD nomenclature

9 Conversion factors

10 Abbreviations and acronyms

11 Notice

12 Foreword

13 Work Group membership

14 Abstract

15 Summary of KDIGO CKD-MBD recommendations

19 Summary and comparison of 2017 updated and 2009 KDIGO CKD-MBD

recommendations

22 Chapter 3.2: Diagnosis of CKD-MBD: bone

25 Chapter 4.1: Treatment of CKD-MBD targeted at lowering high serum

phosphate and maintaining serum calcium

33 Chapter 4.2: Treatment of abnormal PTH levels in CKD-MBD

38 Chapter 4.3: Treatment of bone with bisphosphonates, other osteoporosis

medications, and growth hormone

39 Chapter 5: Evaluation and treatment of kidney transplant bone disease

41 Methodological approach to the 2017 KDIGO CKD-MBD guideline update

49 Biographic and disclosure information

55 Acknowledgments

56 References

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VOL 7 | ISSUE 1 | JULY 2017

2 Kidney International Supplements (2017) 7, 1–59

TABLES

24 Table 1. Utility of KDOQI and KDIGO PTH thresholds for diagnostic decision making

42 Table 2. Research questions

45 Table 3. Question-speciﬁc eligibility criteria

46 Table 4. GRADE system for grading quality of evidence for an outcome

47 Table 5. Final grade for overall quality of evidence

47 Table 6. Balance of beneﬁts and harms

47 Table 7. Implications of the strength of a recommendation

47 Table 8. Determinants of strength of recommendation

SUPPLEMENTARY MATERIAL

Appendix A. PubMed search strategy

Appendix B. Summary of search and review process

Table S1. Summary table of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5: study characteristics

Table S2. Summary table of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5: study population characteristics

Table S3. Summary table of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5: results

Table S4. Summary table of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5: quality

Table S5. Evidence matrix of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5

Table S6. Evidence proﬁle of randomized controlled trials examining the treatment of CKD-MBD with

bisphosphonates in CKD G3a–G5

Table S7. Summary table of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5: study characteristics

Table S8. Summary table of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5: study population characteristics

Table S9. Summary table of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5: results

Table S10. Summary table of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5: quality

Table S11. Evidence matrix of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5

Table S12. Evidence proﬁle of studies evaluating the ability of bone mineral density results to predict fracture or

renal osteodystrophy among patients with CKD G3a–G5

Table S13. Summary table of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D: study characteristics

Table S14. Summary table of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D: study population characteristics

Table S15. Summary table of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D: results

Table S16. Summary table of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D: quality

Table S17. Evidence matrix of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D

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Kidney International Supplements (2017) 7, 1–59 3

Table S18. Evidence proﬁle of randomized controlled trials examining the treatment of CKD-MBD with varying

dialysate calcium concentration levels in CKD G5D

Table S19. Summary table of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders: study characteristics

Table S20. Summary table of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders: study population characteristics

Table S21. Summary table of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders: results

Table S22. Summary table of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders: quality

Table S23. Evidence matrix of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders

Table S24. Evidence proﬁle of randomized controlled trials examining the treatment of CKD-MBD with calcium-

containing phosphate binders versus calcium-free phosphate binders

Table S25. Summary table of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate: study characteristics

Table S26. Summary table of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate: study population characteristics

Table S27. Summary table of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate: results

Table S28. Summary table of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate: quality

Table S29. Evidence matrix of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate

Table S30. Evidence proﬁle of randomized controlled trials examining the treatment of CKD-MBD with dietary

phosphate

Table S31. Summary table of randomized controlled trials examining the treatment of PTH in CKD-MBD: study

characteristics

Table S32. Summary table of randomized controlled trials examining the treatment of PTH in CKD-MBD: study

population characteristics

Table S33. Summary table of randomized controlled trials examining the treatment of PTH in CKD-MBD: results

Table S34. Summary table of randomized controlled trials examining the treatment of PTH in CKD-MBD: quality

Table S35. Evidence matrix of randomized controlled trials examining the treatment of PTH in CKD-MBD

Table S36. Evidence proﬁle of randomized controlled trials examining the treatment of PTH in CKD-MBD

Table S37. Summary table of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis: study characteristics

Table S38. Summary table of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis: study population characteristics

Table S39. Summary table of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis: results

Table S40. Summary table of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis: quality

Table S41. Evidence matrix of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis

Table S42. Evidence proﬁle of randomized controlled trials examining the treatment of high levels of PTH with

calcitriol or activated vitamin D analogs in CKD G3a–G5 not on dialysis

Table S43. Summary table of randomized controlled trials examining the treatment of high levels of PTH in CKD

G5D: study characteristics

Table S44. Summary table of randomized controlled trials examining the treatment of high levels of PTH in CKD

G5D: study population characteristics

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Kidney International Supplements (2017) 7, 1–59

Table S45. Summary table of randomized controlled trials examining the treatment of high levels of PTH in

CKD G5D: results

Table S46. Summary table of randomized controlled trials examining the treatment of high levels of PTH in

CKD G5D: quality

Table S47. Evidence matrix of randomized controlled trials examining the treatment of high levels of PTH in

CKD G5D

Table S48. Evidence proﬁle of randomized controlled trials examining the treatment of high levels of PTH in

CKD G5D

Table S49. Summary table of studies evaluating different concentrations of serum phosphate or calcium among

patients with CKD G3a–G5 or G5D: study characteristics

Table S50. Summary table of studies evaluating different concentrations of serum phosphate or calcium among

patients with CKD G3a–G5 or G5D: study population characteristics

Table S51. Summary table of studies evaluating different concentrations of serum phosphate among patients with

CKD G3a–G5 or G5D: results

Table S52. Summary table of studies evaluating different concentrations of serum calcium among patients with

CKD G3a–G5 or G5D: results

Table S53. Summary table of studies evaluating different concentrations of serum phosphate or calcium among

patients with CKD G3a–G5 or G5D: quality

Table S54. Evidence matrix of studies evaluating different concentrations of serum phosphate or calcium among

patients with CKD G3a–G5 or G5D

Table S55. Evidence proﬁle of studies evaluating different concentrations of serum phosphate or calcium among

patients with CKD G3a–G5 or G5D

Supplementary material is linked to the online version of the paper at www.kisupplements.org.

www.kisupplements.org contents

Kidney International Supplements (2017) 7, 1–59 5

KDIGO EXECUTIVE COMMITTEE

Garabed Eknoyan, MD

Norbert Lameire, MD, PhD

Founding KDIGO Co-chairs

Bertram L. Kasiske, MD

Immediate Past Co-chair

David C. Wheeler, MD, FRCP

KDIGO Co-chair

Wolfgang C. Winkelmayer, MD, MPH, ScD

KDIGO Co-chair

Ali K. Abu-Alfa, MD

Olivier Devuyst, MD, PhD

Jürgen Floege, MD

John S. Gill, MD, MS

Kunitoshi Iseki, MD

Andrew S. Levey, MD

Zhi-Hong Liu, MD

Ziad A. Massy, MD, PhD

Roberto Pecoits-Filho, MD, PhD

Brian J.G. Pereira, MBBS, MD, MBA

Paul E. Stevens, MB, FRCP

Marcello A. Ton elli, MD, SM, FRCPC

Angela Yee-Moon Wang, MD, PhD, FRCP

Angela C. Webster, MBBS, MM (Clin Ep), PhD

KDIGO Staff

John Davis, Chief Executive Ofﬁcer

Danielle Green, Managing Director

Michael Cheung, Chief ScientiﬁcOfﬁcer

Tanya Green, Communications Director

Melissa McMahan, Programs Director

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Kidney International Supplements (2017) 7, 1–59

Reference keys

NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE

RECOMMENDATIONS

Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2,ornot graded, and the quality of the

supporting evidence is shown as A, B, C,orD.

Grade

Implications

Patients Clinicians Policy

Level 1

“We recommend”

Most people in your situation would

want the recommended course of

action, and only a small proportion

would not.

Most patients should receive the

recommended course of action.

The recommendation can be

evaluated as a candidate for

developing a policy or a performance

measure.

Level 2

“We suggest”

The majority of people in your

situation would want the

recommended course of action, but

many would not.

Different choices will be appropriate

for different patients. Each patient

needs help to arrive at a management

decision consistent with her or his

values and preferences.

The recommendation is likely to

require substantial debate and

involvement of stakeholders before

policy can be determined.

*The additional category “not graded” is used, typi cally, to provide guidance based on common sense or when the topic does not allow adequate application of evidence.

The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations

are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Grade Quality of evidence Meaning

A High We are conﬁdent that the true effect lies close to that of the estimate of the effect.

B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility

that it is substantially different.

C Low The true effect may be substantially different from the estimate of the effect.

D Very low The estimate of effect is very uncertain, and often will be far from the truth.

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Kidney International Supplements (2017) 7, 1–59 7

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

CKD is deﬁned as abnormalities of kidney structure or function, present for > 3 months, with implications for health. CKD is

classiﬁed

based on cause, GFR category (G1–G5), and albuminuria category (A1–A3), abbreviated as CGA.

Prognosis of CKD by GFR and albuminuria category

Prognosis of CKD by GFR

and albuminuria categories:

KDIGO 2012

Persistent albuminuria categories,

description and range

Normal to

mildly

increased

Moderately

increased

Severely

increased

<30 mg/g

<3 mg/mmol

30–300 mg/g

3–30 mg/mmol

>300 mg/g

>30 mg/mmol

GFR categories (ml/min/1.73 m

description and range

Normal or high

≥90

Mildly decreased

60–89

G3a

Mildly to moderately

decreased

45–59

G3b

Moderately to

severely decreased

30–44

Severely decreased

15–29

Kidney failure

<15

green, low risk (if no other markers of kidney disease, no CKD); yellow, moderately increased risk;

orange, high risk; red, very high risk.

web 4C/FPO

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Kidney International Supplements (2017) 7, 1–59

CONVERSION FACTORS OF CONVENTIONAL UNITS TO SI UNITS

Conventional unit Conversion factor SI unit

Calcium, total mg/dl 0.2495 mmol/l

Calcium, ionized mg/dl 0.25 mmol/l

Creatinine mg/dl 88.4

mol/l

Parathyroid hormone pg/ml 0.106 pmol/l

Phosphate (inorganic) mg/dl 0.3229 mmol/l

Note: conventional unit  conversion factor ¼ SI unit.

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Kidney International Supplements (2017) 7, 1–59 9

Abbreviations and acronyms

1,25(OH)

D 1,25-dihydroxyvitamin D

25(OH)D 25-hydroxyvitamin D

AUC area under the curve

bALP bone-speciﬁc alkaline phosphatase

BMD bone mineral density

CAC coronary ar tery calciﬁcation

CI conﬁdence interval

CT computed tomography

CV coefﬁcient of variation

DXA dual-energ y X-ray absorptiometry

eGFR estimated glomerular ﬁltration rate

ERT evidence review team

FGF ﬁbroblast growth factor

FRAX fracture risk assessment tool

GFR glomerular ﬁltration rate

GI gastrointestinal

GRADE Grading of Recommendations Assessment,

Development, and Evaluation

HD hemodialysis

HPT hyperparathyroidism

HR hazard ratio

iPTH intact parathyroid hormone

ISCD International Society of Clinical

Densitometry

ITT intention-to-treat

IU international unit

KDIGO Kidney Disease: Improving Global

Outcomes

KDOQI Kidney Disease Outcomes Quality

Initiative

LVH left ventricular hypertrophy

LVMI left ventricular mass index

MRI magnetic resonance imaging

OR odds ratio

P1NP amino-terminal propeptide of type 1

procollagen

PTH parathyroid hormone

RCT randomized controlled trial

ROC receiver operating characteristic

SD standard deviation

SHPT secondary hyperparathyroidism

VDR vitamin D receptor

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Kidney International Supplements (2017) 7, 1–59

Notice

SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE

This Clinical Practice Guideline Update is based upon systematic literature searches last conducted in Septemb er 2015 sup-

plemented with additional evidence through February 2017. It is designed to assist decision making. It is not intended to deﬁne

a standard of care, and should not be interpreted as prescribing an exclusive course of management. Variations in practice will

inevitably and appropriately occur when clinicians consider the needs of individual patients, available resources, and limitations

unique to an institution or type of practice. Health care professionals using these recommendations should decide how to apply

them to their own clinical practice.

SECTION II: DISCLOSURE

Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or reasonably perceived conﬂicts

of interest that may arise from an outside relationship or a personal, professional, or business interest of a member of the Work

Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing

all such relationships that might be perceived as or are actual conﬂicts of interest. This document is updated annually, and

information is adjusted accordingly. All reported information is published in its entirety at the end of this document in the

Work Group members’ Biographic and Disclosure section, and is kept on ﬁle at KDIGO.

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Single copies may be made for personal use as allowed by national copyright laws. Special rates are available fo r educational

institutions that wish to make photocopies for nonproﬁt educational use. No part of this publication may be reproduced,

amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any

information storage and retrieval system, without explicit permission in wr iting from KDIGO. Details on how to seek

permission for reproduction or translation, and further information about KDIGO’s permissions policies can be obtained by

contacting Danielle Green, Managing Director, at danielle.g[email protected].

To the fullest extent of the law, neither KDIGO, Kidney International Supplements, nor the authors, contributors, or editors,

assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or

otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59 11

Foreword

Kidney International Supplements (2017) 7, 1–59; http://dx.doi.org/10.1016/j.kisu.2017.04.001

With the growing awareness that chronic kidney disease is an

international health problem, Kidney Disease: Improving

Global Outcomes (KDIGO) was established in 2003 with its

stated mission to “improve the care and outcomes of kidney

disease patients worldwide through promoting coordination,

collaboration, and integration of initiatives to develop and

implement clinical practice guidelines.”

When the KDIGO Clinical Practice Guideline for the

Diagnosis, Evaluation, Prevention, and Treatment of Chronic

Kidney Disease–Mineral and Bone Disorder (CKD-MBD)

was originally published in 2009, the Work Group acknowl-

edged the lack of high-quality evidence on which to base

recommendations. The Guideline included speciﬁc research

recommendations to encourage investigators to help ﬁll the

gaps and bolster the evidence base.

Multiple randomized controlled trials and prospective cohort

studies have been published since the 2009 Guideline, and

therefore KDIGO recognizes the need to reexamine the currency

of all of its guidelines on a periodic basis. Accordingly, KDIGO

convened a Controversies Conference in 2013, titled “CKD-

MBD: Back to the Future,” whose objective was to determine

whether sufﬁcient new data had emerged to support a reassess-

ment of the 2009 CKD-MBD Clinical Practice Guideline and, if

so, to determine the scope of the potential revisions.

Although most of the recommendations were still

considered to be cur rent, the conference identiﬁed a total of

12 recommendations for reevaluation based on new data. In

addition, the conference prepared a table of additional topic

questions to be considered by the guideline update Work

Group. The conference noted that, in spite of the completion

of several key clinical trials since the 2009 publication of the

CKD-MBD guideline, large ga ps of knowledge still remained,

as demonstrated by the relatively small number of recom-

mendation statements identi ﬁed for reevaluation. Interested

readers should refer to the conference publicat ion for further

details regarding its processes and deliberations.

Therefore, KDIGO commissioned an update to the CKD-

MBD guideline and formed a Work Group, led by Drs.

Markus Ketteler and Mary Leonard. The Work Group

convened in June 2015 to review and appraise the evidence

accumulated since the 2009 Guideline. The topics addressed

for revision are listed in Table 2 and included issues prompted

by EVOLVE post hoc analyses, which were published after the

2013 Controversies Conference. Though 8 years have passed

since the 2009 CKD-MBD guideline, evidence in many areas

is still lacking, which has resulted in many of the “opinion-

based” recommendation statements from the original guide-

line document remaining unchanged .

In keeping with the standard KDIGO policy of maintain-

ing transparency during the guideline development process

and attesting to its rigor, we conducted an open public review

of the draft CKD-MBD guideline update, and all feedback

received was reviewed and considered by the Work Group

before ﬁnalizing this guideline document for publication. The

comments and suggestions greatly assisted us in shaping a

ﬁnal document that we felt would be as valuable as possible to

the entire nephrology community.

We wish to thank the Work Group co-chairs, Drs. Markus

Ketteler and Mary Leonard, along with all of the Work Group

members, who volunteered countless hours of their time to

develop this guideline. We also thank Dr. Karen Robinson and

her Evidence Review Team at Johns Hopkins University, the

KDIGO staff, and many others for their support that made

this project possible.

David C. Wheeler, MD, FRCP

Wolfgang C. Winkelmayer, MD, MPH, ScD

KDIGO Co-chairs

foreword www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Work Group membership

WORK GROUP CO-CHAIRS

Markus Ketteler, MD, FERA

Klinikum Coburg

Coburg, Germany

Mary B. Leonard, MD, MSCE

Stanford University School of Medicine

Stanford, CA, USA

WORK GROUP

Geoffrey A. Block, MD

Denver Nephrology

Denver, CO, USA

Pieter Evenepoel, MD, PhD, FERA

University Hospitals Leuven

Leuven, Belgium

Masafumi Fukagawa, MD, PhD, FASN

Tokai University School of Medicine

Isehara, Japan

Charles A. Herzog, MD, FACC, FAHA

Hennepin County Medical Center

Minneapolis, MN, USA

Linda McCann, RD, CSR

Eagle, ID, USA

Sharon M. Moe, MD

Indiana University School of Medicine

Roudebush Veterans Affairs Medical Center

Indianapolis, IN, USA

Rukshana Shroff, MD, FRCPCH, PhD

Great Ormond Street Hospital for Children

NHS Foundation Trust,

London, UK

Marcello A. Tonelli, MD, SM, FRCPC

University of Calgary

Calgary, Canada

Nigel D. Toussaint MBBS, FRACP, PhD

The Royal Melbourne Hospital

University of Melbourne

Melbourne, Australia

Marc G. Vervloet, MD, PhD, FERA

VU University Medical Center Amsterdam

Amsterdam, The Netherlands

EVIDENCE REVIEW TEAM

Johns Hopkins University

Baltimore, MD, USA

Karen A. Robinson, PhD, Associate Professor of Medicine and Project Director

Casey M. Rebholz, PhD, MPH, MS, Co-investigator

Lisa M. Wilson, ScM, Project Manager

Ermias Jirru, MD, MPH, Research Assistant

Marisa Chi Liu, MD, MPH, Research Assistant

Jessica Gayleard, BS, Research Assistant

Allen Zhang, BS, Research Assistant

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Kidney International Supplements (2017) 7, 1–59 13

Abstract

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline

Update for the Diagnosis, Evaluation, Prevention, and Treatment of chronic kidney disease–

mineral and bone disorder (CKD-MBD) represents a selective update of the prior guideline

published in 2009. This update, along with the 2009 publication, is intended to assist the

practitioner caring for adults and children with CKD, those on chronic dialysis therapy, or in-

dividuals with a kidney transplant. Speciﬁcally, the topic areas for which updated recommen-

dations are issued include diagnosis of bone abnormalities in CKD-MBD; treatment of CKD-

MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities

in parathyroid hormone in CKD-MBD; treatment of bone abnormalities by antiresorptives and

other osteoporosis therapies; and evaluation and treatment of kidney transplant bone disease.

Development of this guideline update followed an explicit process of ev idence review and

appraisal. Treatment approaches and guideline recommendations are based on systematic reviews

of relevant trials, and appraisal of the quality of the evidence and the strength of recommen-

dations followed the GRADE (Grading of Recommendations Assessment, Development,

and Evaluation) approach. Limitations of the ev idence are discussed, with areas of future research

also presented.

Keywords: bone abnormalities; bone mineral density; calcium; chronic kidne y disease; CKD-

MBD; dialysis; guideline ; hyperparathyroidism; hyperphosphatemia; KDIGO; kidney trans-

plantation; mineral and bone disorder; parathyroid hormone; phosphate; phosphorus; systematic

review

CITATION

In citing this document, the following format should be used: Kidney Disease: Improving

Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice

Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic

Kidney Disease–Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2017;7:1–59.

www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Summary of KDIGO CKD-MBD recommendations

Updated recommendations are denoted in boxes

Chapter 3.1: Diagnosis of CKD-MBD: biochemical abnormalities

3.1.1: We recommend monit oring serum levels of calcium, phosphate, PTH, and alkaline phosphatase activity beginning in

CKD G3a (1C). In children, we suggest such monitoring beginning in CKD G2 (2D).

3.1.2: In patients with CKD G3a– G5D, it is reasonable to base the frequency of monitoring serum calcium,

phosphate, and PTH on the presence and magnitude of abnormalities, and the rate of progression of CKD

(Not Graded ).

Reasonable monitoring intervals would be:

 In CKD G3a–G3b: for serum calcium and phosphate, every 6–12 months; and for PTH, based on baseline level and

CKD progression.

 In CKD G4: for serum calcium and phosphate, every 3 –6 months; and for PTH, every 6–12 months.

 In CKD G5, including G5D: for serum calcium and phosphate, every 1–3 months; and for PTH, every 3–6

months.

 In CKD G4–G5D: for alkal ine phosphatase activity, every 12 months, or more frequently in the presence of

elevated PTH (see Chapter 3.2).

In CKD patients receiving treatments for CKD-MBD, or in whom biochemical abnormalities are identiﬁed, it is

reasonable to increase the frequency of measurements to monitor for trends and treatment efﬁcacy and side effects

(Not Graded).

3.1.3: In patients with CKD G3a–G5D, we suggest that 25(OH)D (calcidiol) levels might be measured, and repeated testing

determined by baseline values and therapeutic interventions (2C). We suggest that vitamin D deﬁciency and

insufﬁciency be corrected using treatment strategies recommended for the general population (2C).

3.1.4: In patients with CKD G3a–G5D, we recommend that therapeutic decisions be based on trends rather than on a

single laboratory value, taking into account all available CKD-MBD assessments (1C).

3.1.5: In patients with CKD G3a–G5D, we suggest that individual values of serum calcium and phosph ate, evaluated

together, be used to gui de clinical practice rather than the mathematical construct of calcium-phosphate product

(Ca 3 P) (2D).

3.1.6: In reports of laboratory tests for patients with CKD G3a–G5D, we recommend that clinical laboratories inform

clinicians of the actual assay method in use and report any change in methods, sample source (plasma or serum), or

handling speciﬁcations to facilitate the appropriate interpretation of biochemistry data (1B).

Chapter 3.2: Diagnosis of CKD-MBD: bone

3.2.1: In patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, we suggest

BMD testing to assess fracture risk if results will impact treatment decisions (2B).

3.2.2: In patients with CKD G3a–G5D, it is reasonable to per form a bone biopsy if knowledge of the type of renal

osteodystrophy will impact treatment decisions (Not Graded).

3.2.3: In patients with CKD G3a–G5D, we suggest that measurements of serum PTH or bone-speciﬁc alkalin e

phosphatase can be used to evaluate bone dis ease because markedly high or low values predict underlying

bone turnover (2B).

3.2.4: In patients with CKD G3a– G5D, we suggest not to routinely measure bone-derived turnover markers of collagen

synthesis (such as procollagen type I C-terminal propeptide) and breakdown (such as type I collagen cross-linked

telopeptide, cross-laps, pyridinoline, or deoxypyridinoline) (2C).

The 2009 Guideline Chapters 1 and 2 provide the Introduction and Methodological Approach, respectively, and therefore guideline recommendations

begin in Chapter 3.1.

www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59 15

3.2.5: We recommend that infants with CKD G2–G5D have their length measured at least quarterly, while children with

CKD G2–G5D should be asses sed for linear growth at least annually (1B).

Chapter 3.3: Diagnosis of CKD-MBD: vascular calciﬁcation

3.3.1: In patients with CKD G3a–G5D, we suggest that a lateral abdominal radiograph can be used to detect the presence or

absence of vascular calciﬁcation, and an echocardiogram can be used to detect the presence or absence of valvular

calciﬁcation, as reasonable alternatives to computed tomography-based imaging (2C).

3.3.2: We suggest that patients with CKD G3a–G5D with known vascular or valvular calciﬁ cation be considered at

highest cardiovascular risk (2A). It is reasonable to use this information to guide the management of CKD-MBD

(Not Graded).

Chapter 4.1: Treatment of CKD-MBD targeted at lowering high serum phosphate and maintaining

serum calcium

4.1.1: In patients with CKD G3a–G5D, treatments of CKD-MBD should be based on serial assessments of phosphate,

calcium, and PTH levels, considered together (Not Graded).

4.1.2: In patients with CKD G3a–G5D, we suggest lowering elevated phosphate levels toward the normal range (2C).

4.1.3: In adult patients with CKD G3a–G5D, we suggest avoiding hypercalcemia (2C). In children with CKD G3a–G5D,

we suggest maintaining serum calcium in the age-appropriate normal range (2C).

4.1.4: In patients with CKD G5D, we suggest using a dialysate calcium concentration between 1.25 and 1.50 mmol/l

(2.5 and 3.0 mEq/l) (2C).

4.1.5: In patients with CKD G3a-G5D, decisions about phosphate-lowering treatment should be based on progressively

or persistently elevated serum phosphate (Not Graded).

4.1.6: In adult patients with CKD G3a–G5D receiving phosphate-lowering treatment, we suggest restricting the dose of

calcium-based phosphate binders (2B). In children with CKD G3a–G5D, it is reasonable to base the choice of

phosphate-lowering treatment on serum calcium levels (Not Graded).

4.1.7: In patients with CKD G3a-G5D, we recommend avoiding the long-term use of alumin um-containing phosphate

binders and, in patients with CKD G5D, avoiding dialysate aluminum contamination to prevent aluminum

intoxication (1C).

4.1.8: In patients with CKD G3a–G5D, we suggest limiting dietary pho sphate intake in the treatment of hyper-

phosphatemia alone or in combination with other trea tments (2D). It is reasonable to consider phosphate source

(e.g., animal, vegetable, additives) in making dietary recommendations (Not Graded ).

4.1.9: In patients with CKD G5D , we suggest increasing dialytic phosphat e removal in the treatment of persistent

hyperphosphatemia (2C).

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

4.2.1: In patients with CKD G3a–G5 not on dialysis, the optimal PTH level is not known. However, we suggest that

patients with levels of intact PTH progressively rising or persistently above the upper normal limit for the assay

be evaluate d for modiﬁable factors, including hyperphosphatemia, hypocalcemia, high phosphate intake, and

vitamin D deﬁciency (2C).

4.2.2: In adult patients with CKD G3a– G5 not on dialysis, we suggest that calcitriol and vitamin D analogs not be

routinely used (2C). It is reasonable to reserve the use of calcitriol and vitamin D analogs for patients with CKD

G4–G5 with severe and progres sive hyperparathyroidism (Not Graded).

In children, calcitriol and vitamin D analogs may be considered to maintain serum calcium levels in the

age-appropriate normal range (Not Graded).

summary of recommendation statements www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

4.2.3: In patients with CKD G5D, we suggest maintaining iPTH levels in the range of approximately 2 to 9 times the upper

normal limit for the assay (2C).

We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in

therapy to avoid progression to levels outside of this range (2C).

4.2.4: In patients with CKD G5D requiring PTH-lowering therapy, we suggest calcimimetics, calcitriol, or vitamin D

analogs, or a combination of calcimimetics with calcitriol or vitamin D analogs (2B).

4.2.5: In patients with CKD G3a–G5D with severe hyperparathyroidism (HPT) who fail to respond to medical or phar-

macological therapy, we suggest parathyroidectomy (2B).

Chapter 4.3: Treatment of bone with bisphosphonates, other osteoporosis medications, and

growth hormone

4.3.1: In patients with CKD G1–G2 with osteoporosis and/or high risk of fract ure, as identiﬁed by World Health Orga-

nization criteria, we recommend management as for the general population (1A).

4.3.2: In patients with CKD G3a–G3b with PTH in the normal range and osteoporosis and/or high risk of fracture, as

identiﬁed by World Health Organization criteria, we suggest treatment as for the general population (2B).

4.3.3: In patients with CKD G3a–G5D with biochemical abnormalities of CKD-MBD and low BMD and/or fragility

fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical

abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).

4.3.4: In children and adolescents with CKD G2–G5D and related heig ht deﬁcits, we recommend treatment with re-

combinant human growth hormone when additional growt h is desired, after ﬁ rst addressing malnutrition and

biochemical abnormalities of CKD-MBD (1A).

Chapter 5: Evaluation and treatment of kidney transplant bone disease

5.1: In patients in the immediate post–kidney transplant period, we recommend measuring serum calcium and phosphate

at least weekly, until stable (1B).

5.2: In patients after the immediate post–kidney transplant period, it is reasonable to base the frequency of monitoring

serum calcium, phosphate, and PTH on the presence and magnitude of abnor malities, and the rate of progression of

CKD (Not Graded).

Reasonable monitoring intervals would be:

 In CKD G1T–G3bT, for serum calcium and phosphate, every 6–12 months; and for PTH, once, with subsequent

intervals depending on ba seline level and CKD progression.

 In CKD G4T, for serum calcium and phosphate, every 3–6 months; and for PTH, every 6 – 12 months.

 In CKD G5T, for serum calcium and phosphate, every 1–3 months; and for PTH, every 3 – 6 months.

 In CKD G3aT–G5T, measurement of alkaline phosphatases annually, or more frequently in the presence of elevated

PTH (see Chapter 3.2).

In CKD patients receiving treatments for CKD-MBD, or in whom biochemical abnormalities are identiﬁed, it is

reasonable to increase the freq uency of measurements to monitor for efﬁcacy and side effects (Not Graded).

It is reasonable to manage these abnormalities as for patients with CKD G3a–G5 (see Chapters 4.1 and 4.2)

(Not Graded).

5.3: In patients with CKD G1T–G5T, we suggest that 25(OH)D (calcidiol) levels might be measured, and repeated testing

determined by baseline values and interventions (2C).

5.4: In patients with CKD G1T–G5T, we suggest that vitamin D deﬁciency and insufﬁciency be corrected using treatment

strategies recommended for the general population (2C).

www.kisupplements.org summary of recommendation statements

Kidney International Supplements (2017) 7, 1–59 17

5.5: In patients with CKD G1T–G5T with risk factors for osteoporosis, we suggest that BMD testing be used to assess

fracture risk if results will alter therapy (2C).

5.6: In patients in the ﬁrst 12 months after kidney transplant with an estimated glomerular ﬁltration rate greater than

approximately 30 ml/min/1.73 m

and low BMD, we suggest that treatment with vitamin D, calcitriol/alfacalcidol,

and/or antiresorptive agents be considered (2D).

 We suggest that treatment choices be inﬂuenced by the presence of CKD-MBD, as indicated by abnormal levels

of calcium, phosphate, PTH, alkaline phosphatases, and 25(OH)D (2C).

 It is reasonable to consider a bone biopsy to guide treatment (Not Graded).

There are insufﬁcient data to guide treatment after the ﬁrst 12 months.

5.7: In patients with CKD G4T–G5T with known low BMD, we suggest management as for patients with CKD G4–G5 not

on dialysis, as detailed in Chapters 4.1 and 4.2 (2C).

The 2017 updated recommendations resulted in renumbering of several adjacent guideline statements. Speciﬁcally, 2009

Recommendation 4.1.6 now becomes 2017 Recommendation 4.1.7; 2009 Reco mmendation 4.1.8 now becomes 2017

Recommendation 4.1.9; 2009 Recommendation 4.3.5 now becomes 2017 Recommendation 4.3.4; and 2009 Recommen-

dation 5.8 now becomes 2017 Recommendation 5.7.

summary of recommendation statements www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Summary and comparison of 2017 updated and 2009

KDIGO CKD-MBD recommendations

2017 revised KDIGO CKD-MBD

recommendations 2009 KDIGO CKD-MBD recommendations Brief rationale for updating

3.2.1. In patients with CKD G3a–G5D with

evidence of CKD-MBD and/or risk factors for

osteoporosis, we suggest BMD testing to

assess fracture risk if results will impact

treatment decisions (2B).

3.2.2. In patients with CKD G3a–G5D with evidence

of CKD-MBD, we suggest that BMD testing not be

performed routinely, because BMD does not

predict fracture risk as it does in the general

population, and BMD does not predict the type of

renal osteodystrophy (2B).

Multiple new prospective studies have

documented that lower DXA BMD predicts

incident fractures in patients with CKD G3a–

G5D. The order of these ﬁrst 2

recommendations was changed because a

DXA BMD result might impact the decision to

perform a bone biopsy.

3.2.2. In patients with CKD G3a–G5D, it is

reasonable to perform a bone biopsy if

knowledge of the type of renal osteodystrophy

will impact treatment decisions (Not Graded).

3.2.1. In patients with CKD G3a–G5D, it is

reasonable to perform a bone biopsy in various

settings including, but not limited to: unexplained

fractures, persistent bone pain, unexplained

hypercalcemia, unexplained hypophosphatemia,

possible aluminum toxicity, and prior to therapy

with bisphosphonates in patients with CKD-MBD

(Not Graded).

The primary motivation for this revision was

the growing experience with osteoporosis

medications in patients with CKD, low BMD,

and a high risk of fracture. The inability to

perform a bone biopsy may not justify

withholding antiresorptive therapy from

patients at high risk of fracture.

4.1.1. In patients with CKD G3a–G5D,

treatments of CKD-MBD should be based on

serial assessments of phosphate, calcium, and

PTH levels, considered together (Not Graded).

This new recommendation was provided in

order to emphasize the complexity and

interaction of CKD-MBD laboratory parameters.

4.1.2. In patients with CKD G3a–G5D, we

suggest lowering elevated phosphate levels

toward the normal range (2C).

4.1.1. In patients with CKD G3a–G5, we suggest

maintaining serum phosphate in the normal

range (2C). In patients with CKD G5D, we suggest

lowering elevated phosphate levels toward the

normal range (2C).

There is an absence of data supporting that

efforts to maintain phosphate in the normal

range are of beneﬁt to CKD G3a–G4 patients,

including some safety concerns. Treatment

should aim at overt hyperphosphatemia.

4.1.3. In adult patients with CKD G3a–G5D, we

suggest avoiding hypercalcemia (2C).

In children with CKD G3a–G5D, we suggest

maintaining serum calcium in the age-

appropriate normal range (2C).

4.1.2. In patients with CKD G3a–G5D, we suggest

maintaining serum calcium in the normal range (2D).

Mild and asymptomatic hypocalcemia (e.g., in

the context of calcimimetic treatment) can be

tolerated in order to avoid inappropriate

calcium loading in adults.

4.1.4. In patients with CKD G5D, we suggest

using a dialysate calcium concentration

between 1.25 and 1.50 mmol/l (2.5 and 3.0

mEq/l) (2C).

4.1.3. In patients with CKD G5D, we suggest using

a dialysate calcium concentration between 1.25

and 1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).

Additional studies of better quality are

available; however, these do not allow for

discrimination of beneﬁts and harms between

calcium dialysate concentrations of 1.25 and

1.50 mmol/l (2.5 and 3.0 mEq/l). Hence, the

wording is unchanged, but the evidence grade

is upgraded from 2D to 2C.

4.1.5. In patients with CKD G3a–G5D, decisions

about phosphate-lowering treatment should

be based on progressively or persistently

elevated serum phosphate (Not Graded).

4.1.4. In patients with CKD G3a–G5 (2D) and G5D

(2B), we suggest using phosphate-binding agents

in the treatment of hyperphosphatemia. It is

reasonable that the choice of phosphate binder

takes into account CKD stage, presence of other

components of CKD-MBD, concomitant therapies,

and side effect proﬁle (Not Graded).

Emphasizes the perception that early

“preventive” phosphate-lowering treatment is

currently not supported by data (see

Recommendation 4.1.2).

The broader term “phosphate-lowering”

treatment is used instead of phosphate

binding agents since all possible approaches

(i.e., binders, diet, dialysis) can be effective.

(Continued on next page)

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Kidney International Supplements (2017) 7, 1–59 19

2017 revised KDIGO CKD-MBD

recommendations 2009 KDIGO CKD-MBD recommendations Brief rationale for updating

4.1.6. In adult patients with CKD G3a–G5D

receiving phosphate-lowering treatment, we

suggest restricting the dose of calcium-based

phosphate binder (2B). In children with CKD

G3a–G5D, it is reasonable to base the choice of

phosphate-lowering treatment on serum

calcium levels (Not Graded).

4.1.5. In patients with CKD G3a–G5D and

hyperphosphatemia, we recommend restricting

the dose of calcium-based phosphate binders

and/or the dose of calcitriol or vitamin D analog in

the presence of persistent or recurrent

hypercalcemia (1B).

New evidence from 3 RCTs supports a more

general recommendation to restrict calcium-

based phosphate binders in

hyperphosphatemic patients across all

severities of CKD.

In patients with CKD G3a–G5D and

hyperphosphatemia, we suggest restricting the

dose of calcium-based phosphate binders in the

presence of arterial calciﬁcation (2C) and/or

adynamic bone disease (2C) and/or if serum PTH

levels are persistently low (2C).

4.1.8. In patients with CKD G3a–G5D, we

suggest limiting dietary phosphate intake in

the treatment of hyperphosphatemia alone or

in combination with other treatments (2D). It is

reasonable to consider phosphate source (e.g.,

animal, vegetable, additives) in making dietary

recommendations (Not Graded).

4.1.7. In patients with CKD G3a–G5D, we suggest

limiting dietary phosphate intake in the treatment

of hyperphosphatemia alone or in combination

with other treatments (2D).

New data on phosphate sources were deemed

to be included as an additional qualiﬁer to the

previous recommendation.

4.2.1. In patients with CKD G3a–G5 not on

dialysis, the optimal PTH level is not known.

However, we suggest that patients with levels

of intact PTH progressively rising or

persistently above the upper normal limit for

the assay be evaluated for modiﬁable factors,

including hyperphosphatemia, hypocalcemia,

high phosphate intake, and vitamin D

deﬁciency (2C).

4.2.1. In patients with CKD G3a–G5 not on dialysis,

the optimal PTH level is not known. However, we

suggest that patients with levels of intact PTH

above the upper normal limit of the assay are ﬁrst

evaluated for hyperphosphatemia, hypocalcemia,

and vitamin D deﬁciency (2C ).

It is reasonable to correct these abnormalities with

any or all of the following: reducing dietary

phosphate intake and administering phosphate

binders, calcium supplements, and/or native

vitamin D (Not Graded).

The Work Group felt that modest increases in

PTH may represent an appropriate adaptive

response to declining kidney function and has

revised this statement to include “persistently”

above the upper normal PTH level as well as

“progressively rising” PTH levels, rather than

“above the upper normal limit.” That is,

treatment should not be based on a single

elevated value.

4.2.2. In adult patients with CKD G3a–

G5 not on

dialysis, we suggest that calcitriol and vitamin D

analogs not be routinely used. (2C)Itis

reasonable to reserve the use of calcitriol and

vitamin D analogs for patients with CKD G4–G5

with severe and progressive

hyperparathyroidism (Not Graded).

4.2.2. In patients with CKD G3a–G5 not on dialysis,

in whom serum PTH is progressively rising and

remains persistently above the upper limit of

normal for the assay despite correction of

modiﬁable factors, we suggest treatment with

calcitriol or vitamin D analogs (2C).

Recent RCTs of vitamin D analogs failed to

demonstrate improvements in clinically

relevant outcomes but demonstrated

increased risk of hypercalcemia.

In children, calcitriol and vitamin D analogs

may be considered to maintain serum calcium

levels in the age-appropriate normal range

(Not Graded).

4.2.4. In patients with CKD G5D requiring PTH-

lowering therapy, we suggest calcimimetics,

calcitriol, or vitamin D analogs, or a

combination of calcimimetics with calcitriol or

vitamin D analogs (2B).

4.2.4. In patients with CKD G5D and elevated or

rising PTH, we suggest calcitriol, or vitamin D

analogs, or calcimimetics, or a combination of

calcimimetics and calcitriol or vitamin D analogs

be used to lower PTH (2B).

 It is reasonable that the initial drug selection for

the treatment of elevated PTH be based on

serum calcium and phosphate levels and other

aspects of CKD-MBD (Not Graded).

 It is reasonable that calcium or non-calcium-based

phosphate binder dosage be adjusted so that

treatments to control PTH do not compromise

levels of phosphate and calcium (Not Graded).

 We recommend that, in patients with hyper-

calcemia, calcitriol or another vitamin D sterol

be reduced or stopped (1B).

This recommendation originally had not been

suggested for updating by the KDIGO

Controversies Conference in 2013. However,

due to a subsequent series of secondary and

post hoc publications of the EVOLVE trial, the

Work Group decided to reevaluate

Recommendation 4.2.4 as well. Although

EVOLVE did not meet its primary endpoint, the

majority of the Work Group members were

reluctant to exclude potential beneﬁts of

calcimimetics for G5D patients based on

subsequent prespeciﬁed analyses. The Work

Group, however, decided not to prioritize any

PTH-lowering treatment at this time because

calcimimetics, calcitriol, or vitamin D analogs

are all acceptable ﬁrst-line options in G5D

patients.

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Kidney International Supplements (2017) 7, 1–59

2017 revised KDIGO CKD-MBD

recommendations 2009 KDIGO CKD-MBD recommendations Brief rationale for updating

 We suggest that, in patients with hyper-

phosphatemia, calcitriol or another vitamin D

sterol be reduced or stopped (2D).

 We suggest that, in patients with hypocalcemia,

calcimimetics be reduced or stopped depend-

ing on severity, concomitant medications, and

clinical signs and symptoms (2D).

 We suggest that, if the intact PTH levels fall

below 2 times the upper limit of normal for the

assay, calcitriol, vitamin D analogs, and/or cal-

cimimetics be reduced or stopped (2C).

4.3.3. In patients with CKD G3a–G5D with

biochemical abnormalities of CKD-MBD and

low BMD and/or fragility fractures, we suggest

that treatment choices take into account the

magnitude and reversibility of the biochemical

abnormalities and the progression of CKD,

with consideration of a bone biopsy (2D).

4.3.3. In patients with CKD G3a–G3b with

biochemical abnormalities of CKD-MBD and low

BMD and/or fragility fractures, we suggest that

treatment choices take into account the

magnitude and reversibility of the biochemical

abnormalities and the progression of CKD, with

consideration of a bone biopsy (2D).

Recommendation 3.2.2 now addresses the

indications for a bone biopsy prior to

antiresorptive and other osteoporosis

therapies. Therefore, 2009 Recommendation

4.3.4 has been removed and 2017

Recommendation 4.3.3 is broadened from CKD

G3a–G3b to CKD G3a–G5D.

4.3.4. In patients with CKD G4–G5D having

biochemical abnormalities of CKD-MBD, and low

BMD and/or fragility fractures, we suggest

additional investigation with bone biopsy prior to

therapy with antiresorptive agents (2C).

5.5. In patients with G1T–G5T with risk factors

for osteoporosis, we suggest that BMD testing

be used to assess fracture risk if results will

alter therapy (2C).

5.5. In patients with an estimated glomerular

ﬁltration rate greater than approximately 30 ml/

min/1.73 m

, we suggest measuring BMD in the

ﬁrst 3 months after kidney transplant if they

receive corticosteroids, or have risk factors for

osteoporosis as in the general population (2D).

2009 Recommendations 5.5 and 5.7 were

combined to yield 2017 Recommendation 5.5.

5.7. In patients with CKD G4T–G5T, we suggest

that BMD testing not be performed routinely,

because BMD does not predict fracture risk as it

does in the general population and BMD does

not predict the type of kidney transplant bone

disease (2B).

5.6. In patients in the ﬁrst 12 months after

kidney transplant with an estimated

glomerular ﬁltration rate greater than

approximately 30 ml/min/1.73 m

and low

BMD, we suggest that treatment with vitamin

D, calcitriol/alfacalcidol, and/or antiresorptive

agents be considered (2D).

 We suggest that treatment choices be

inﬂuenced by the presence of CKD-MBD, as

indicated by abnormal levels of calcium,

phosphate, PTH, alkaline phosphatases, and

25(OH)D (2C).

 It is reasonable to consider a bone biopsy to

guide treatment (Not Graded).

There are insufﬁcient data to guide treatment

after the ﬁrst 12 months.

5.6. In patients in the ﬁrst 12 months after kidney

transplant with an estimated glomerular ﬁltration

rate greater than approximately 30 ml/min/1.73

and low BMD, we suggest that treatment with

vitamin D, calcitriol/alfacalcidol, or

bisphosphonates be considered (2D).

 We suggest that treatment choices be inﬂu-

enced by the presence of CKD-MBD, as indi-

cated by abnormal levels of calcium, phosphate,

PTH, alkaline phosphatases, and 25(OH)D (2C).

 It is reasonable to consider a bone biopsy to

guide treatment, speciﬁcally before the use of

bisphosphonates due to the high incidence of

adynamic bone disease (Not Graded).

There are insufﬁcient data to guide treatment after

the ﬁrst 12 months.

The second bullet is revised, consistent with

the new bone biopsy recommendation (i.e.,

2017 Recommendation 3.2.2).

25(OH)D, 25-hydroxyvitamin D; BMD, bone mineral density; CKD, chronic kidney disease; CKD-MBD, chronic kidney disease–mineral bone disorder; DXA, dual-energy x-ray

absorptiometry; PTH, parathyroid hormone; RCT, randomized controlled trial.

Changes to above summarized recommendations resulted in renumbering of several adjacent guideline statements. Speciﬁcally, 2009 Recommendation 4.1.6 now becomes

2017 Recommendation 4.1.7; 2009 Recommendation 4.1.8 now becomes 2017 Recommendation 4.1.9; 2009 Recommendation 4.3.5 now becomes 2017 Recommendation

4.3.4; and 2009 Recommendation 5.8 now becomes 2017 Recommendation 5.7.

www.kisupplements.org summary and comparison of 2017 updated and 2009 KDIGO CKD-MBD recommendations

Kidney International Supplements (2017) 7, 1–59 21

Chapter 3.2: Diagnosis of CKD-MBD: bone

3.2.1: In patients with CKD G3a– G5D with evidence of

CKD-MBD and/or risk factors for osteoporosis, we

suggest BMD testing to assess fracture risk if results

will impact treatment decisions (2B).

Rationale

It is well established that patients with CKD G3a– G5D have

increased fracture rates compared with the general popula-

tion,

2–4

and moreover, incident hip fractures are associated

with substantial morbidity and mortality.

5–9

At the time of

the 2009 KDIGO CKD-MBD guideline, pu blications

addressing the ability of dual-energy X-ray absorptiometry

(DXA) measures of bone mineral density (BMD) to estimate

fracture risk in CKD were limited to cross-sectional studies

comparing BMD in CKD patien ts with and without a prev-

alent fracture. The results were variable across studies and

across skeletal sites. In light of the lack of evidence that DXA

BMD predicted fractures in CKD patients as it does in the

general population, and the inability of DXA to indicate the

histological type of bone disease, the 2009 Guideline recom-

mended that BMD testing not be performed routinely in

patients with CKD G3a to G5D with CKD-MBD. Further-

more, the lack of clinical trials in patients with low BMD and

CKD also limited the enthusiasm for measuring BMD in the

ﬁrst place.

The current evidence-based review identiﬁed 4 prospective

cohort studies of DXA BMD and incident fractures in adults

with CKD G3a to G5D (Supplementary Tables S7–S12).

These studies demonst rated that DXA BMD predicted frac-

tures across the spectrum from CKD G3a to G5D

(Supplementary Tables S7–S12).

10–13

In the earlies t study,

DXA BMD was measured annually in 485 hemodialysis (HD)

patients (mean age: 60 years) in a single center in Japan.

adjusted Cox proportional analyses, lower baseline femoral

neck and total hip BMD predicted a greater risk of fracture;

for example, the hazard ratio (HR) was 0.65 (95% conﬁdence

interval [CI]: 0.47–0.90) for each standard deviation (SD)

higher femoral neck BMD. In receiver operating character istic

(ROC) analyses stratiﬁed according to parathyroid hormone

(PTH) below or above the median value of 204 pg/ml (21.6

pmol/l), the area under the curve (AUC) for femoral neck

BMD was 0.717 in the lower stratum and 0.512 in the higher

stratum. Of note, higher serum bone-speciﬁc alkaline phos-

phate levels also predicted incident fractures.

In the second study, Yenchek et al. assessed whether DXA

total hip and femoral neck BMD were associated with incident

nonspine fragility fractures in participants with estimated

glomerular ﬁltration rate (eGFR) < 60 ml/min/1.73 m

and

without CKD in the Health, Aging and Body Composition

Study, a prospective study of community-living individuals, 70

to 79 years of age at enrollment.

A total of 587 (21%) of the

2754 participants had CKD, and among those, 83% and 13%

had CKD G3a and G3b, respectively. In adjusted analyses, the

fracture HR for each SD lower femoral neck BMD was 2.14

(95% CI: 1.80–2.55) in participants w ithout CKD, and 2.69

(95% CI: 1.96– 3.69) in those with CKD. Similar results were

obser ved for total hip BMD. When limited to hip fractures, the

adjusted femoral neck BMD HRs were 5.82 (95% CI: 3.27–

10.35) among those with CKD and 3.08 (95% CI: 2.29–4.14)

among those without CKD. Interaction terms demonstrated

that the association of BMD with fracture did not differ in those

with versus without CKD. However, the association of femoral

neck BMD with fract ure was signiﬁcantly less pronounced (test

for interaction, P ¼ 0.04) among those with PTH > 65 pg/ml

(6.9 pmol/l; HR: 1.56, 95% CI: 0.90–2.70) compared with those

with a PTH # 65 pg/ml (6.9 pmol/l; HR: 2.41, 95% CI: 2.04–

2.85) in all participants combined. This is noteworthy in light

of the similar pattern observed in dialysis patients, as descr ibed

above.

West et al. repor ted the results of a prospective cohort

study of 131 predialysis participants, mean age 62 years, fol-

lowed up over a 2-year interval.

At baseline, the proportions

with CKD G3a to G3b, G4, and G5 were 34%, 40%, and 26%,

respectively. DXA BMD was measured in the total hip, lum-

bar spine, and ultradistal and one-third radius at baseline and

2 years. Low BMD at all sites, and a greater annualized per-

centage decrease in BMD predicted fracture. For example, in

multivariate models, each SD lower total hip BMD was

associated with an odds ratio (OR) of fracture of 1.75 (95%

CI: 1.30–2.20). The ROC AUC ranged from 0.62 in the spine

to 0.74 in the ultradistal radius in adjusted models.

Most recently, Naylor, et al.

assessed the ability of the

Fracture Risk Assessment Tool (FRAX) to predict a major

osteoporotic fracture in 2107 adu lts $ 40 years of age in the

Canadian Multicenter Osteoporosis Study, including 320 with

an eGFR # 60 ml/min/1.73 m

. Of these, 72% and 24% had

CKD G3a and G3b, respectively. FRAX with BMD, FRAX

without BMD, and the femoral neck T-score all predicted

fractures (AUC: 0.65 to 0.71); the AUC was highest for femoral

neck T-score with inclusion of fall history. Importantly, the

AUCs did not differ between those with and without CKD.

There is growing evidence that DXA BMD predicts frac-

tures in healthy children and adolescents, and those with

chronic disease.

14,15

However, no studies have examined the

associations among DXA BMD and fractures in children and

adolescents with CKD. In light of the lack of evidence that the

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Kidney International Supplements (2017) 7, 1–59

ability of DXA BMD to predict fracture in children with CKD

is different than in adults, no speciﬁc recommendations are

provided for children. However, it should be noted that

children and adolescents with CKD frequently exhibit sub-

stantial growth failure. Given that DXA measures of areal

BMD (g/cm

) underestimate volumetric BMD (g/cm

)in

children with short stature,

DXA results should be adjusted

for bone size, consistent with the 2013 International Society

of Clinical Densitometry (ISCD) Pediatric Ofﬁcial Posi-

tions.

Prediction equations to adjust DXA results for height

Z-score are now available,

and the impact on DXA BMD

Z-scores in children with CKD is substantial.

Finally, a single-

center study in 171 children with CKD G2 to G5D reported

that lower cor tical volumetric BMD in the tibia, as measured

by peripheral quantitative computed tomography (CT), pre-

dicted fractures over a 1-year interval (Supplementary

Tables S7–S12).

The HR per unit lower cortical BMD

Z-score was 1.75 (95% CI: 1.15–2.67; P < 0.01).

The evidence-based review also evaluated clinical trials of

the effects of osteoporosis medications on BMD in CKD G3a

to G5D (Supplementary Tables S1–S6). Prior analyses of large

randomized clinical trials (RCTs) evaluating medications for

the treatment of postmenopausal osteoporosis (risedronate,

alendronate, teriparatide, and raloxifene) were described in

the 2009 Guideline. These trials speciﬁcally excluded patients

with an elevated serum creatinine, hyperparathyroidism, or

abnormal alkaline phosphate levels (i.e., CKD-MBD).

20–23

However, post hoc analyses found that these drugs had

similar efﬁcacy on improving BMD and reducing fracture

incidence in individuals with moderately reduced eGFR,

compared with those with mildly decreased or normal eGFR.

Three new trials were identiﬁed. The denosumab study was

also a post hoc analysis of an RCT in women with post-

menopausal os teoporosis and normal PTH levels.

The

analysis demonstrated efﬁcacy of denosumab in decreasing

fracture r isk and increasing BMD in 2817 women with CKD

G3a to G3b and 73 with CKD G4. Here, the risk of hypo-

calcemia associated w ith denosumab in advanced CKD re-

quires mentioning. The remaining 2 new trials on

alendronate

and raloxifene

were small studies (<60 par-

ticipants) that did not exclude patients with evidence of CKD-

MBD. These studies did not show consistent beneﬁcial effects

on DXA BMD. Generally, a major limitation is the lack of

data on fracture prevention by such therapeutic interventions

in advanced CKD (especially in CKD G5–G5D).

In summary, the aforementioned 4 prospective studies

evaluating BMD testing in adults with CKD represent a

substantial advance since the orig inal guideline from 2009.

Despite the fact that they were conducted across a spectrum

of CKD severity, the ﬁnding that hip BMD predicted fractures

was consistent across studies, and 2 studies demonstrated

associations comparable to those seen in the absence of

CKD.

11,13

Based on these insights, if a low or declining BMD

will lead to additional interventions to reduce falls or use

osteoporosis medications, then BMD assessment is

reasonable.

Research recommendations

 RCTs are needed to determine whether interventions based

on DXA BMD are associated with lower fracture rates, and

whether the effects vary based on clinical variables such as

the baseline PTH level, underlying cause of kidney disease,

and CKD GFR category.

 Prospective studies are needed to determine whether

alternative imaging techniques, such as quantitative CT,

improve fracture prediction in CKD.

 Prospective studies are needed in child ren and adolescents

to determine whether DXA predicts fractures in children

and to determine whether the ISCD recommendations to

measure whole-body and spine BMD in children are the

appropriate sites in the context of CKD.

Hip and radius

BMD pediatric reference data are now available and predict

incident fractures in healthy children and adolescents.

27,28

3.2.2: In patients with CKD G3a–G5D, it is reasonable to

perform a bone biopsy if knowledge of the type of

renal osteodystrophy will impac t trea tment decisions

(Not Graded).

Rationale

Renal osteodystrophy is deﬁned as abnormal bone histology

and is 1 component of the bone abnormalities of CKD-

MBD.

Bone biopsy is the gold standard for the diagnosis

and classiﬁcation for renal osteodystrophy. As detailed in the

2009 KDIGO CKD-MBD Guideline,

DXA BMD does not

distinguish among types of renal osteodystrophy, and the

diagnostic utility of biochemical markers is limited by poor

sensitivity and speciﬁcity. Differences in PTH assays (e.g.,

intact vs. whole PTH) and reference ranges have contributed

to differences across studies. Unfortunately, cross-sectional

studies have provided conﬂicting information on the use of

biomarkers to predict underlying bone histology. This is not

surprising given the short half-lives of most of the circulating

biomarkers, and the long (3–6 months) bone remodeling

(turnover) cycle.

KDIGO recently led an international consortium to

conduct a cross-sectional retrospective diagnostic study of

biomarkers (all run in a single laboratory) and bone biopsies

in 492 dialysis patients.

The objective was to determine the

predictive value of PTH (determined by both intact PTH

[iPTH] and whole PTH assays), bone-speciﬁc alkaline phos-

phatase (bALP), and amino-terminal propeptide of type 1

procollagen (P1NP) as markers of bone turnover. Altho ugh

iPTH, whole PTH, and bALP levels were associated with bone

turnover, no biomarker singly or in combination was sufﬁ-

ciently robust to diagnose low, normal, and high bone turn-

over in an individual patient. The conclusion was in support

of the 2009 KDIGO Guideline to use trends in PTH rather

than absolute “target” values when making decisions as to

whether to start or stop treatments to lower PTH. Table 1

provides the sensitivity, speciﬁcit y, and positive and negative

predictive value of PTH in helping clinicians determine

therapies, demonstrating the challenges clinicians face. Thus,

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Kidney International Supplements (2017) 7, 1–59 23

the Work Group encourages the continued use of trends in

PTH to guide therapy, and when trends in PTH are incon-

sistent, a bone biopsy should be considered.

A bone biopsy should also be considered in patients with

unexplained fractures, refractory hypercalcemia, suspicion of

osteomalacia, an atypical response to standard therapies for

elevated PTH, or progressive decreases in BMD despite

standard therapy. The goal of a bone biopsy would be to: (i)

rule out atypical or unexpected bone pathology ; (ii) deter-

mine whether the patient has high- or low-turnover disease,

which may alter the dose of medications to treat renal

osteodystrophy (e.g., initiate or discontinue calcimimetics,

calcitriol, or vitamin D analogs); or (iii) identify a minerali-

zation defect that would alter treatment (e.g., stop intake of

aluminum, or aggressively treat hypophosphatemia or

vitamin D deﬁciency).

The 2009 Guideline recommended a bone biopsy prior to

antiresorptive therapy in patients with CKD G4 to G5D and

evidence of biochemical abnormalities of CKD-MBD, low

BMD, and/or fragility fractures. The rationale was that low

BMD may be due to CKD-MBD (e.g., high PTH) and that

lowering PTH is a safer and more appropriate therapy than an

antiresorptive. In addition, there was concern that

bisphosphonates would induce low-turnover bone disease.

This was based on a single cross-sectional study in 13 patients

with CKD G2 to G4 that were refer red for bone biopsy after a

variable duration of bisphosphonate therapy.

To date,

studies in patients with CKD have not deﬁniti vely demon-

strated that bisphosphonates cause adynamic bone disease.

Furthermore, the concerns in patients with CKD are only

theoretical, as it is w ell established that antiresorptive medi-

cations suppress bone formation rates, even in the absence of

kidney disease. For examp le, in an RCT of zoledronic acid for

the treatment of postmenopausal osteoporosis, bALP levels

were 59% lower in the zoledronic acid group compared with

the placebo group at 12 months.

Despite these limitations, in weighing the risk-beneﬁt ratio

of bisphosphonate treatment, the 2009 KDIGO Guideline

suggested a biopsy prior to therapy. Since 2009, an additional

antiresorptive treatment (denosumab) has proven to be

effective in CKD G3a to G3b and G4, as discussed in

Recommendation 3.2.1. The g rowing experience with osteo-

porosis medications in patients with CKD increases the

comfort of treating patients with low BMD and a high risk of

fracture with antiresorptive therapy, although deﬁnitive trials

are lacking. Furthermore, additional data clearly support that

the incidence of fracture is markedly increased in patients

with CKD, and thus the inability to perform a bone biopsy

may not justify withholding antiresorptive therapy to patients

at high risk of fracture. Thus, the Work Group voted to

remove the requirement of bone biopsy prior to the use of

antiresorptive ther apy for osteoporosis because the use of

these drugs must be individualized in patients with CKD.

However, it is still prudent that these drugs be used with

caution and that the underlying renal osteodystrophy be

addressed ﬁrst. With regard to efﬁcacy, one may speculate that

antiresorptive therapies confer less beneﬁt in the absence of

activated osteoclasts, as is the case in adynamic bone disease.

Moreover, additional side effects such as acute kidney injury

may also merit consideration in CKD G3a to G5.

In summary, bone biopsy is the gold standard for the

assessment of renal osteodystrophy and should be considered

in patients in whom the etiology of clinical symptoms and

biochemical abnormalities is in question, and the results may

lead to changes in therapy. With this statement, the Work

Group is well aware that experience concerning performance

and evaluation of bone biopsies is limited in many centers.

With this in mind, in addition to the growing evidence that

antiresorptive therapies are effective in patients with CKD

G3a to G3b and G4, and the lack of robust evidence that these

medications induce adynamic bone disease, the guideline no

longer suggests that a bone biopsy be performed prior to

initiation of these medications.

Research recommendation

 Prospective studies of circulating biomarkers are needed to

determine whether they can predict changes in bone

histology.

Table 1 | Utility of KDOQI and KDIGO PTH thresholds for diagnostic decision making

KDOQI

KDIGO

Sens Spec PPV NPV Sens Spec PPV NPV

Differentiating low-turnover from non–low-turnover bone disease,

or “When do I stop therapy?”

69% 61% 72% 58% 66% 65% 73% 57%

Differentiating high-turnover from non–high-turnover bone disease,

or “When do I start therapy?”

58% 78% 35% 90% 37% 86% 35% 87%

iPTH, intact parathyroid hormone; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Outcomes Quality Initiative; NPV, negative predictive value;

PPV, positive predictive value; PTH, parathyroid hormone; Sens, sensitivity; Spec, speciﬁcity.

*Using serum iPTH < 150 pg/ml (16 pmol/l) for lower and > 300 pg/ml (32 pmol/l) for upper threshold.

Using serum iPTH < 130 pg/ml (14 pmol/l) for lower and > 585 pg/ml (62 pmol/l) for upper threshold (2X and 9X of upper limit of normal for assay).

Reproduced with permission from Sprague SM, Bellorin-Font E, Jorgetti V, et al. Diagnostic accuracy of bone turnover markers and bone histology in patients with CKD treated

by dialysis. Am J Kidney Dis. 2016;67:559 –566.

chapter 3.2 www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Chapter 4.1: Treatment of CKD-MBD targeted at

lowering high serum phosphate and maintaining

serum calcium

4.1.1: In patients with CKD G3a–G5D, treatments of CKD-

MBD should be based on serial assessments of

phosphate, calcium, and PTH levels, considered

together (Not Graded).

Rationale

The previous Recommendation 4.1.1 from the 2009 KDIGO

CKD-MBD guideline gave treatment directions concerning

serum phosphate levels in different GFR categories of CKD.

The accumulated evidence on this issue to date is now

depicted in Supplementary Tables S49 –S51, S53–S55. Results

of this evidence review can be summar ized as follows: most

studies showed increasing risk of all-cause mortality with

increasing levels of serum phosphate in a consistent and

direct fashion, with moderate risk of bias and low quality of

evidence, thus not essentially different from the study results

before 2009. For GFR decline and cardiovascular event rate,

results were considered less conclusive.

Serum phosphate, calcium, and PTH concentrations are all

routinely measured in CKD patients, and clinical decisions

are often made bas ed on these values. However, the results of

these tests are inﬂuenced by food intake, adherence to and the

timing of drug intake and dietary modiﬁcations, differences

in assay methods and their intra-assay coefﬁcient of variation

(CV), and also by the interval from the last dialysis session in

CKD G5D patients. Furthermore, it has recently been sug-

gested that these mar kers undergo signiﬁcant diurn al changes

even in CKD patients.

35,36

Accordingly, the decision should be

based not on a single result, but rather on the trends of serial

results, which stands very much in accordance to 2009

Recommendation 3.1.4. In addition, recent post hoc analyses

of large dialysis cohorts suggest that the prognostic implica-

tions of individual biochemical components of CKD-MBD

largely depend on their context with regard to constellations

of the full array of MBD bioma rkers.

This analysis identiﬁed

a wide range of CKD-MBD phenotypes, based on phosphate,

calcium, and PTH measurements categorized into mutually

exclusive categories of low, medium, and high levels using

previous Kidney Disease Outcomes Quality Initiative

(KDOQI)/KDIGO guideline targets, further illustrating

important potential interactions between components of

CKD-MBD in terms of risk prediction for death or cardio-

vascular events. This analysis, however, did not provide

guidance for treatment, because it is unknown whether

switching from “risk classes” parallels changes in incidence of

complications or mortality over time. Of note, biomarkers

such as bALP and 25(OH)vitamin D were also still considered

valuable, but as no new evidence has been published on their

account, recommendations remained unchanged from the

previous guideline (2009 Recommendations 3.1.3, 3.2.3).

Finally, therapeutic maneuvers aimed at improving 1

parameter often have unin tentional effects on other parame-

ters, as exempliﬁed by the recent EVOLVE trial.

The guideline

Work Group considered it reasonable to take the context of

therapeutic interventions into account when assessing values of

phosphate, calcium, and PTH, and felt that it was important to

emphasize the interdependency of these biochemical param-

eters for clinical therapeutic decision making.

Based on these assumptions, it was also decided to split

previous 2009 Recommendation 4.1.1 into 2 new Recom-

mendations, 4.1.1 (diagnostic recommendation based on

accumulated observational evidence) and 4.1.2 (therapeutic

recommendation based mostly on RCTs).

Research recommendations

 Prospective cohort studies or RCTs are needed to evaluate

whether changes in CKD-MBD risk marker patterns over time

associate with changes in risk (e.g., multiple interventions).

 Prospective cohort studies or RCTs are needed to examine

whether biochemical abnormalities of CKD-MBD must be

weighed differently when induced by pharmacotherapy

compared with baseline values (e.g., past experience with

hemoglobin as risk predictor vs. active treatment to targets

by erythropoiesis-stimulating agents).

 Investigations contributing to the understanding of the

usefulness of ﬁbroblast g rowth factor 23 (FGF23) as a

complementary marker for treatment indications (e.g.,

phosphate-lowering therapies to halt CKD progression)

and direct treatment target (e.g., regression of left ventric-

ular hypertrophy [LVH]) should be undertaken.

4.1.2: In patients with CKD G3a–G5D, we suggest lowering

elevated phosphate levels toward the normal range

(2C).

Rationale

As outlined above, since publication of the 2009 KDIGO

CKD-MBD Guideline, additional high-quality evidence now

links higher concentrations of phosphate with mortality

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Kidney International Supplements (2017) 7, 1–59 25

among patients with CKD G3a to G5 or after trans-

plantation

39–48

(Supplementary Tables S49–S51, S53–S55),

although some studies did not conﬁrm this association.

49,50

However, trial data demonstrating that treatments that lower

serum ph osphate will improve patient-centered outcomes are

still lacking, and therefore the strength of this recommendation

remains weak (2C). The rationale of interventions, therefore, is

still only based on epidemiological evidence as described above

and biological plausibility pointing to possible phosphorus

toxicity as recently summarized.

Three recent historical

cohort analyses from DOPPS, ArMORR, and COSMOS were

not eligible for this evidence-based review ; however, it is

noteworthy that these analyses suggeste d that those dialysis

patients who had been prescribed phosphate-binder therapy

showed improved survival.

52–54

It is important to note that

phosphate-binder prescription was associate d with better

nutritional status. Indeed, correction for markers of nutritional

status in the DOPPS study did mitigate the strength of the

association, yet a statistically signiﬁcant beneﬁt persisted. In

addition, propensity scoring attempting to correct for selection

bias and subgroup analysis applied by Isakova et al.

in the

ArMORR cohort suggested robustness of the beneﬁcial ﬁnd-

ings for those treated with phosphate binders. However, re-

sidual confounding still cannot be completely ruled out, and

due to the nature of the observational data, these studies did

not affect the current recommendation.

Methods to prevent the development of hyper-

phosphatemia essentially includ e dietary modiﬁcation, the

use of phosphate-lowering therapy, and intensiﬁed dialysis

schedules for those with CKD G5D. In the 2009 KDIGO

Guideline it was suggeste d to maintain serum phosphate in

the normal range in the predialysis setting and lower serum

phosphate toward the normal range in patients on dialysis.

Interestingly, in the prospective observational COSMOS

study cohort of HD patients (Supplementary Tables S49–S51,

S53–S55), the best patient survival was observed with serum

phosphate close to 4.4 mg/dl (1.42 mmol/l).

The previous recommendation suggested that clinicians

“maintain serum phosphate in the normal range” fo r patients

with CKD G3a to G3b and G4. The Work Group reevaluated

the evidence underlying this assu mption. The majorit y of

studies (Supplementary Table S49) found ph osphate to be

consistently associated with excess mortality at levels above

and below the limits of normal, but not in the normal

range.

40–43,47,48,56,57

This ﬁnding is in line with the previously

found U-shaped relation of phosphate with mortality risk in

dialysis patients.

However, a recent trial comparing placebo

with active phosphate-binder therapy in predialysis patients

(CKD G3b–G4) with a mean baseline phosphate concentration

of 4.2 mg/dl (1.36 mmol/l), found a minimal decline in serum

phosphate, no effect on FGF23, and increases in coronary

calciﬁcation scores for the active treatment group

—calling

into question the efﬁcacy and safety of phosphate binding in

this population, with normal phosphate concentration prior to

initiation of binder treatment (Supplementary Tables S19–24).

In this analysis, all phosphate binders were analyz ed

collectively, and the study was underpowered to detect differ-

ences between phosphate binders. Although the data suggested

that the observed increase in coronary artery calciﬁcation

(CAC) was mainly driven by the group treated with calcium-

containing phosphate binders, those treated with calcium-

free binders had no advantage over placebo in terms of pro-

gression of CAC. In addition, a well-executed mineral balance

study in predialysis patients using calcium-containing phos-

phate binders demonstrated the absence of any effect on

phosphate balance (while showing in the short term a positive

calcium balance).

The second principal option to control phosphate in pre-

dialysis patients is dietary restriction, as will be addressed in

Recommendation 4.1.8. However, in both the NHANES and

MDRD cohorts that examined the general population and

advanced CKD, respectively, dietary intake or intervention to

reduce dietary phosphate intake as assessed by either ur inary

excretion or dietary recall had only minimal effects on serum

phosphate.

61,62

It is unknown whether this minimal decline in

serum phosphate concentrations or the more robust lower

phosphate intake translates into beneﬁcial clinical outcome. A

subsequent analysis of the MDRD study found no impact of

low phosphate intake as compared with hig her intake on car-

diovascular disease or all-cause mortalit y.

It needs to be noted

that in this study baseline phosphate levels were normal on

average, so results are possibly not applicable to CKD patients

with progressively or persistently elevated serum phosphate

(see rationale for Recommendation 4.1.5).

Taken together, the key insights from these data were: (i)

the association between serum phosphate and cli nical

outcome is not monotonic; (ii) there is a lack of demon-

strated efﬁcacy of phosphate binders for lowering serum

phosphate in patients with CKD G3a to G4; (iii) the safety of

phosphate binders in this population is unproven; and (iv)

there is an absence of data showing that dietary phosphate

restriction improves clinical outcomes. Consequently, the

Work Group has abandoned the previous suggestion to

maintain phosphate in the normal range, instead suggesting

that treatment be focused on patients with hyper-

phosphatemia. The Work Group recognizes that preventing,

rather than treating, hyperphosphatemia may be of value in

patients with CKD G3a to G5D, but acknowledges that current

data are inadequate to support the safety or efﬁcacy of such an

approach and encourages research in this speciﬁc area.

Only 2 RCTs have examined phosphate-lowering therapy in

children with CKD or on dialysis;

64,65

due to the low number

of patients and short follow-up, both studies did not meet

literature inclusion criteria set a priori together with the

evidence review team (ERT). The ﬁrst RCT examined

biochemical endpoints only and showed equivalent phosphate

control with calcium acetate and sevelamer hydrochloride in

an 8-week cross-over trial.

In the second, 29 children were

randomized to different combinations of phosphate binders

and vitamin D analogs; bone biopsies suggested that the

sevelamer group had reduced bone formation versus baseline

at 8-month follow-up, but numbers were too small for

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Kidney International Supplements (2017) 7, 1–59

comparison versus the calcium carbonate–treated group.

Several studies in children on dialysis have shown an associ-

ation between high phosphate levels and increased vessel

thickness,

66–68

vessel stiffness

68,69

and CAC.

67,68,70,71

In young

adults on dialysis, the CAC score was shown to double within

20 months, and progression was associated with higher serum

phosphate levels.

Research recommendations

 RCTs for controlling hyperphosphatemia in patients with

CKD G3a to G5D, with appropriate follow-up and power,

should be conducted to assess various phosphate-lowering

therapy strategies for reducing the incidence of patient-

level endpoints (e.g., CKD progression) in children and

adults.

 RCTs of low and high dietary phosphate intake in patients

in CKD G3a to G5 should be conducted to test the hy-

pothesis that high dietary phosphate intake increases car-

diovascular risk either directly or indirectly through

induction of FGF23.

 If the feasibility of a placebo-controlled trial is threatened

due to perceived lack of equipoise (i.e., “unethical” to not

lower elevated serum phosphate levels, despite the lack of

high-quality data), a prospective trial comparing 2 different

phosphate targets in patients with CKD G3 a to G5D is

encouraged.

 RCTs should be conducted in normophosphatemic CKD

patients in order to test the hypothesis that active

compensatory mechanisms to counter balance increased

phosphate intake (such as increases in FGF23 and PTH) are

associated with poorer clinical outcome, des pite compara-

ble serum phosphate concentration. Interventions could

include dietary phosphate restriction, phosphate-binder

therapy, novel compounds to limit phosphate uptake, or a

combination thereof.

4.1.3: In adult patients with CKD G3a–G5D , we suggest

avoiding hypercalcemia (2C). In children with CKD

G3a–G5D, we suggest maintaining serum calcium in

the age-appropriate normal range (2C).

Rationale

As is the case for phosphate, novel epidemiological evidence

linking higher calcium concentrations to increased

mortality in adults with CKD has accumulated since the

2009 KDIGO CKD-MBD guideline (Supplementary

Tables S49–S50, S52–S55).

42–44,47,50,60,72–74

Moreover, and in

addition to previous observations,

novel studies link higher

concentrations of serum calcium to nonfatal cardiovascular

events.

75,76

This consistency justiﬁes the change of this

recommendation from 2D to 2C, although the overall evi-

dence base remains limited due to the lack of prospective

controlled trial data.

Hypocalcemia is a classical feature of untreated CKD, in

part secondary to diminished gastrointestinal (GI) uptake of

calcium due to vitamin D deﬁciency.

Hypocalcemia

contributes to the pathogenesis of secondary hyperparathy-

roidism (SHPT) and renal osteodystrophy. Therefore, the

previous recommendation suggested maintaining serum cal-

cium in the normal range, including the correction of hy-

pocalcemia. A more recent retrospective observational

analysis of a large dialysis cohort conﬁrmed the association

between hypocalcemia and mortality risk.

Two other recent

obser vations, however, raised doubt within the KDIGO

guideline Work Group about the generalizabilit y of the sug-

gestion to correct hypocalcemia. The ﬁrst is the potential

harm for some adults associated with a positive calcium

balance (while serum calcium levels do not necessarily reﬂect

calcium balance).

78,79

The second observation is that the

prevalence of hypocalcemia may have increased after the

introduction of calcimimetics (cinacalcet) in patients on

dialysis.

38,80,81

The clinical implications of this increased

incidence of low calcium due to the therapeutic institution of

a calcimimetic is uncertain, but may be less harmful. With

regard to the intention-to-treat (ITT) population of the

EVOLVE trial, no negative signals were associated with the

persistently low serum calcium levels in the cinacalcet arm of

the trial. Retaining the 2009 KDIGO Guideline on this issue

would support the concept that patients developing hypo-

calcemia during calcimimetic treatment require aggressive

calcium treatment. Given the unproven beneﬁts of this

treatment and the potential for harm, the Work Group

emphasizes an individua lized approach to the treatment of

hypocalcemia rather than recommending the correction of

hypocalcemia for all patients. However, signiﬁcant or symp-

tomatic hypocalcemia should still be addressed. Symptomatic

or severe hypocalcemia may beneﬁt from correction to

prevent adverse consequences such as bone disease, hyper-

parathyroidism, and QTc interval prolongation.

Childhood and adolescence are critical periods for bone

mass accrual: in healthy children the calcium content of the

skeleton increases from w25 g at birth to w1000 g in adults,

and w25% of total skeletal mass is laid down during the 2-

year interval of peak height velocity.

The mean calcium

accretion rate in healthy pubertal boys and girls peaks at 359

and 284 mg/d, respectively.

The updated evidence review

identiﬁed a prospective cohort study in 170 children

and adolescents with CKD G2 to G5D (Supplementary

Table S49–S50, S52 – S55) that showed that lower serum cal-

cium levels were independently associated with lower cortical

volumetric BMD Z-scores.

Over 1 year of follow-up in 89

children, a change in the cortical BMD Z-score positively

correlated with baseline calcium (P ¼ 0.008) and increase in

calcium (P ¼ 0.002) levels, particularly in growing children.

During the 1-year follow-up, 6.5% of children sustained a

fracture. Notably, a lower cortical BMD Z-score predicted

future fractures: the HR for fracture was 1.75 (95% CI: 1.15–

2.67; P ¼ 0.009) per SD decrease in baseline BMD.

Thus, the Work Group recognizes the higher calcium re-

quirements of the growing skeleton and suggests that serum

calcium levels are maintained in the age-appropriate normal

range in children and adolescents.

www.kisupplements.org chapter 4.1

Kidney International Supplements (2017) 7, 1–59 27

Research recommendations

 Calcium balance study in dialysis patients should be pur-

sued at baseline versus after start of calcimimetic treatment

(with and without calcium supplementation, adaptations in

dialysate calcium concentrations, and/or concomitant active

vitamin D analog treatment).

 RCTs in children and adolescents w ith CKD should be

conducted to determine whether calcium-based phosphate

binders, as compared with calcium-free phosphate binders,

promote bone accrual (as measured by bone density and

structure, and fractures), and to determine the impact of

phosphate binders on arterial calciﬁcation in the context of

the high calcium requirement of growing bones.

4.1.4: In patients with CKD G5D, we suggest using a dial-

ysate calcium concentration between 1.25 and 1.50

mmol/l (2.5 and 3.0 mEq/l) ( 2C).

Rationale

Based on the available evidence, the 2009 Work Group

considered that a dialysate calcium concentration of 1.25

mmol/l (2.5 mEq/l) would yield neutral calcium balance, but

this statement was subsequently challenged by kinetic

modeling studies.

Two relevant new RCTs are available concerning this topic

(Supplementary Tables S13–S18).

85,86

In the study by Spa-

sovski et al.,

the effects of 2 different dialysate calcium

concentrations were examined in patients with adynamic

bone disease, and the lower dialysate calcium (1.25 mmol/l

[2.5 mEq/l]) was found to improve bone and mineral pa-

rameters compared with the higher concentration of 1.75

mmol/l (3.5 mEq/l). Their data conﬁrmed the results of

previous papers and also support individualization of dialy-

sate calcium concentrations as recommended previously by

the Work Group. The comparator in this study, however, was

a high dialysate calcium concentration of 1.75 mmol/l

(3.5 mEq/l), leaving open the possibility that lower levels

of dialysate calcium (>1.25 mmol/l [2.5 mEq/l] but

<1.75 mmol/l [3.5 mEq/l]) would be equally beneﬁcial.

Ok et al. randomized 425 HD patients with iPTH levels

< 300 pg/ml (32 pmol/l) and baseline dialysate calcium

concentrations between 1.5 and 1.75 mmol/l (3.0–3.5 mEq/l)

to concentrations of either 1.25 mmol/l (2.5 mEq/l) or

1.75 mmol/l (3.5 mEq/l).

Lowering dialysate calcium levels

slowed the progression of CAC and improved biopsy-proven

bone turnover (low bone turnover decreased from 85.0% to

41.8%) in this cohort of patients on HD. In this trial, the

comparative effects of a 1.5 mmol/l (3.0 mEq/l) calcium

concentration were not addressed.

Retrospective observational data by Brunelli et al.

sug-

gested safety concerns (i.e., heart failure events, hypotension)

associated with the default use of dialysate calcium

concentrations < 1.25 mmol/l (2.5 mEq/l). Conversely, at the

high end of dialysate calcium concentration (1.75 mmol/l

[3.5 mEq/l]), Kim et al.

found increased risk for all-cause

mortality and cardiovascular or infection-related

hospitalization in incident HD patients for hig h dialysate cal-

cium. However, observational studies, in general, may not be

sufﬁcient to warrant changes to treatment recommendations.

Patients with mild hypocalcemia might potentially even

have a positive calcium mass transfer when dialyzed against a

concentration of 1.25 mmol/l (2.5 mEq/l), but no such

metabolic balance studies exist. Taken together, the Work

Group felt that this recommendation remains valid as written

in 2009 and that there is no new evidence justifying a change

in the wording. However, additional studies of better quality

are now available, and as such the evidence grade has been

upgraded from 2D to 2C.

Research recommendation

 Calcium balance studies should be performed with non–

calcium-containing versus calcium-containing phosphate

binders, and vitamin D sterols versus cinacalcet in different

calcium dialysate settings. These studies should include

children and adolescents and assess calcium balance in the

context of skeletal calcium accrual.

4.1.5: In patients with CKD G3a–G5D, decisions about

phosphate-lowering treatment should be based on

progressively or persistently elevated serum phos-

phate (Not Graded).

Rationale

With regard to 2017 Recommendation 4.1.5 (formerly 2009

Recommendation 4.1.4), the previous 2009 KDIGO CKD-

MBD guideline commented that available phosphate

binders are all effective in the treatment of hyper-

phosphatemia, and that there is evidence that calciu m-free

binders may favor halting progression of vascular calciﬁca-

tions compared with calcium-containing binders.

Concerns

about calcium balance and uncertainties about phosphate

lowering in CKD patients not on dialysis, coupled with

additional hard endpoint RCTs and a systematic review

(comparing effects on mortality for calcium-free vs. calcium-

containing phosphate binders), resulted in the decision to

reevaluate this recommendation.

Based on new pathophysiological insights into phosphate

regulation and the roles of FGF23 and (soluble) Klotho in

early CKD, clinical studies had been initiated investigating

phosphate-lowering therapies in CKD patients in whom

hyperphosphatemia had not yet developed. Here, the

concept of early phosphate retention, possibly represented

by increases in FGF23 serum or plasma concentrations, was

the focus of scientiﬁc attention. The most notable RCT

was performed by Block et al.

In this study, predialysis

patients (CKD G3b–G4) with mean baseline serum phos-

phate concentrations of 4.2 mg/dl (1.36 mmol/l) were

exposed to 3 different phosphate binders (sevelamer,

lanthanum, or calcium acetate) versus matching placebos, in

order to explore effects on serum phosphate levels, urinary

phosphate excretion, serum FGF23 levels, vascular calciﬁca-

tion, bone densit y, etc., w ith a 9-month follow-up

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Kidney International Supplements (2017) 7, 1–59

(Supplementary Tables S19–S24). While there was a small

decrease in serum phosphate concentrations (for those allo-

cated to active treatment) and a 22% decrease in urinary

phosphate excretion (sugge sting adherence to therapy), no

differences in changes in FGF23 levels were observed versus

placebo, as already discussed in Recommendation 4.1.2. In

contrast to the authors’ expectations, progression of coronary

and aortic calciﬁcation was obser ved with active phosphate-

binder treatment, while there was no progression in the

placebo arm. Subgroup analysis suggested that this negative

effect was accounted for by calcium acetate treatment, but

neither calcium-free binders were superior to placebo with

regard to this surrogate endpoint.

This study was further supported by another meta bolic

study in a small group of patients with CKD G3b to G4, in

whom the addition of 3  500 mg calcium carbonate to meals

containing 1 g of calcium and 1.5 g of phosphorus per day did

not affect baseline neutral phosphate balance, but caused a

signiﬁcant ly positive calcium balance,

at least in the short

term. Due to its low number of patients and short duration , this

study did not ful ﬁll the predeﬁned inclusion criteria for full

evidence review. Nevertheless, in the Work Group’s opinion,

this well-performed metabolic study may present a plausible

and relevant safety signal, and thus should be mentioned here.

Both Block et al.

and Hill et al.

studied subjects with

essentially normal phosphate concentrations at baseline.

Thus, there may be 2 key messages from these studies. First,

normophosphatemia may not be an indication to start

phosphate-lowering treatments. Second, the concept that not

all phosphate binders are interchangeable must be noted.

Whether disproportional elevations in FGF23 serum con-

centrations may become a signal in order to start phosphate-

lowering therapies in early CKD will need to be investigated

in appropriate trial settings.

Considering these insights, especially regarding CKD pa-

tients not on dialysis, and as already suggested in the rationale

of Recommendation 4.1.2, the Work Group felt that the

updated guideline should clarify that phosphate-lowering

therapies may only be indicated in the event of “progressive

or persistent hyperphosphatemia,” and not to prevent

hyperphosphatemia. When thinking about risk-beneﬁt ratios,

even calcium-free binders may poss ess a potential for harm

(e.g., due to side effects such as GI distress and binding of

essential nutrients). The broader term “phosphate-lowering

therapies” instead of phosphate-binding agents was intro-

duced, because all possible approaches (i.e., binders, diet, and

dialysis) can be effective and because phosphate transport

inhibitors may expand the therapeutic armamentarium in the

not-so-distant future.

There have been no additional data since 2008 with regard

to “safe” phosphate level thresholds or hard endpoints (i.e.,

mortality, cardiovascular events, and progression of CKD)

from RCTs treating patients toward different phosphate (or

FGF23) targets. The previous qualiﬁers (presence of other

components of CKD -MBD, concomitant therapies, side effect

proﬁle) were deleted because the Work Group thought that

their consideration was self-evident. Diurnal variation of

serum phosphate concentrations was discussed as another

pathophysiologically relevant aspect of evaluation. While it was

felt that these variations in daily phosphate levels do affect the

accuracy of evaluations, the notion of variable timing for blood

sampling was considered unfeasible in clinical routine practice

and therefore not included in the guideline text.

Research recommendations

 Prospective clinical trials studying the value of levels of

FGF23 (and possibly soluble Klotho) as indicators for

establishing phosphate-lowering therapies should be un-

dertaken; desirable endpoints should include: CKD pro-

gression, cardiovascular calciﬁcation, cardiovascular events,

and mortality.

 See research recommendations following Recommendation

4.1.2.

4.1.6: In adult patients with CKD G3a–G5D receiving

phosphate-lowering treatment, we suggest restrict-

ing the dose of calcium-based phosphate binders

(2B). In children with CKD G3a–G5D, it is reason-

able to base the choice of phosphate-lowering

treatment on serum calcium levels (Not Graded).

Rationale

The Work Group thought that the new available data and the

changes applied to 2009 Recommendation 4.1.4 (now

Recommendation 4.1.5) suggested a need to revise the 2009

Recommendation 4.1.5 (now Recommendation 4.1.6). The

balance study by Hill et al.

supported results reported by

Spiegel and Brady

in normophosphatemic adults with CKD

G3b to G4, which suggested potential harms of liberal cal-

cium exposure in such cohorts, but due to their study designs

were not eligible for full evidence review by the ERT. The RCT

by Block et al.

in a much larger, similar cohort and 2

additional RCTs in hyperphosphatemic CKD patients have

added hard endpoint data when prospectively comparing the

calcium-free binders, mostly sevelamer, with calcium-

containing binders in predialysis or dialysis adult patients,

respectively (Supplementary Tables S19–S24)

59,89,90

These

results were also supported by results from recent systematic

reviews;

91–94

however, because the evidence review team

(ERT) had considered all includ ed studies separately and

individually during this updat e process, the se meta-analyses

did not have addit ional bearing on the decision making by

the Work Group.

Overall, the Work Group determined that there is new

evidence suggesting that excess exposure to calcium through

diet, medications, or dialysate may be harmful across all GFR

categories of CKD, regardless of whether other cand idate

markers of risk such as hypercalcemia, arterial calciﬁcation,

adynamic bone disease, or low PTH levels are also present.

Therefore, these previous qualiﬁers in the 2009 KDIGO

recommendation were deleted, acknowledging that they may

still be valid in high-risk scenarios.

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Kidney International Supplements (2017) 7, 1–59 29

Di Iorio et al. reported RCTs in both predialysis and dialysis

patients showing signiﬁcant survival beneﬁts over a 3-year

interval for patients treated with sevelamer versus calcium-

containing binders (Supplementary Tables S19–S24).

89,90

Both studies w ere analyzed by the ERT and were

graded as relevant RCTs with a moderate risk of bias

(Supplementary Tables S23 and S24), leading to a 2B

recommendation. Overall, the ﬁndings from all identiﬁed

studies seemed to show either a potential for bene ﬁtoran

absence of harm associated with calcium-free phosphate-

binding agents to treat hyperphosphatemia compared with

calcium-based agents (Supplementary Tables S20 and S21).

The wording in Recommendation 4.1.6 of “restricting the

dose of calcium-based phosphate binders” was retained from

previous 2009 Recommendation 4.1.5; however, the qualiﬁer

that the recommendation applies to patients with persistent

or recurrent hypercalcemia was removed. Given the fact of 2

reasonably large RCTs demonstrating mortality risks associ-

ated w ith calcium-containing binder treatment, it was debated

within the Work Group whether the recommendation should

be stronger, possibly using “avoid” instead of “restrict.” How-

ever, some members of the Work Group felt that available

evidence does not conclusively demonstrate that calcium-free

agents are superior to calcium-based agents. In addition,

none of the studies provided sufﬁcient dose threshold infor-

mation about calcium exposure, nor did they give information

on the safety of moderately dosed calcium-containing binders

in combination therapies. Finally, because KDIGO guidelines

are intended for a global audience and calcium-free agents are

not available or affordable in all jurisdictions, recommending

against the use of calcium-based binders would imply that no

treatment is preferable to using calcium-based agents. Despite

the understandable clinical desire to have numeric targets and

limits, the Work Group could not make an explicit recom-

mendation about a maximum dose of calcium-based binders,

preferring to leave this to the judgment of individual physicians

while acknowledging the potential existence of a safe upper

limit of calcium dose. Of note, 2 short-term studies in stable

CKD patients not on dialysis found that positive calcium

balance may occur with total intakes as low as 800 and

1000 mg/d, respectively.

60,79

Such short-terms results are

informative but not conclusive, and decisions must be indi-

vidualized for each patient.

The recent availability of iron-containing phosphate binders

was discussed within the Work Group but did not affect the

recommendations given the absence of data on long-term pa-

tient-centered outcomes in the published phase 3 trials.

95–97

All of the above studies were limited to adults. Importantly,

concerns regarding the adverse effects of excess exposure to

calcium through diet, medications, or dialysate may not be

generalizable to children. Skeletal growth and development are

characterized by rapid calcium accrual,

as described in

Recommendation 4.1.3. Furthermore, recent studies demon-

strated that bone accrual continues into the third decade of

life in healthy individuals, well beyond cessation of linear

growth.

98,99

Of relevance to adolescents with CKD, bone accrual

between ages 18 and 24 was especially pronounced among those

with late puberty.

100

Therefore, studies of calcium- and non–

calcium-containing binders and other therapies that impact

calcium balance should consider the needs of the developing

skeleton. The observation that serum calcium levels were

positively associated with increases in BMD in children with

CKD, and that this association was signiﬁcantly more pro-

nounced with greater linear growth velocity,

illustrates the

unique needs of the growing skeleton (see Recommendation

4.1.3). Lastly, a recent prospective cohort study in 537 children

with predialysis CKD demonstrated that phosphate-binder

treatment (calcium-based in 82%) was associated with

decreased risk of incident fractures (HR: 0.37, 95% CI: 0.15–

0.91), independent of age, sex, eGFR, and PTH levels.

101

Although this study did not meet the criteria for inclusion in

the evidence review, it highlights the need for additional studies

in children. There is a lack of data suggesting adverse effects of

excess exposure to calcium through diet, medications or dial-

ysate in children. The Work Group concluded that there was

insufﬁcient evidence to change this recommendation in chil-

dren, who may be uniquely vulnerable to calcium restriction.

Research recommendations

 Calcium and phosphate balance studies should be con-

ducted using different calcium-based binder doses and

combinations with calcium-free binders in hyper-

phosphatemic patients across all GFR categories of CKD.

 RCTs assessing the effect of iron-based phosphate binders on

patient-centered and surrogate outcomes across all GFR cat-

egories of CKD should be undertaken; comparators should be

placebo, calcium-based binders, or other calcium-free binders.

 RCTs using phosphate transport inhibitors (e.g., nicotin-

amide,

102

tenapanor

103

)as“add-on” treatments in patients

with resistant hyperphosphatemia should be investigated.

 Prospective clinical and balance studies should examine the

role of magnesium as a phosphate binder, with regard to

patient-centered outcomes, calciﬁcation, and cardiovascular

event rates.

 RCTs in children and adolescents with CKD should be

conducted to determine whether calcium-based phosphate

binders, as compared with calcium-free phosphate binders,

promote bone accrual (as measured by bone density and

structure, and fractures), and to determine the impact of

phosphate binders on arterial calciﬁcation in the context of

the high calcium requirement of growing bones.

4.1.8: In patients with CKD G3a–G5D, we suggest limiting

dietary phosphate intake in the treatment of hyper-

phosphatemia alone or in combination with other

treatments (2D). It is reasonable to consider phos-

phate source (e.g., animal, vegetable, additives) in

making dietary recommendations (Not Graded).

Rationale

There was no general controversy toward the 2009 KDIGO

CKD-MBD Guideline on dietary phosphate restriction as an

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Kidney International Supplements (2017) 7, 1–59

important standard of practice to lower elevated phosphate

levels, but previous 2009 recommendatio n 4.1.7 (now 4.1.8)

on limiting dietary phosphate intake was considered vague,

especially with regard to new evidence on different phosphate

and phosphoprotein sources. Within this guideline update,

predeﬁned criteria on study duration and cohort size pro-

hibited inclusion of some study reports for full evidence

review. Nevertheless, the Work Group felt that some of these

reports presented safety signals demanding a brief discussion.

As summar ized in Supplementary Tables S25–S30 , only 2

studies on this topic in dialysis patients fulﬁlled the evidence

review criteria.

104,105

Both studies investigated the impact of

intensiﬁed versus routine dietary counseling on serum

phosphate levels after a follow-up of 6 months. In both

studies, the intensiﬁed counseling groups more successfully

reached the laboratory targets; however, no hard endpoints

were documented. Accordingly, the quality of evidence

for outcome was rated as very low. Similarly, a recent

Cochrane review concluded that there is low-quality evidence

that dietary interventions positively affect CKD-MBD

biomarkers.

106

The daily phosphate intake for a typical American diet

varies with age and gender. A majority of young to middle-

aged men take in more than 1600 mg/d, whereas women in

the same age groups take in about 1000 mg/d.

107

On a

global scale, there are quite signiﬁcant differences in diet

compositions to be considered. Estimates of dietary phos-

phate from food composition tables likely underestimate the

phosphate content because they may mostly reﬂect the

“natural” phosphate content of foods that are highest (e.g.,

dairy products, meats, poultry, ﬁsh, and grains). There are

actually 3 major sources of phosphates: natural phosphates

(as cellular and protein constituents) contained in raw or

unprocessed foods, phosphates added to foods during pro-

cessing, and phosphates in dietary supplements/medications.

Russo et al.

108

assessed the effect of dietary phosphate

restriction on the progression of CAC. This study was not

designed to compare the efﬁcacy of phosphate binders against

dietary phosphate restriction. However, they found that di-

etary phosphate restriction alone did not lead to a decrease in

urinary phosphate excretion, nor did it prevent progression of

CAC. However, the urine data cast doubt on compliance with

the diet, and there was no control group on a normal or high-

phosphate diet.

Aggressive dietary phosphate restriction is difﬁcult because

it has the potential to compromise adequate intake of other

nutrients, especially protein. Zeller et al.

109

showed that the

restriction of dietary protein and phosphate could be achieved

with maintenance of good nutrition status with intense

counseling. They demonstrated that dietary protein/phos-

phate restriction resulted in a signiﬁcant reduction in urinary

phosphate excretion when compared with a control diet.

Dietary supplements and over-the-counter or prescription

medications are hidden sources of phosphate. They may

contain phosphate salts within their inactive ing redients. The

data on the amount of phosphate in oral medications and

vitamin/mineral supplements is limited, but they have the

potential to contribute signiﬁcantly to the ph osphate load

considering the number of medications CKD patients are

required to take.

110,111

Another consideration for modiﬁcation of dietary phos-

phate and control of serum phosphate is the “bioavailability”

of phosphorus in different foods based on the form—organic

versus inorganic sources of phosphate. Animal- and plant-

based foods contain the organic form of phosphate. Food

additives contain inorganic phosphate. About 40% to 60% of

animal-based phosphate is absorbed, depending on the GI

vitamin D receptor activations. Plant phosphate, mostly

associated with phytates, is less absorbable (generally 20%–

50%) in the human GI tract. It be hooves the dietitian and

other interdisciplinary staff to include education about the

best food choices as they relate to absorbable phosphate.

Additionally, it is important for patients to be guided toward

fresh and homemade foods rather than processed foods in

order to avoid additives.

Organic phosphate in such plant foods as seeds and

legumes is less bioavailable because of limited GI absorption

of phytate-based phosphorus. In this context, Moe et al.

recently demonstrated that a vegetable-based diet showed

signiﬁcantly lower phosphate absor ption versus a meat-based

diet with similar phosphate content. Inorganic phosphate is

more readily absorbed, and its presence in additive-laden

processed, preserved, or enhanced foods or soft drinks is

likely to be underreported in nutrient databases. Hence, the

phosphate burden from food additives is disproport ionately

high relative to natural sources that are derived from organic

(animal and vegetable) food proteins, and these additives are

almost completely absorbed in the GI tract. For example,

Benini et al. showed that foods that contain phosphate

additives have a phosphorus content nearly 70% higher than

those that do not contain additives.

112

Sherman and Mehta

also demonstrated that phosphate contents between unpro-

cessed and processed meat or poultry may differ by more than

60%, and thus the absorbable phosphate may even be 2 to 3

times higher per weight in processed food.

113

In contrast, many of the foods that are traditionally labeled

as high phosphorus may be more acceptable with the

knowledge that the phosphorus is absorbed more slowly and

not as efﬁciently. For example, beans and nuts have always

been listed as very high in phosphorus; however, considering

their lower absorption rate, they may be acceptable as protein

sources, if they are not too high in other nutrients such as

potassium.

The amount of phosphorus contributed by food intake is

increasing with current and new processing practices that

utilize phosphorus-containing ingredients, including popular

foods such as restructured meats (formed, pressed, rolled, and

shaped for ease of preparation and ingestion), processed and

spreadable cheeses, “instant” products (puddings, sauces),

frozen breaded products, and soft drinks.

114

Phosphate ad-

ditives are also widely used in fast foods and convenience

foods that are fully or partially pre-made or instant.

110

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Kidney International Supplements (2017) 7, 1–59 31

Various types of nutrition education have had mixed

results for control of serum phosphate. Intense education

focusing on phosphate intake has been useful to reduce

retention in some studies.

105,115

A simple education tool on

how to read food labels and “look for PHOS” (the study

acronym) was successful in helping dialysis patients reduce

their phosphate intake. A magnifying glass was provided to

help patients read labels,

116

as well as instructions available to

guide “better choices” in fast-food restaurants. Other studies

have had less favorable results.

117

Taken together, these insights led the Work Group to the

decision to not change the principal recommendation, but to

add a qualiﬁer statement suggesting that phosphate sources

should be better substantiated and patient education should

focus on best choices. Finally, it must be emphasized that

efforts to restr ict dietary phosphate must not compromise

adequate protein intake.

Research recommendations

 RCTs comparing low, medium, and high phosphate intake on

phosphate metabolism and homeostasis, including responses

concerning FGF23, PTH, calciﬁcation, and CKD progression,

in patients in CKD G3b to G4, should be performed.

 In such study designs, the role of the phosphate quality

should be studied: vegetable versus meat versus additive

sources.

 Kinetic and balance studies on the uptake of phosphate

additives in dialysis patients should be per formed.

 Prospective trials identifying the most effective phosphate-

lowering approach (beneﬁt-risk-cost ratio) should be per-

formed across all CKD GFR categories—such as how best

to combine phosphate binders, phosphate transport in-

hibitors and diet (plus dialysis treatment in CKD G5D)—

with appropriate patient-centered and surrogate endpoints

in mind (e.g., calciﬁcation, FGF23 levels, and LVH) .

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Kidney International Supplements (2017) 7, 1–59

Chapter 4.2: Treatment of abnormal PTH levels in

CKD-MBD

4.2.1: In patients with CKD G3a–G5 not on dialysis, the

optimal PTH level is not known. However, we suggest

that patients with levels of intact PTH progressively

rising or persistently above the upper normal limit

for the assay be evaluated for modiﬁable factors,

including hyperphosphatemia, hypocalcemia, high

phosphate intake, and vitamin D deﬁciency (2C).

Rationale

The pathogenesis of SHPT is complex and driven by several

factors, including vitamin D deﬁciency, hypocalcemia, and

hyperphosphatemia. Elevated FGF23 concentrations exacer-

bate SHPT through further reductions in 1,25(OH)

vitamin

D (calcitriol) levels. Calcitriol deﬁciency results in decreased

intestinal absorption of calcium and may lead to hypocalce-

mia, a major stimulus for PTH secretion. This leads to

parathyroid cell proliferation, contributing to SHPT. The

incidence and severity of SHPT increases as kidney function

declines and can lead to signi ﬁcant abnormalities in bone

mineralization and turnover.

The 2009 KDIGO CKD-MBD Guideline recommended

addressing modiﬁable risk factors for all patients with a PTH

level above the upper limit of normal for the assay used.

Unfortunately, there is still an absence of RCTs that deﬁne

an optimal PTH level for patients with CKD G3a to G5, or

clinical endpoints of hospitalization, fracture, or mortality.

The Work Group felt that modest increases in PTH may

represent an appropriate adaptive response to declining kid-

ney function, due to its phosphaturic effects and increasing

bone resistance to PTH,

118

and have revised this statement to

include “persistently” above the upper normal PTH level as

well as “progressively rising” PTH levels, rather than simply

“above the upper normal limit” as in the 2009 KDIGO

Guideline. Thus, treatment should not be based on a single

elevated value.

Although the optimal PTH is not known, the Work Group

felt that rising PTH levels in CKD G3a-G5 warrant exami-

nation of modiﬁable factors , such as vitamin D insufﬁci ency

or deﬁ ciency, hypocalcemia, and hyperphosphatemia. In the

interval since the 2009 KDIGO Guideline, 1 eligible RCT

examined the impact of cholecalciferol supplementation

(Supplementary Table S31) and 3 examined the impact of

phosphate binders on PTH levels in the nondialysis

CKD population. Oksa et al.

119

reported an RCT of a

high (20,000 international units [IU]/wk) versus low

(5,000 IU/wk) dose of cholecalciferol supplementation in 87

adults with CKD G2 to G4 (Supplementary Tables S31–S36).

Serum 25(OH) v itamin D levels increased signiﬁcantly in

both groups and were signiﬁcantly greater in the high-dose

arm at the completion of the 12-month intervention. PTH

levels decreased signiﬁcantly in both groups; however, the

PTH levels did not differ signiﬁcantly between groups at the

completion of the study. In this context, Recommendation

3.1.3 on native vitamin D supplementation remains valid

from the previous 2009 guideline publication.

Three recent RCTs in the nondialysis CKD population

evaluated phosphate binders and their effects on surrogate

endpoints, such as vascular calciﬁcation, arterial compliance,

left ventricular mass, and BMD, as well as calcium, phosphate,

and PTH levels. Two RCTs compared sevelamer with placebo

(Supplementary Tables S31 – S36), the ﬁrst in 109 nondiabetic

CKD G3a to G3b patients

120

and the second in 117 CKD

patients with a mean eGFR of 36  17 ml/min/1.73 m

121

The studies were conducted over 36 weeks and 24 months,

respectively, and neither study demonstrated signiﬁcant dif-

ferences in PTH levels between sevelamer and placebo groups.

Another RCT involving 148 CKD patients (eGFR: 20–45 ml/

min/1.73 m

) compared placebo w ith 3 different phosph ate

binders (calcium-based, lanthanum, and sevelamer) over a

9-month per iod and reported that PTH levels remained stable

in those on active therapy (combined phos phate-binder

groups) but increased by 21% in the placebo group

(P ¼ 0.002)

(Supplementary Table S33).

In the updated recommendation, an additional modiﬁable

risk factor, “high phosphate intake,” was added because of the

increasing recognition that excess phosphate intake does not

always result in hyper phosphatemia, especially in early CKD,

and that high phosphate intake may promote SHPT. While

dietary phosphate, whether from food or additives, is modi-

ﬁable, better methods for assessment of dietary phosphate

intake are required.

4.2.2: In adult patients with CKD G3a–G5 not on dialysis,

we suggest that calcitriol and vitamin D analogs not

be routinely used (2C). It is reasonable to reserve the

use of calcitriol and vitamin D analogs for patients

with CKD G4–G5 with severe and progressive

hyperparathyroidism (Not Graded).

In children, calcitriol and vitamin D analogs may be

considered to maintain serum calcium levels in the

age-appropriate normal range (Not Graded).

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Kidney International Supplements (2017) 7, 1–59 33

Rationale

Prevention and treatment of SHPT is important because

imbalances in min eral metabolism are associated with CKD-

MBD and higher PTH levels are associated with increased

morbidity and mor tality in CKD patients. Calcitriol and other

vitamin D analogs have been the mainstay of treatment of

SHPT in individuals with CKD for many decades. The 2009

KDIGO CKD-MBD Guideline summarized multiple studies

demonstrating that administratio n of calcitriol or vitamin D

analogs (such as paricalcitol, doxercalciferol, and alfacalcidol)

resulted in suppression of PTH levels.

However, there was a

notable lack of trials demonstrating improvements in patient-

centered outcomes.

Multiple well-conducted RCTs cited in the 2009 guideline

reported beneﬁts of calcitriol or vitamin D analogs in treating

SHPT in patients with CKD G3a to G5; 2 primarily involved

biochemical endpoints,

122,123

and 2 evaluated bone histo-

morphometry.

124,125

Despite the lack of hard clinical end-

points, these data led to the original recommendation to treat

elevated PTH with calcitriol or vitamin D analogs early in

CKD to prevent parathyroid hyperplasia and its skeletal

consequences (2C). Although beneﬁts were predominantly

related to suppression of SHPT, adverse effects of hypercal-

cemia were noted to be of concern in the 2009 KDIGO CKD-

MBD Guideline.

The effects of vitamin D therapy on biochemical endpoints

in CKD have been previously documented, especially with

regard to reduced PTH levels. Numerous previous studies

have reported signiﬁcant reductions of PTH levels with cal-

citriol or vitamin D analogs in CKD G3a to G3b and G4 when

compared with placebo

123,125,126

and recent RCTs have also

demonstrated that vitamin D treatment effectively lowers

PTH levels in CKD G3a to G5.

127,128

Additional RCTs of calcitriol or vitamin D analog therapy

have been published since the 2009 KDIGO CKD-MBD

Guideline (Supplementary Tables S37–S42). Two, in partic-

ular, demonstrated a signiﬁcantly increased risk of hypercal-

cemia in patients treated with paricalcitol, compared with

placebo, in the absence of beneﬁcial effects on surrogate

cardiac endpoints, as detailed below.

127,128

These results,

combined with the opinion that moderate PTH elevati ons

may represent an appropriate adaptive response, led the Work

Group to conclude that the risk-beneﬁt ratio of treating

moderate PTH elevations was no longer favorable and that

the use of calcitriol or vitamin D analogs should be reserved

for only severe and progressive SHPT.

The 2 recent RCTs were designed to detect potential beneﬁts

of calcitriol or vitamin D analogs on cardiac structure and

function, as measured by magnetic resonance imaging (MRI),

in adults with CKD (Supplementary Tables S37–S42). The

rationale for these studies is that calcitriol and vitamin D an-

alogs act through the vitamin D receptor (VDR) to exert their

beneﬁts to inhibit PTH secretion, and the VDR is also present

in many tissues and organs including vascular smooth muscle,

endothelial cells, and the heart. The key evidence for changes in

Recommendation 4.2.2 predominantly came from these trials.

The ﬁrst study was a double-blind RCT by Thadhani et al.

(the PRIMO study), where participants with CKD G3a to G4,

mild to moderate LVH, and PTH levels between 50 and 300

pg/ml (5.3–32 pmol/l) were assigned to placebo (n ¼ 112) or

paricalcitol (n ¼ 115) to test the primary hypothesis that

paricalcitol will reduce left ventricular mass index (LVMI)

over a 48-week interval.

128

Paricalcitol was administered at a

dose of 2

g/d, with protocol-speciﬁed dose reduction to

g/d, if the serum calcium was > 11 mg/dl (2.75 mmol/l).

Baseline PTH levels were approximately 1.5 times the upper

limit of normal. The ITT analysis revealed that paricalcitol did

not reduce LVMI, nor did it modify diastolic function. Of

subjects on paricalcitol, the mean serum calcium increased by

0.32 mg/dl (0.08 mmol/l) (95% CI: 0.19–0.45 mg/dl; 0.05–

0.11 mmol/l) versus a decrease by 0.25 mg/dl (0.06 mmol/l)

(95% CI: 0.37 to  0.12 mg/dl; 0.09 to –0.03 mmol/l) in

the placebo group. Hypercalcemia was deﬁned as 2 consec-

utive measurements of serum calcium > 10.5 mg/dl (> 2.63

mmol/l), and the number of patients requiring dose

reductions from 2

g/d to 1

g/d and episodes of

hypercalcemia were more common in the paricalcitol group

(22.6%) compared with the placebo (0.9%) group.

In the second key study, a double-blind RCT by Wang et al.

(the OPERA study), subjects with CKD G3a to G5, LVH, and

PTH $ 55 pg/ml (5.83 pmol/l) were randomly assigned to

receive paricalcitol (n ¼ 30) or placebo (n ¼ 30).

127

The

primary endpoint was change in LVMI over 52 weeks. Base-

line PTH levels were approximately twice the upper limit of

normal. Change in LVMI did not differ signiﬁcantly between

groups, nor did secondary outcomes such as measures of

systolic and diastolic function. The median (interquartile

range) changes in serum calcium were 0.08 mmol/l (0.32 mg/

dl) (95% CI: 0.02–0.16 mmol/l; 0.08–0.64 mg/dl) and 0.01

mmol/l (0.04 mg/dl) (95% CI: –0.06 to 0.05 mmol/l; –0.24 to

0.2 mg/dl) in the paricalcitol and placebo arms, respectively.

Hypercalcemia, deﬁned as any serum calcium > 2.55 mmol/l

(> 10.2 mg/dl), occurred in 43.3% and 3.3% of participants

in the paricalcitol and placebo arms, respectively. Of note,

70% of those who were hypercalcemic received concomitant

calcium-based ph osphate binders. Generally the hypercalce-

mia was mild and could be corrected by stopping the binder

without changing the paricalcitol dose.

Recent meta-analyses were largely conﬁrmatory and sup-

ported the hypercalcemia risk association with calcitriol and

vitamin D analogs.

129,130

The evidence review identiﬁed 2 RCTs comparing par-

icalcitol with calcitriol (Supplementary Tables S37–S42);

neither demonstrated differences in the incidence of hypercal-

cemia.

131,132

Coyne et al.

131

compared calcitriol (0.25

g/d)

with paricalcitol (1

g/d) in 110 patients with CKD G3a to G3b

and G4 and PTH > 120 pg/ml (12.7 pmol/l). The change in

PTH was comparable in the 2 arms (a decline of 52% vs. 46%)

over the 6-month trial, and the incidence of hypercalcemia was

very low in both groups (only 3 with paricalcitol and 1 with

calcitr iol). Further details regarding changes in biochemical

parameters are provided in Supplementary Tables S37–S42.

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Kidney International Supplements (2017) 7, 1–59

An alternative to calcitriol and its analogs is “nutritional”

vitamin D supplementation (cholecalciferol and ergo-

calciferol), which can also suppress PTH (especially in CKD

G3a–G3b) and decrease hypercalcemia because the nor mal

homeostatic loops that suppress the CYP27B remain intact.

However, no studies of sufﬁ cient duration were identiﬁed in

this evidence review, and thus this therapy remains unproven.

Several studies have assessed the effect of PTH-lowering

comparing nutritional vitamin D supple ments and calcitriol

or vitamin D analogs.

133,134

However, these studies were not

identiﬁed in this evidence review because of their short

duration.

The use of extended-release calcifediol, a novel vitamin D

prohormone, to correct low serum 25(OH) vitamin D levels

and lower PTH has also been recently studied. This agent

reduces the catabolism of both 25(OH) vitamin D and

1,25(OH)

vitamin D and increases levels of both. An RCT of

429 patients with CKD G3a to G3b and G4 published after our

guideline systematic rev iew reported at least a 10% reduction of

intact PTH levels in 72% of participants after 12 months, with

no signiﬁcant impact on calcium, phosphate, or FGF23

levels.

135

No patient-level outcomes were reported, and thus

this study did not impact the current recommendation.

All of the above studies were conducted in adults. A recent

Cochrane review examined vita min D therapy for bone dis-

ease in children with CKD G2 to G5 on dialysis.

136

Bone

disease, as assessed by changes in PTH levels, was improved

by all vitamin D preparations regardless of route or

frequency of administration. The prospective cohort study

demonstrated that high PTH levels were independently

associated with reduced cortical BMD Z-scores at baseline

(P ¼ 0.002) and 1-year follow-up (P < 0.001).

High PTH

levels are associated with CAC in children on dialysis.

67,68

The

Cochrane review has not shown any signiﬁcant difference in

hypercalcemia risk with vitamin D preparations compared

with placebo, but 1 study showed a signiﬁcantly greater risk of

hypercalcemia with i.v. calcitriol administration.

136

No dif-

ference in growth rates was detected between different

vitamin D analogs or use of oral or i.v. vitamin D treat-

ments.

136

As noted in Recommendation 4.1.3, the Work

Group recommended that serum calcium should be main-

tained within age-appropriate reference range in children, and

given the association of high PTH levels with reduced bone

mineralization and increased vascular calciﬁcation, child ren

are likely to require calcitriol or other active vitamin D analog

therapy.

In summar y, the PRIMO and OPERA studies failed to

demonstrate improvements in clinically relevant outcomes

but demonstrated increased r isk of hypercalcemia. Accord-

ingly, the guideline no longer recommends routine use of

calcitriol or its analogs in CKD G3a to G5. This was not a

uniform consensus among the Work Group. It should be

noted that the participants in the PRIMO and OPERA trials

only had moderately increased PTH levels, thus therapy with

calcitriol and vitamin D analogs may be considered in those

with progressive and severe SHPT.

There are still no RCTs demonstrating beneﬁcial effects of

calcitriol or vitamin D analogs on patient-level outcomes,

such as cardiac events or mortality, and the optimal level of

PTH in CKD G3a to G5 is not known. Furthermore, therapy

with these agents may have additional harmful effects related

to increases in serum phosphate and FGF23 levels. If initiated

for severe and progressive SHPT, calcitr iol or vitamin D an-

alogs should be started with low doses, independent of the

initial PTH concentration, and then titrated based on the

PTH response. Hypercalcemia should be avoided.

Research recommendation

 Multicenter RCTs should be conducted in children and

adults to determine the beneﬁts or harms of calcitriol or

vitamin D analogs in patients with CKD G3a to G5;

patient-level outcomes including falls, fractures, sarcopenia,

muscle strength, physical function, progression to end-stage

kidney disease, cardiovascular events, hospitalizations, and

mortality should be assessed. Additional important patient-

level outcomes to include are bone pain, pruritus, and

health-related quality of life. Studies should also include

patients with more severe SHPT and should determine the

impact of reducing PTH to different target levels, such as

the normal range versus higher levels.

4.2.4: In patients with CKD G5D requiring PTH-lowering

therapy, we suggest calcimimetics, calcitriol, or

vitamin D analogs, or a combination of calcimimetics

with calcitriol or vitamin D analogs (2B).

Rationale

New data published since the 2013 KDIGO Madrid Contro-

versies Conference prompted the Work Group to reappraise

the use of PTH-lowering therapies in patients with CKD G5D.

As shown in Supplementary Table S43, the ERT identiﬁed 2

new trials evaluating treatment with cinacalcet versus placebo

and 1 new trial evaluating calcitriol versus a vitamin D analog.

One open-label clinical trial was conducted evaluating the

effect of cinacalcet on bone histomorphometry.

145

There are

still no new trials of calcitriol or vitamin D analogs that

demonstrated clear beneﬁts in patient-level outcomes.

The Work Group discussed the EVOLVE trial at length.

EVOLVE evaluated the effect of cinacalcet versus placebo on

patient-level outcomes in 3883 HD patients using a composite

endpoint of all-cause mortality, nonfatal myocardial infarc-

tion, hospitalization for unstable angina, congestive heart

failure, and per ipheral vascular events. Secondary endpoints

included individual components of the primary endpoint,

clinical fracture, stroke, parathyroidectomy, and cardiovas-

cular events and cardiovascular death.

The results of EVOLVE have proven controversial. The

unadjusted primary composite endpoint showed a nonsig-

niﬁcant reduction (HR: 0.93; P ¼ 0.112) with cinacalcet use.

However, analyses adjusted for imbalances in baseline char-

acteristics demonstrated a nominally signiﬁcant reduction in

the primary composite endpoint (HR: 0.88; P ¼ 0.008), as did

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Kidney International Supplements (2017) 7, 1–59 35

sensitivity analyses accounting for patient nonadherence to

randomized study medication (HR: 0.77; 95% CI: 0.70–

0.92)

137

or when patients were censored at the time of kidney

transplant, parathy roidectomy, or the use of commercial

cinacalcet (HR: 0.84; P # 0.001).

Further challenging the

interpretation of the nonsigniﬁcant reduction in risk seen

with the unadjusted primary endpoint was a signiﬁcant

treatment-age interaction (P ¼ 0.03),

leading to speculation

that cinacalcet may be effective predominantly in older dial-

ysis patients. Approximately one-third of the EVOLVE par-

ticipants were under the age of 55, and prespeciﬁed analyses

that evaluated subjects above or below age 65 demonstrated a

signiﬁcant reduction in risk associated with use of cinacalcet

for both the primary endpoint (HR: 0.74; P # 0.001) and all-

cause mortality (HR: 0.73; P # 0.001) for those aged

above 65.

138

The Work Group also considered additional prespeciﬁ ed

and post hoc analyses from EVOLVE. These included a

demonstrated signiﬁcant reduction in the r isk of severe un-

remitting SHPT (deﬁned by the persistence of markedly

elevated PTH concentrations [2 consecutive PTH values over

1000 pg/ml (106 pmol/l)] together with hy percalcemia

[serum calcium > 10.5 mg/dl (2.63 mmol/l)] or para-

thyroidectomy). Cinacalcet appeared to consistently reduce

the risk of this endpoint regardless of baseline PTH (HR: 0.31,

P # 0.001 for those with baseline PTH 300–600 pg/ml [32–64

pmol/l]; HR: 0.49, P # 0.001 for those with baseline PTH

600–900 pg/ml [64 –95 pmol/l]; HR: 0.41, P < 0.001 for those

with PTH > 900 pg/ml [95 pmol/l]).

139

Cinacalcet had no

effect on the risk of clinical fractures in unadjusted analyses

(HR: 0.93; P ¼ 0.111) and showed a nominally signiﬁcant

reduction in risk of fracture when adjusted for age (HR: 0.88;

P ¼ 0.007).

140

Thus, EVOLVE did not meet its primary endpoint that

cinacalcet reduces the risk of death or clinically imp ortant

vascular events in CKD G5D patients. However, the results of

secondary analyses suggest that cinacalcet may be beneﬁcial in

this population or a subset. There was a lack of uniform

consensus among the Work Group members in their inter-

pretation of these data with regard to establishing cinacalcet as

the recommended ﬁrst-line therapy for patients with CKD

G5D requiring PTH-lowering therapy. While some felt that

only the primary analysis should be used to interpret the

outcome, others w ere equally conv inced that the secondary

analyses strongly suggested a beneﬁt of treatment with cina-

calcet on important patient-level outcomes.

Despite these differences in interpretation, there was

agreement among Work Group membe rs that the higher cost

of cinacalcet was also a relevant consideration given its un-

certain clinical bene ﬁts. There was al so agreement that the

documented associat ion between good clinical outcomes and

the extent of FGF23 reduction with cinacalcet warrants

further study.

141

No trials demonstrated the beneﬁts of combination ther-

apy (cinacalcet plus another agent) on clinically relevant

outcomes. However, several additional RCTs were identiﬁed

that studied the effect of combination therapy on putative

surrogate outcomes (summarized in Supplementary

Tables S43–S48). Two trials evaluated the use of cinacalcet

with low-dose active vitamin D versus standard therapy.

Urena-Torres et al.

142

demonstrated improved PTH-lowerin g

efﬁcacy in subjects treated with cinacalcet or low-dose active

vitamin D, while Raggi et al.

143

found that cinacalcet with

low-dose vitamin D attenuated the progression of coronary

artery calcium accumulation when assessed using calcium

volume scores (P ¼ 0.009) although not when using the more

common Agatston score (P ¼ 0.07). Two open-label trials of

cinacalcet were considered important in reaching consensus

for Recommendation 4.2.4. The PARADIGM trial compared a

cinacalcet-based treatment strate gy with an active vitamin D–

based strategy in 312 HD patients and demonstrated similar

reductions in PTH in both treatment arms.

144

The BONA-

FIDE trial evaluated bone histomorphometry in 77 paired

bone biopsy samples in cinacalcet-treated subjects with

proven high-turnover bone disease and demonstrated re-

ductions in bone formation rates and substantial increase in

the number of subjects with normal bone histology (from 0 at

baseline to 20 after 6–12 months of therapy).

145

Two subjects

developed adynamic bone disease, both of whom had PTH

values < 150 pg/ml (16 pmol/l), and 1 patient developed

osteomalacia coincident with hypophosphatemia. Despite

being a prospective interventional trial, the BONAFIDE trial

did not fulﬁll our literature inclusion criteria, because there

was no control group and only longitudinal assessments were

available, and thus is not listed in the Supplementary Tables.

It was recognized by the Work Group that newer, i.v.

calcimimetic agents have undergone clinical trial investigation

and were published after our guideline systematic review.

However, while data on safety and efﬁcacy were generated, no

patient-level outcomes were reported. Therefore, these trials

did not impact the current recommendation.

146,147

In summary, the Work Group was divided as to whether

the EVOLVE data are sufﬁcient to recommend cinacalcet as

ﬁrst-line therapy for all patients with SHPT and CKD G5D

requiring PTH lowering. One viewpoint is that the primary

endpoint of the EVOLVE study was negative. The alternative

viewpoint is that secondary analyses found effects on patient-

level endpoints, while there are no positive data on mortality

or patient-centered endpoints from trials with calcitriol or

other vitamin D analogs. Given the lack of uniform consensus

among the Work Group and the higher acquisition cost of

cinacalcet, it was decided to modify the 2009 recommenda-

tion to list all acceptable treatment options in alphabetical

order. The individual choice should continue to be guided by

considerations about concomitant therapies and the present

calcium and phosphate levels. In addition, the choice of

dialysate calcium concentrations will impact on serum PTH

levels. Finally, it should be pointed out that para-

thyroidectomy remains a valid treatment option especially in

cases when PTH-lowering therapies fail, as advocated in

Recommendation 4.2.5 from the 2009 KDIGO CKD-MBD

guideline.

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Kidney International Supplements (2017) 7, 1–59

To date, studies of cinacalcet in children are limited to case

reports,

148

case series,

149,150

a single-center experience (with

28 patients with CKD G4–G5),

151

and an open-label study of

a single dose in 12 children on dialysis.

152

In recognition of

the unique calcium demands of the growing skeleton, PTH-

lowering therapies should be used with caution in children

to avoid hypocalcemia. Future studies are needed in children

before pediatric-speciﬁc recommendations can be issued.

Research recommendations

 The Work Group expli citly endorses the presence of clinical

equipoise and the need to conduct placebo-controlled trials

with calcimimetics versus standard therapy for the

treatment of SHPT in patients with CKD G5D with

emphasis on those at greatest risk (e.g., older, with

cardiovascular disease).

 Prospective RCTs aiming at patient-centered surrogate

outcomes (primary endpoints: mortality, cardiovascular

events; secondary endpoints: FGF23, LVH progression,

calciﬁcation) should be performed with the new parenteral

calcimimetic compound (e.g., etelcalcitide).

 Given the disparate effects of calcimimetic and active

vitamin D therapies on FGF23 and data suggesting a clinical

beneﬁt from FGF23 reduction, RCTs evaluating the speciﬁc

reduction of FGF23 as a therapeutic endpoint should be

undertaken.

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Kidney International Supplements (2017) 7, 1–59 37

Chapter 4.3: Treatment of bone with

bisphosphonates, other osteoporosis medications,

and growth hormone

4.3.3: In patients with CKD G3a–G5D with biochemical

abnormalities of CKD-MBD and low BMD and/or

fragility fractures, we suggest that treatment choices

take into account the magnitude and reversibility of

the biochemical abnormalities and the progression

of CKD, with consideration of a bone biopsy (2D).

Rationale

Recommendation 3.2.2 now addresses the indications for a

bone biopsy prior to antiresorptive and other osteoporosis

therapies. Therefore, the original Recommendation 4.3.4

from the 2009 KDIGO CKD-MBD Guideline has been

removed, and Recommendation 4.3.3 has broadened from

CKD G3a to G3b to CKD G3a to G5D. Nevertheless, when

such treatment choices are considered, their speciﬁc side ef-

fects must also be taken into account (e.g., antiresorptives will

exacerbate low bone turnover, denosumab may induce sig-

niﬁcant hypocalcemia), and the risk of their administration

must be weighed against the accuracy of the diagnosis of the

underlying bone phenotype.

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Kidney International Supplements (2017) 7, 1–59

Chapter 5: Evaluation and treatment of kidney

transplant bone disease

5.5: In patients with CKD G1T–G5T with risk factors for

osteoporosis, we suggest that BMD testing be used to

assess fracture risk if results will alter therapy (2C).

Rationale

Fracture risk is 4-fold higher in patients with end-stage kid-

ney disease

153

compared with the general population and

increases further in the early post-transplant period .

154

2002 study examined the risk of hip fracture in kidney

transplant recipients and estimated the fracture rate at 3.3

events per 1000 person-years, a 34% higher risk compared

with patients receiving dialysis who were waitlisted for

transplantation.

Bone disease in transplant recipients is

complex and heterogeneous.

155

Essentially, transplant bone

disease is the composite of preexistin g damage to the bone

acquired during the period of renal insufﬁciency and damage

to the bone starting in the period of transplantation. In

contrast to older studies,

156

recent cohort studies showed

minimal BMD losses in the early post-transplant period,

which seem to be restricted to sites rich in cortical bone such

as the distal radius.

157

A low cumulative steroid exposure

along with persistent hyperparathyroidism most likely ac-

counts for this shift.

157

The widespread implementation of

steroid minimization protocols may explain the favorable

trend in fracture risk in kidney transplant recipients observed

over the last 2 decades.

158–160

The 2009 KDIGO CKD-MBD Guideline

recommended

BMD testing in the ﬁrst 3 months following transplantation

in patient s with an eGFR greater than 30 ml/min/1.73 m

they receive corticosteroids or have risk factors for osteopo-

rosis (Recommendation 5.5), but recommended that DXA

BMD not be performed in those with CKD G4T to G5T

(Recommendation 5.7). As detailed in the new aforemen-

tioned Recommendation 3.2.1, there is growing evidence that

DXA BMD predicts fractures across the spectrum of CKD

severity, including 4 prospective cohort studies in patients

with CKD G3a to G5D

10–13

(Supplementary Tables S7–S12).

To date, there are no prospective studies addressing the ability

of DXA to predict fractures in transplant recipients. However,

a retrospective cohort study conducted in 238 kidney trans-

plant recipients with CKD G1T to G5T examined the asso-

ciations of DXA BMD with fracture events.

161

Lumbar spine

and total-hip BMD results were expressed as T-scores and

categorized as normal (T-score $ 1), osteopenic (T-

score < 1 and > 2.5), or osteoporotic ( T-score # 2.5).

A total of 46 incident fractures were recorded in 53 patients.

In a multivariate Cox analysis of DXA BMD results in the

total hip, osteopenia (HR: 2.7, 95% CI: 1.6–4.6) and osteo-

porosis (HR: 3.5, 95% CI: 1.8–6.4) were associated with

signiﬁcantly increased risk of fracture compared with normal

BMD, independent of age, sex, and diabetes. Multivariate

models were not provided for the lumbar spine BMD T-score

results; however, unadjusted analyses suggested that spine

BMD provided less fracture prediction compared with total-

hip BMD. Although this DXA study in kidney transplant

recipients was not eligible for the evidence-based review due

to its retrospective design, the Work Group concluded that

the ﬁndings were consistent with the other studi es in CKD

G3a to G5D described above.

In summary, there is growing evidence that DXA BMD

predicts fractures in patients with CKD across the spectrum,

with limited data suggesting these ﬁndings extend to trans-

plant recipients. The revised guideline statement recommends

BMD testing in transplant recipients, as in those with CKD

G3a to G5D, if the results will impact treatment decisions.

Research recommendations

 The research recommendations outlined for Recommen-

dation 3.2.1 should be expand ed to include studies in

kidney transplant recipients.

 Prospective studi es in patients with CKD G1T to G5T

should be performed to determine the value of BMD and

bone biomarkers as predictors of fractures.

5.6: In patients in the ﬁrst 12 months after kidney trans-

plant with an estimated glomerular ﬁltration rate

greater than approximately 30 ml/min/1.73 m

and low

BMD, we suggest that treatment with vitamin D, cal-

citriol/alfacalcidol, and/or antiresorptive agents be

considered (2D).

 We suggest that treatment choices be inﬂuenced by

the presence of CKD-MBD, as indicated by abnormal

levels of calcium, phosphate, PTH, alkaline phos-

phatases, and 25(OH)D (2C).

 It is reasonable to consider a bone biopsy to guide

treatment (Not Graded).

There are insufﬁcient data to guide treatment after the

ﬁrst 12 months.

Rationale

The rationale for revised guideline Recommendation 3.2.2

now addresses the indications for a bone biopsy prior to

antiresorptive and other osteoporosis therapies. Therefore,

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Kidney International Supplements (2017) 7, 1–59 39

the second bullet statement above concerning bone biopsies

has been modiﬁed.

Cinacalcet is not approved for the treatment of hyper-

parathyroidism in kidney transplant recipients; however, it is

clinically used, especially in patients with signiﬁcant hyper-

calcemia. While efﬁciently correcting hypercalcemia, cina-

calcet so far has failed to show a beneﬁcial impact on bone

mineralization in the transplant population.

162

Denosumab

was recently shown to effectively increase BMD in de novo

kidney transplant recipients.

163

However, baseline BMD on

average was not very low in this trial, and there was no

progressive BMD loss in the control group. Fur thermore, an

increased rate of urinary tract infections was observed. In

terms of safety and efﬁcacy, an RCT comparing denosumab

and bisphosphonates in eligible patients at risk may be a

reasonable future study approach. As pointed out in the

rationale for Recommendation 5.5, however, the urgency for

correcting bone mineralization in transplant recipients may

diminish due to the wide application of steroid minimization

schemes.

159

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Kidney International Supplements (2017) 7, 1–59

Methodological approach to the 2017 KDIGO

CKD-MBD guideline update

Purpose

In 2009, KDIGO developed a clinical practice guideline on

the diagnosis, evaluation, prevention, and treatment of

CKD-MBD.

Because of the limited evidence, many of the

recommendations were deliberately vague.

In October of 2013, KDIGO held a Controversies

Conference to determine whether there was sufﬁcient new

evidence to support updating any of the recommendations.

Based on the discussions at the conference, the participants

opted for a “selective update” of the guideline.

The purpose of this chapter is to describe the methods

used to conduct the evidence review and to develop and

update the guideline recommendations.

Overview of the Process

The process of updatin g the guideline consisted of the

following steps:

 Convening of a Controversies Conference to determine

whether sufﬁcient new data exist to support a reassessment

of the guideline

 Appointing a Work Group and an ERT

 Reﬁning the research questions

 Developing the search strategy, inclusion/exclusion criteria,

and data extraction tables

 Drafting the evidence matrices and evidence proﬁles

 Revising the recommendations

 Grading the quality of the evidence

 Grading the strength of the recommendation

Controversies Conference

In October 2013, KDIGO held a Controversies Conference

entitled, “CKD-MBD: Back to the Future,” in Madrid, Spain.

The purpose of the conference was to determine whether there

was sufﬁcient new evidence to support updating any of the rec-

ommendations from the 2009 KDIGO guideline on the diag-

nosis, evaluation, prevention, and treatment of CKD-MBD.

Seventy-four experts in adult, pediatric, and transplant

nephrology, endocrinology, cardiology, bone histomorphometry

pathology, and epidemiology attended the conference.

Four topic areas were considered: (i) vascular calciﬁcation;

(ii) bone quality; (iii) calcium and phosphate; and (iv)

vitamin D and PTH. Each participant was assigned to 1 of the

4 topics based on their area of expertise. Participants identi-

ﬁed new studies in their topic area and answered a set of

questions to determine which recommendations required

reevaluation.

The result was a list of recommendations to be

addressed in a s elected update (i.e ., t o use speci ﬁcmethods

to update only those parts of the guideline in need of

update).Therewasapublicreviewofthescopeofworkfor

the guidelin e.

Appointment of guideline Work Group and evidence

review team

The KDIGO co-chairs appointed 2 chairs for the Guideline

Work Group, who then assembled the Work Group to be

responsible for the development of the guideline. The Work

Group comprised domain experts, including individuals with

expertise in adult and pediatric nephrology, bone disease,

cardiology, and nutrition. The Johns Hopkins University in

Baltimore, MD, was contracted as the ERT to provide

expertise in guideline development methodology and sys-

tematic evidence review. KDIGO support staff provided

administrative assistance and facilitated communication.

The ERT consisted of methodologists with expertise in

nephrology and internal medicine, and research associates

and assistants. The ERT and the Work Group worked closely

throughout the project. In January 2015, the ERT and the

Work Group Co-Chairs held a 2-day meeting in Baltimore,

MD, to discuss the guideline development and systematic

review processes and to reﬁne the key questions.

The ERT performed systematic reviews for each of the

questions conducting literature searches, abstract and full-text

screening, data extracti on, risk of bias assessment, and syn-

thesis. The ERT provided suggestions and edits on the

wording of recommendations, and on the use of speciﬁc

grades for the strength of the recommendations and the

quality of evidence. The Work Group took on the primary

role of writing the recommendations and rationale, and

retained ﬁnal responsibility for the content of the recom-

mendations and the accompanying narrative.

Reﬁnement of the research questions

The ﬁrst task was to deﬁne the overall topics and goals for the

guideline. Using the recomm endations identiﬁed during the

Controversies Conference, the ERT drafted research ques-

tions and identiﬁed the population , interventions, compari-

son, and outcomes (PICO elements) for each research

question.

The ERT recruited a technical exper t panel to review the

research questions. The technical expert panel included in-

ternal and external clinicians and researchers in nephrology

and CKD. During a conference call, the technical expert panel

provided feedback on the research questions.

The Work Group Co-Chairs and the ERT reﬁned the

research questions at the 2-day meeting in Baltimore, MD.

www.kisupplements.org methodological approach

Kidney International Supplements (2017) 7, 1–59 41

Table 2 | Research questions

Section

2009

rec. no. Research question Key outcomes Additional outcomes

Bone quality 3.2.1 In patients with CKD G3a–G5D, what is the

effect on bone quality of bisphosphonates,

teriparatide, denosumab, and raloxifene?

 TMV (as measured by bone

biopsy)

 BMD/bone mineral content

 Fracture

4.3.4 In patients with CKD G4–G5D, what is the

effect on bone quality of bisphosphonates,

teriparatide, denosumab, and raloxifene?

 TMV (as measured by bone

biopsy)

 BMD/bone mineral content

 Fracture

3.2.2 (a) In patients with CKD G3a–G5D, how well do

BMD results predict fractures?

(b) In patients with CKD G3a –G5D, how well do

BMD results predict renal osteodystrophy?

(a) Fracture

(b) TMV

5.5 In patients with CKD G1–G3b and transplant

recipients, how well do BMD results predict

fractures?

 Fracture

5.7 In patients with CKD G4–G5 and transplant

recipients, how well do BMD results predict

fractures?

 Fracture

Calcium and

phosphate

4.1.1 In patients with G3a–G5 or G5D, what is the

evidence for beneﬁt or harm in maintaining

serum phosphate in the normal range

compared with other targets of serum

phosphate in terms of biochemical outcomes,

other surrogate outcomes, and patient-

centered outcomes?

 Mortality

 GFR decline

 Cardiovascular and cerebrovas-

cular events

 Phosphate

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.1.3 In patients with CKD G5D, what is the evidence

for beneﬁt or harm in using a dialysate calcium

concentration between 1.25 and 1.50 mmol/l

(2.5 and 3.0 mEq/l) compared with other

concentrations of dialysate calcium in terms of

biochemical outcomes, other surrogate

outcomes, and patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Calcium

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.1.2 In patients with CKD G3a–G5D, what is the

evidence for beneﬁt or harm in maintaining

serum calcium in the normal range compared

with other targets of serum calcium in terms of

biochemical outcomes, other surrogate

outcomes, and patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Calcium

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

methodological approach www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Section

2009

rec. no. Research question Key outcomes Additional outcomes

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.1.4 In patients with CKD G3a–G5 or G5D with

hyperphosphatemia, what is the evidence for

beneﬁt or harm in using calcium-containing

phosphate-binding agents to treat

hyperphosphatemia compared with calcium-

free phosphate-binding agents in terms of

biochemical outcomes, other surrogate

outcomes, and patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Phosphate

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.1.7 In patients with CKD G3a–G5D with

hyperphosphatemia, what is the evidence for

beneﬁt or harm in limiting dietary phosphate

intake compared with a standard diet in terms

of biochemical outcomes, other surrogate

outcomes, and patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Vascular and valvular calciﬁcation

 Phosphate

 Bone histology, BMD

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

Vitamin D

and PTH

4.2.1 In patients with CKD G3a–G5 not on dialysis

with levels of intact PTH above the upper

normal limit of the assay, what is the evidence

for beneﬁt or harm in reducing dietary

phosphate intake or treating with phosphate-

binding agents, calcium supplements, or

native vitamin D in terms of biochemical

outcomes, other surrogate outcomes, and

patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 GFR decline

 Calcium

 Phosphate

 Parathyroid hormone

 25-hydroxyvitamin D [25(OH)D]

 1,25-dihydroxyvitamin D

[1,25(OH)

 Alkaline phosphatases

 Bone-speciﬁc alkaline

phosphatase

 Bicarbonate

 FGF23

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.2.2 In patients with CKD G3a–G5 not on dialysis, in

whom serum PTH is progressively rising and

remains persistently above the upper limit of

normal for the assay despite correction of

modiﬁable factors, what is the evidence for

 LVH

 Hypercalcemia

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Calcium

 Phosphate

 Parathyroid hormone

 25-hydroxyvitamin D [25(OH)D]

(Continued on next page)

Table 2 | (Continued)

www.kisupplements.org methodological approach

Kidney International Supplements (2017) 7, 1–59 43

During this meeting decisions were also made abou t out-

comes, including those considered most important for deci-

sion making that would be graded (key outcomes). The

ﬁnalized research questions and outcomes are presented in

Table 2.

Search strategy

The ERT searched MEDLIN E and the Cochrane Central

of December 2006 through September 2015. The December

2006 date provided the recommended 1-year overlap with the

end of the previous search.

164

The search yield was also

supplemented by articles provided by the Work Group

members through February 2017.

The search strategy included MeSH and text terms for

CKD and the interventions and markers of interest

(Supplementary Appendix A) and was limited to the Eng lish

language. The ERT also rev iewed the list of references that

were suggested during the Controversies Conference.

All studi es that had been included in the prior guideline

were rereviewed to ensure that they met the eligibility criteria.

Inclusion and exclusion criteria. With in put from the Work

Group, the ERT deﬁned the eli gibility criteria a priori. The

eligibility criteria for all studies were: (i) original data pub-

lished in English, (ii) followed up at least 10 patie nts with

CKD for at least 6 months, and (iii) addressed 1 of the

research questions. The minimum mean duration of follow-

up of 6 months was chosen on the basis of clinical

Section

2009

rec. no. Research question Key outcomes Additional outcomes

beneﬁt or harm in treating with calcitriol or

vitamin D analogs compared with placebo or

active control in terms of biochemical

outcomes, other surrogate outcomes, and

patient-centered outcomes?

 1,25-dihydroxyvitamin D

[1,25(OH)

 Alkaline phosphatases

 Bone-speciﬁc alkaline

phosphatase

 Bicarbonate

 FGF23

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

4.2.4 In patients with CKD G5D, what is the evidence

for beneﬁt or harm in treating with calcitriol,

vitamin D analogs, calcimimetics or

combination thereof compared with placebo

or active control in terms of biochemical

outcomes, other surrogate outcomes, and

patient-centered outcomes?

 Mortality

 Cardiovascular and cerebrovas-

cular events

 Fracture

 Vascular and valvular calciﬁcation

imaging

 Calcium

 Phosphate

 Parathyroid hormone

 25-hydroxyvitamin D [25(OH)D]

 1,25-dihydroxyvitamin D

[1,25(OH)

 Alkaline phosphatases

 Bone-speciﬁc alkaline

phosphatase

 Bicarbonate

 FGF23

 Bone histology, BMD

 Vascular and valvular calciﬁcation

imaging

 Measures of GFR

 Hospitalizations

 Quality of life

 Kidney or kidney graft failure

 Fracture

 Parathyroidectomy

 Clinical adverse events

 Growth, skeletal deformities,

bone accrual

 Calciphylaxis/CUA

BMD, bone mineral density; CKD, chronic kidney disease; CUA, calciﬁc uremic arteriolopathy; GFR, glomerular ﬁltration rate; FGF23, ﬁbroblast growth factor 23; LVH, left

ventricular hypertrophy; PTH, parathyroid hormone; rec. no., recommendation number; TMV, bone turnover mineralization volume.

Table 2 | (Continued) Research questions

methodological approach www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

reasoning, accounting for the hypothetical mechanisms of

action. For treatments of interest, the proposed effects on

patient-centered outcomes require long-term exposure and

typically would not be evident before several months of

follow-up. The question-speciﬁc eligibility criteria are pro-

vided in Table 3, and the overall search yield for the guideline

systematic review is summarized in Supplementary Appendix

Two reviewers independently screened titles and abstracts

and full-text articles for inclusion. Differences regarding in-

clusion were resolved through consensus adjudication.

Any study not meeting the inclusion criteria could be cited

in the narrative but was not considered part of the body of

evidence for a particular recommendation.

Data extraction

The ER Tmodiﬁed the online supplementary tables from the prior

guideline. One reviewer abstracted data directly into the modiﬁed

tables, and a second reviewer conﬁrmed the data abstraction.

The ER T abstracted data on general study characteristics,

participant characteristics, interventions and co-interventions,

and outcome measures, including measures of variability .

Two reviewers independently assessed individual study

quality using the Cochrane Collaboration’s tool

165

for

assessing risk of bias for RCTs and using the Quality in

Prognosis Studies tool

166

for observational studies.

The Work Group critically reviewed draft tables, and tables

were revised as appropriate.

Evidence matrices and evidence proﬁles

The ERT created evidence matrices for each of the key out-

comes for each research question. For each key outcome, the

matrix lists the individual studies, their sample size, follow-up

duration, and the individual study quality. The ERT also

drafted evidence proﬁles to display the total number and

overall quality of the studies addressing each key outcome for

each research question.

Revising recommendations

In June 2015, the Work Group and the ERT convened a 3-day

meeting in Baltimore, MD, to review the summary tables,

evidence proﬁles, and evidence matrices; to decide whether and

how the recommendations should be rev ised; and to determine

a grade that described the quality of the overall evidence and a

grade for the strength of each recommendation.

Grading

A structured approach—modeled after Grading of Recom-

mendations Assessment, Development, and Evaluation

(GRADE)

167–172

and facilitated by the use of evidence proﬁles

and evidence matrices—was used to determine a grade that

described the quali ty of the overall evidence and a grade for

the strength of a recommendation. For each topic, the

Table 3 | Question-speciﬁc eligibility criteria

2009 recommendation no. Exposure or intervention Eligibility criteria

3.2.1, 4.3.4 Bisphosphonates, teriparatide,

denosumab, or raloxifene

 RCT with at least 10 participants per arm for the outcome of bone quality and

at least 25 participants per arm for all other outcomes

 Evaluates bone quality, bone mineral density, or fracture

3.2.2, 5.5, 5.7 Predictive value of BMD results

 RCT with at least 25 participants per arm or a prospective cohort study with

50 participants

 Evaluates fractures or renal osteodystrophy

4.1.1, 4.1.2 Serum phosphate or serum calcium

levels

 RCT with at least 25 participants per arm or a prospective cohort study with

50 participants

 Evaluates mortality, GFR decline, cardiovascular or cerebrovascular events,

phosphate levels, calcium levels, bone histology, bone mineral density, bone

volume, vascular and valvular calciﬁcation imaging, hospitalizations, quality

of life, kidney or kidney graft failure, fractures, parathyroidectomy, clinical

adverse events, growth, skeletal deformities, bone accrual, or calciphylaxis or

calciﬁc uremic arteriolopathy

4.1.3 Dialysate calcium concentrations

 RCT with at least 25 participants per arm

 Evaluates mortality, cardiovascular or cerebrovascular events, calcium levels,

bone histology, bone mineral density, bone volume, vascular and valvular

calciﬁcation imaging, measures of GFR, hospitalizations, quality of life, kidney

or kidney graft failure, fractures, parathyroidectomy, clinical adverse events,

growth, skeletal deformities, bone accrual, or calciphylaxis or calciﬁc uremic

arteriolopathy

4.1.4, 4.1.7, 4.2.1, 4.2.2, 4.2.4 Dietary phosphate intake,

phosphate-binding agents, calcium

supplements, native vitamin D,

vitamin D analogs, calcitriol, or

calcimimetics

 RCT with at least 25 participants per arm

 Evaluates mortality, cardiovascular or cerebrovascular events, GFR decline,

calcium levels, phosphate levels, parathyroid hormone levels, 25-

hydroxyvitamin D or 1,25-dihydroxyvitamin D levels, alkaline phosphatases,

bone-speciﬁc alkaline phosphatase, bicarbonate, FGF23, bone histology, bone

mineral density, bone volume, vascular and valvular calciﬁcation imaging,

measures of GFR, hospitalizations, quality of life, kidney or kidney graft failure,

fractures, parathyroidectomy, clinical adverse events, growth, skeletal de-

formities, bone accrual, calciphylaxis or calciﬁc uremic arteriolopathy for any of

the above interventions, or LVH or hypercalcemia for vitamin D analogs

BMD, bone mineral density; FGF23, ﬁbroblast growth factor 23; GFR, glomerular ﬁltration rate; LVH, left ventricular hypertrophy; RCT, randomized controlled trial.

www.kisupplements.org methodological approach

Kidney International Supplements (2017) 7, 1–59 45

discussion on g rading of the quality of evidence was led by the

ERT, and the discussion regarding the strength of the rec-

ommendations was led by the Work Group Chairs.

Grading the quality of evidence for each outcome

The ‘quality of a body of evidence’ refers to the extent to

which our conﬁdence in an estimate of effect is sufﬁcient to

support a particular recommendation. Following GRADE, the

quality of a body of evidence pertaining to a particular

outcome of interest is initially categorized on the basis of

study design. For questions of interventions, the initial quality

grade is “high” if the body of evidence consists of RCTs, “low”

if it consists of observational studies, or “very low” if it

consists of studies of other study designs. For questions of

interventions, the Work Group graded only RCTs. The g rade

for the quality of evidence for each intervention–outcome

pair was then decreased if there were serious limitations to the

methodological quality of the aggregate of studies; if there

were important inconsistencies in the results across studies; if

there was uncertainty about the directness of evidence

including a limite d applicability of ﬁndings to the population

of interest; if the data were imprecise or sparse; or if there was

thought to be a high likelihood of bias. The ﬁnal grade for the

quality of evidence for an inter vention–outcome pair could be

1 of the following 4 grades: “high,”“moderate,”“low,” or

“very low” (Table 4).

Grading the overall quality of evidence

The quality of the overall body of evidence was then deter-

mined on the basis of the quality grades for all outcomes of

interest, taking into account explicit judgments about the

relative importance of each outcome. The resulting 4 ﬁnal

categories for the quality of overall ev idence were A, B, C, and D

(Table 5). This grade for overall evidence is indicated behind

the strength of recommendations. The summary of the overall

quality of evidence across all outcomes proved to be very

complex. Thus, as an interim step, the evidence proﬁles

recorded the quality of evidence for each of 3 outcome cate-

gories: patient-centered outcomes, other bone and vascular

surrogate outcomes, and laboratory outcomes. The overall

quality of evidence was determined by the Work Group and is

based on an overall assessment of the evidence. It reﬂects that,

for most interventions and tests, there is no high-quality evi-

dence for net beneﬁt in terms of patient-centered outcomes.

Assessment of the net health beneﬁt across all important

clinical outcomes

Net health beneﬁt was determined on the basis of the antic-

ipated balance of beneﬁts and harm across all clinically

important outcomes. The assessment of net health beneﬁtby

the Work Group and ERT is summarized in one of the

following statements: (i) There is net beneﬁt from interven-

tion when be neﬁts outweigh harm; (ii) there is no net beneﬁt;

(iii) there are trade-offs between beneﬁts and harm when

harm does not altogether offset beneﬁts but requires

consideration in decision making; or (iv) uncertaint y remains

regarding net beneﬁt(Table 6).

Grading the recommendations

The “strength of a recommendation” indica tes the extent to

which one can be conﬁdent that adherence to the recom-

mendation will do more good than harm. The strength of a

recommendation is graded as Level 1 or Level 2.

173

Table 7

shows the nomenclature for grading the strength of a

recommendation and the implications of each level for pa-

tients, clinicians, and policy makers. Recommendations can

be fo r or against doing something. Table 8 shows that the

strength of a recommendation is determined not just by the

Table 4 | GRADE system for grading quality of evidence for an outcome

Step 1: starting grade for quality of

evidence based on study design Step 2: reduce grade Step 3: raise grade

Final grade for quality of

evidence for an outcome

High for randomized controlled trials

Moderate for quasi-randomized trial

Low for observational study

Very low for any other evidence

Study quality

–1 level if serious limitations

–2 levels in very serious limitations

Consistency

–1 level if important inconsistency

Directness

–1 level if some uncertainty

–2 levels if major uncertainty

Other

–1 level if sparse or imprecise data

–1 level if high probability of

reporting bias

Strength of association

þ1 level is strong,

no plausible

confounders, consistent and direct

evidence

þ2 levels if very strong,

no major threats

to validity and direct evidence

Other

þ1 level if evidence of a dose-response

gradient

þ1 level if all residual confounders would

have reduced the observed effect

High

Moderate

Low

Very low

GRADE, grading of recommendations assessment, development, and evaluation; RR, relative risk.

The highest possible grade is “high ” and the lowest possible grade is “very low.”

Strong evidence of association is deﬁned as “signiﬁcant RR of > 2(< 0.5)” based on consistent evidence from two or more observational studies, with no plausible

confounders.

Very strong evidence of association is deﬁ ned as “signiﬁcant RR of > 5(< 0.2)” based on direct evidence with no major threats to validity.

Modiﬁed with permission from Uhlig K, Macleod A, Craig J, et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement

from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;70:2058–2065.

171

methodological approach www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

quality of evidence, but also by other, often complex judg-

ments regarding the size of the net medical beneﬁt, values and

preferences, and costs.

Ungraded statements

The Work Group felt that havi ng a category that allows it to

issue general advice would be useful. For this purpose, the

Work Group chose the categor y of a recommendation that

was not graded. Typically, this type of ungraded statement

met the following criter ia: it provides guidance on the basis of

common sense; it provides reminders of the obvious; and it is

not sufﬁciently speciﬁc to allow an application of evidence to

the issue, and therefore it is not based on a systematic review.

Common examples include recommendations regarding the

frequency of testing, referral to specialists, and routine

medical care. The ERT and Work Group strove to minimize

the use of ungraded recommendations.

Limitations of approach

Although the literature searches were intended to be

comprehensive, they were not exhaustive. MEDLINE and

Cochrane CENTRAL were the only databases searched, and

the search was limited to Eng lish language publications. Hand

searches of journals were not performed, and review articles

and textbook chapters were not systematically searched.

However, Work Group me mbers did identify additional or

new studies for consideration.

Nonrandomized studies were not systematically reviewed

for studies of interventions. The ERT and Work Group re-

sources were devoted to review of randomized trials, as these

Table 5 | Final grade for overall quality of evidence

Grade Quality of evidence Meaning

A High We are conﬁdent that the true effect lies

close to that of the estimate of the effect.

B Moderate The true effect is likely to be close to the

estimate of the effect, but there is a

possibility that it is substantially different.

C Low The true effect may be substantially

different from the estimate of the effect.

D Very low The estimate of effect is very uncertain,

and often will be far from the truth.

Table 6 | Balance of beneﬁts and harms

When there was evidence to determine the balance of medical beneﬁts

and harm of an intervention to a patient, conclusions were categorized

as follows:

Net beneﬁts The intervention clearly does more good than

harm.

Trade-offs There are important trade-offs between the

beneﬁts and harm.

Uncertain trade-offs It is not clear whether the intervention does

more good than harm.

No net beneﬁts The intervention clearly does not do more

good than harm.

Table 7 | Implications of the strength of a recommendation

Grade

Implications

Patients Clinicians Policy

Level 1:

“We recommend”

Most people in your situation would

want the recommended course of

action, and only a small proportion

would not.

Most patients should receive the

recommended course of action.

The recommendation can be evaluated

as a candidate for developing a policy

or a performance measure.

Level 2:

“We suggest”

The majority of people in your situation

would want the recommended course

of action, but many would not.

Different choices will be appropriate

for different patients. Each patient

needs help to arrive at a management

decision consistent with her or his

values and preferences.

The recommendation is likely to require

substantial debate and involvement of

stakeholders before policy can be

determined.

Table 8 | Determinants of strength of recommendation

Factor Comment

Balance between desirable

and undesirable effects

The larger the difference between the

desirable and undesirable effects, the more

likely a strong recommendation is

warranted. The narrower the gradient, the

more likely a weak recommendation is

warranted.

Quality of the evidence The higher the quality of evidence, the

more likely a strong recommendation is

warranted.

Values and preferences The more variability in values and

preferences, or the more uncertainty in

values and preferences, the more likely a

weak recommendation is warranted.

Costs (resource allocation) The higher the costs of an intervention—

that is, the more resources consumed—the

less likely a strong recommendation is

warranted.

www.kisupplements.org methodological approach

Kidney International Supplements (2017) 7, 1–59 47

were deemed most likely to provide data to support treatment

recommendations with higher-quality evidence.

Evidence for patient-relevant clinical outcomes was low.

Usually, low-quality evidence required a substantial use of

expert judgment in deriving a recommendation from the

evidence reviewed.

Formulation and vetting of recommendations

Recommendations were drafted to be clear and actionable,

and the wording also considered the ability of concepts to be

translated accurately into other languages. The ﬁnal wording

of recommendations and corresponding grades for the

strength of the recommendations and the quality of evidence

were voted upon by the Work Group and required a majority

to be accepted.

The process of peer review included an external review by

the public to ensure widespread input from numerous

stakeholders, including patients, experts, and industry and

national organizations.

Format for chapters

Each chapter contains one or more speciﬁc recommenda-

tions. Within each recommendation, the strength of the

recommendation is indicated as level 1 o r level 2, and the

quali ty of the overall suppor tin g evidence is sh own as A, B,

C, or D. The recommendations are followed by a section

that describes the body of evidence and rationale for the

recommendations. In relevant sections, research recom-

mendations suggest future research to resolve current

uncertainties.

methodological approach www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Biographic and disclosure information

web 4C=FPOweb 4C=FPO

Markus Ketteler, MD, FERA (Work

Group co-chair), is professor of

medicine and currently serves as Divi-

sion Chief of Nephrology at the Klini-

kum Coburg in Coburg, Germany. In

2016, he was additionally appointed as

chief medical ofﬁcer at this institution.

He is also chairman of the Medical

Board of a large German not-for-proﬁt

dialysis provider (KfH Kuratorium für

Dialyse und Nierentransplantation

e.V.). His research focus is aimed at the understanding of the

pathomechanisms involved in extraosseous calciﬁcations, and of

phosphate and vitamin D metabolism in CKD. He has authored

more than 190 peer-reviewed publications including in The

Lancet, Journal of the American Society of Nephrology (JASN),

Journal of Clinical Investigation,andKidney International.Dr.

Ketteler has acted as local, national, or European Principal

Investigator in several clinical multicenter trials in the CKD-

MBD ﬁeld (e.g., SVCARB, CALMAG, IMPACT-SHPT, PA-CL-

05A and -05B, and NOPHOS). He serves on the editorial boards

of nephrology journals such as JASN and Nephrology Dialysis

Transplantation (theme editor), acted as a KDIGO Work Group

member on the CKD-MBD Guideline from 2006 to 2009, and

co-leads the German Calciphylaxis Registry. Dr. Ketteler is

currently council member and chairman of the administrative

ofﬁce of the European Renal Association–European Dialysis and

Transplant Association (ERA-EDTA) (2012–2018). He acted as

co-chair of the KDIGO Controversies Conference on CKD-

MBD, which took place in Madrid in October 2013. In 2017,

he was elected into the board of directors of the Kidney Health

Initiative, representing the ERA-EDTA for 3 years.

Consultant: Amgen, Fresenius Medical Care, Pﬁzer, Saniﬁt,

Sanoﬁ, Vifor Fresenius Medical Care Renal Pharma

Speaker: Amgen, BMS, Medice, Pﬁzer, Sano ﬁ , Vifor Fresenius

Medical Care Renal Pharma

Mary B. Leonard, MD, MSCE (Work

Group co-chair), is the Arline and

Pete Harman Professor and chair of

the Department of Pediatrics at Stan-

ford University School of Medicine.

She is also the Adalyn Jay Physician-in-

Chief of Lucile Packard Children’s

Hospital, and the director of the

Stanford Child Health Research Insti-

tute. Dr. Leonard received her MD

degree from Stanford University and

subsequently completed her pediatrics internship, residency,

and nephrology fellowship at the Child ren’s Hospital of

Philadelphia. After completing a master’s degree in clinical

epidemiolog y at the University of Pennsylvania in 1997, she

joined the faculty in the Departments of Pediatrics and

Biostatistics and Epidemiology. She has maintained contin-

uous National Institutes of Health funding for over 20 years,

and her multidisciplinary research program is primarily

focused on the impact of childhood chronic diseases on

growth, skeletal development, nutrition, and physical function,

with an emphasis on the detrimental effects of CKD. She co-

chaired the ISCD Pediatric Position Development Conferences

in 2007 and 2013. Dr. Leonard has served as an Associate

Editor for Journal of the American Society of Nephrology and

Journal of Bone and Mineral Research. She has published over

150 peer-reviewed manuscripts and is a member of the

American Society of Clinical Investigation, American Pediatric

Society, and the Society for Pediatric Research.

Dr. Leonard declared no competing interests.

web 4C=FPOweb 4C=FPO

Geoffrey A. Block, MD, is a clinical

nephrologist and director of research

at Denver Nephrology. He received his

MD at the University of Cincinnati and

completed his fellowship in nephrology

at the University of Michigan, where he

was trained under the mentorship of

Dr. Friedrich Port at the United States

Renal Data System. Dr. Block started a

clinical research department at Denver Nephrology in 1998, and

his primary research focus has been on clinical outcomes asso-

ciated with CKD-MBD. He has published observational reports

on the risks associated with disorders of mineral metabolism and

has designed, conducted, and published numerous RCTs using a

variety of interventions related to mineral metabolism and

complications of CKD. He has served as a Work Group member

on the 2009 KDIGO CKD-MBD guideline, 2 technical expert

panels for Centers for Medicare and Medicaid Services related to

bone and mineral disorders, and as a member of the steering

committee for the EVOLVE trial. He serves as a reviewer for

Clinical Journal of the American Society of Nephrology, Journal of

the American Society of Nephrology, American Journal of Kidney

Diseases, and Kidney International and was associate editor of

Nephron-Clinical Practice.

Consultant: Ardelyx, Amgen, AstraZeneca, Celgene, Keryx,

Kirin, Ono Pharmaceutical, OPKO

Grant/research support: Keryx*

Speaker: OPKO

www.kisupplements.org biographic and disclosure information

Kidney International Supplements (2017) 7, 1–59 49

Development of educational materials: Amgen, Keryx,

OPKO

Stock/stock options: Ardelyx

Other: medical director, DaVita

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Pieter Evenepoel, MD, PhD, FERA,

is head of the dialysis unit, division of

nephrology, at the University Hospi-

tals Leuven. Dr. Evenepoel completed

his medical training at the Catholic

University of Leuven, Belgium, in

1992, where he also received his PhD

for research on protein assimilation

and fermentation in 1997. In 2000, he

joined the University Hospitals

Leuven, where he gained his certiﬁ-

cation as Specialist in Internal Medicine and Nephrology. Dr.

Evenepoel has maintained an active research interest in

mainly clinical aspects of CKD-MBD, as exempliﬁed by

numerous original articles, review papers, and commentaries in

this ﬁeld. He is currently a board member of the European

Renal Association–European Dialysis and Transplant Associa-

tion (ERA-EDTA) working group on CKD-MBD. His research

interests span areas including uremic toxins, nutrition, and

anticoagulation, and he has authored over 200 publications. He

serves presently as associate editor of Nephrology Dialysis

Transplantation and editorial board member for Kidney Inter-

national. He is also an Ordinary Council Member of the ERA-

EDTA.

Consultant: Amgen, Vifor Fresenius Medical Care Renal

Pharma

Grant/research support: Amgen, TECOmedical

Speaker: Amgen, Vifor Fresenius Medical Care Renal Pharma

Miscellaneous travel and meeting expens es unrelated to

above: Amgen, Shire

web 4C=FPOweb 4C=FPO

Masafumi Fukagawa, MD, PhD,

FASN, received his MD in 1983 from

the University of Tokyo School of

Medicine,Tokyo,Japan.Followinga

subspecialty training and PhD pro-

gram in Tokyo, he was a research

fellow at Vanderbilt University School

of Medicine, Nas h ville, TN, until 1995.

From 2000 to 2009 , he was associate

professor and director of the Division

of Nephrology and Kidney Center at

K obe U niv ersity School of Medicine, Kobe, Japan, and he later

moved to Tokai University School of Medicine, Isehara, Japan,

as professor of medicine and the director of the Division of

Nephrology, Endocrinology, and Metabolism. He was interna-

tional associate editor of Clinical Journal of the American Society

of Nephrology (CJASN) (2005–2010) and currently serves as

associate editor for Jo urnal of Bone and Mineral Metabolism.He

is an editorial board member for Kidney International, American

Journal of Kidney Diseases, CJASN, Nephrology Dialysis Trans-

plantation,andClinical and Experimental Nephrology. In addi-

tion, he served as a Work Group member for the 2009 KDIGO

CKD-MBD guideline and also chaired the committee for the

new version of the Japanese clinical guideline on CKD-MBD by

the Japanese Society for Dialysis Therapy.

Consultant: Kyowa Hakko Kirin, Ono Pharmaceutical, Torii

Grant/research support: Bayer Japan*, Kyowa Hakko Kirin*

Speaker: Bayer Japan, Kyowa Hakko Kirin, Tor ii

Manuscript preparation: Bayer Japan, Kyowa Hakko Kirin

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Charles A. Herzog, MD, FACC,

FAHA, is professor of medicine at

University of Minnesota and a cardi-

ologist at Hennepin County Medical

Center (HCMC) for 32 years. He

founded the program in interventional

cardiology at HCMC and served as

cardiac catheterization laboratory di-

rector from 1985 to 1991, and cardiac

ultrasound laboratory director from 1997 to 2012. He was di-

rector of the United States Renal Data System Cardiovascular

Special Studies Center from 1999 to 2014. Dr. Herzog partici-

pated in the development of the National Kidney Foundation’s

K/DOQI Clinical Practice Guidelines for Cardiovascular Dis-

ease in Dialysis Patients and KDIGO Clinical Practice Guideline

on Acute Kidney Injury. He also co-chaired the 2010 KDIGO

Controversies Conference, “Cardiovascular Disease in CKD:

What is it and What Can We Do About It?” and is a co-chair of

the ongoing KDIGO Kidney, Heart, and Vascular Conference

Series. Dr. Herzog was an executive committee member of the

EVOLVE trial, and presently he is chairing the renal committee

of the ISCHEMIA-CKD trial and is co-principal investigator

of the WED-HED (Wearable Cardioverter Deﬁbrillator in He-

modialysis Patients) study. He has over 220 published papers

and has served on the editorial boards of the American

Heart Journal, Journal of Nephrology, Clinical Journal of the

American Society of Nephrology, and liaison editor for Nephrology

Dialysis Transplantation. His special interests include cardiac

disease and CKD, and echocardiography.

Consultant: AbbVie, Fibrogen, Relypsa, Saniﬁt, ZS Pharma

Employment: Hennepin County Medical Center, Chronic

Disease Research Group

Grants/research support: Amgen*, Zoll*

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Linda McCann, RD, CSR, has been a

nephrology dietitian for over 43 years,

focused on quality patient care, pro-

fessional management, and electronic

applications for kidney disease and

nutrition. She is currently a

nephrology nutrition consultant and

speaker. Ms. McCann was a member

of the or iginal KDOQI and KDIGO

biographic and disclosure information www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

advisory committees as well as the KDOQI and KDIGO (original

and update) Work Groups that developed and published clinical

practice guidelines and recommendati ons for bone and

mineral abnormalities in CKD. She is the author of the

popular National Kidney Foundation (NKF) publication,

Pocket Guide to Nutrition Assessment of the Patient with Kidney

Disease, currently in its ﬁfth edition. She has authored book

chapters and published multiple pee r-reviewed papers in the

area of nephrology nutrition. She has a long history of

mentoring other professionals, driving clinical excellence, and

is a dedicated patient advocate. Ms. McCann has also received

numerous awards including: Recognized Renal Dietitian

(Council on Renal Nutrition), Multiple Outstanding Service

Awards (NKF), Award of Distinguished Service (NKF

Northern California), Champion of Hope (NKF Northe rn

California), Joel D. Kopple Award (NKF National), San Jose

Business Journal 100 Women of Inﬂuence 2012, and the

American Association of Kidney Patients Medal of Excellence.

Consultant: Amgen, Relypsa, Sanoﬁ

Speaker: Amgen, Relypsa, Sa no ﬁ

Development of educational presentations: Amgen, Relypsa,

Sanoﬁ

web 4C=FPOweb 4C=FPO

Sharon M. Moe, MD, is the director

of the Division of Nephrology and

Stuart A. Kleit Professor of Medi-

cine for the Indiana University

School of Medicine. She received

her medical degree from t he Uni-

versity of Illinois–College of Medi-

cine at Chicago in 1989 an d

completed her residency in Internal

Medicine at Loyola University

Medical Center in Maywood, IL.

Her research and clinical fellowships were completed in

nephrology at the University of Chicago in Illinois. Dr.

Moe has been a faculty member at In diana University since

1992 and is currently division director for nephrology in

the Departm ent of Medicine at Indiana University School

of Medicine and section chief f or nephrology at the Rou-

debush VA Medical Center. She has also served as the

associate dean for Research Support in the Indiana Uni-

versity School of Medicine and the vice-chair for research

in the Department of Medicine.

Dr. Moe is the principal investigator for several ongoing

basic and clinical research studies in the ﬁeld of CKD-MBD,

including studies on vascular calciﬁcation, mineral meta-

bolism, and bone metabolism in kidney disease. Her research

is funded by the Veterans Affairs Department, the National

Institutes of Health, foundations, and pharmaceutical com-

panies. She has authored over 200 scientiﬁc manuscripts,

teaching manuscripts, and textbook chapters. Dr. Moe served

on the National Kidney Foundation’s (NKF) KDOQI Bone

and Mineral Metabolism Clinical Practice Guideline Work

Group in 2003 and was co-chair of the international KDIGO

CKD-MBD guideline released in 2009.

Dr. Moe’s key honors include: election to the American

Society for Clinical Research in 2005; the NKF Garabed

Eknoyan Award for exceptional contributions to key initia-

tives such as KDOQI in 2009; councilor to the American

Heart Association Kidney Council (2002–2004); International

Society of Nephrology (2005–2007); councilor for the

American Society of Nephrology (2008–2015) and president

of the American Society of Nephrology (2013-2014); and

election to the Association of American Physicians in 2017.

Consultant: Lilly, Ultragenyx

Grants/research support: NIH, Veterans Administration

Speaker: Sanoﬁ, University of Kansas

Stock/stock options: Lilly

web 4C=FPOweb 4C=FPO

Rukshana Shroff, MD, FRCPCH,

PhD, is a consultant in pediatric

nephrology at Great Ormond Street

Hospital for Children in London, UK,

and holds an academic position

(reader) in nephrology at University

College London. Her research focuses

on cardiovascular disease in child-

hood CKD, including laborat ory

work, clinical research studies, and clinical trials. She is the

principal investigator on a multicenter study comparing long-

term outcomes of conventional hemodialysis and hemodia-

ﬁltration in children. She currently holds a prestigious senior

fellowship from the National Institute for Health Research to

continue research into mineral dysregulation in CKD. She has

published more than 130 original articles, reviews, and book

chapters in the ﬁelds of nephrology and dialysis. Dr. Shroff

has also ser ved on 2 guideline committees for the National

Institute for Health and Care Excellence. She is on the council

for the European Society for Pediatric Nephrology. She is

presently an associate editor for Pediatric Nephrology and

serves on the editorial board of Clinical Journal of the Amer-

ican Society of Nephrology.

Consultant: AstraZeneca

Grant/research support: Fresenius Medical Care*

Speaker: Amgen, Fresenius Medical Care

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Marcello A. Tonelli, MD, SM,

FRCPC, is senior associate dean

(clinical research) at the Cumming

School of Medicine and associate vice

president (health research) at the

University of Calgary. He received an

MD from the University of Western

Ontario, specialist certiﬁcation in

nephrology (FRCPC) at Dalhousie

University, an SM in epidemiology

from Harvard University, and an MSc

in health policy from Imperial College London. He is a

nephrologist and professor at the University of Calgary.

www.kisupplements.org biographic and disclosure information

Kidney International Supplements (2017) 7, 1–59 51

Dr. Tonell i is the past president of the Canadian Society of

Nephrology, a past councilor of the International Society

of Nephrology, and the chair of the International Societ y of

Nephrology Research Committee. He is a fellow of the Ca-

nadian Academy of Health Sciences, and a member of the

American Society for Clinical Investigation. Dr. Tonelli is the

chair of the Canadian Task Force for Preventive Health Care, a

national panel of experts that makes recommendations about

preventive health services to Canada’s 36,000 family

physicians.

Dr. Tonelli was the recipient of the 2013 United States

National Kidney Foundation Medal for Distinguished Service

and also the 2013 Kidney Foundation of Canada Medal for

Research Excellence.

Dr. Tonelli declared no competing interests.

web 4C=FPOweb 4C=FPO

Nigel D. Toussaint, MBBS, FRACP,

PhD, is the deputy director of

nephrology at Melbourne He al th

and a clinic al a ssociate p rofessor

within the De par tment of Medicine

at the University of Melbourne ,

Australia. Dr. Toussaint completed

his nephrology training in Mel-

bourne in 2005 and completed his

PhD studies at Monash Universit y in

2009, undertaking clinical research

in the a rea of vascular calciﬁcat ion and cardiovascular r isk

in patients w ith CKD. He has also completed a graduate

diploma in clinical epidemiology (Monash University,

2007), and a National Health and Medical Research Council

National Institute of Clinic al Studies Fellowship (2011) in

the area of implementation research. He i s a member of the

Editorial Board for Nephrology and is cur rently a member of

council for the Australian and New Zealand Societ y of

Nephrology.

Dr. Toussaint practices nephrology at The Royal Mel-

bourne Hospital, where he is also the lead physician for

clinical research within the Nephrology Department. His

current research involves clinical epidemiology and clinical

trials, as well as translational research, in the areas of CKD-

MBD biomarkers, vascular calciﬁcation, and renal osteodys-

trophy. He has been an awardee of the Royal Australasian

College of Physicians Jacquot Research Establishment Award

and is a member of the Scientiﬁc Committee for the Aus-

tralasian Kidney Trials Network and the steering committee

for the Australia and New Zealand Dialysis and Transplant

Registry.

Advisory board: Amgen, Sanoﬁ, Shire

Consultant: Amgen, Sanoﬁ, Shire

Grants/research support: Amgen*, Shire*

Speaker: Amgen, Sanoﬁ, Shire

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Marc G. Vervloet, MD, PhD, FERA,

is a nephrologist, associate professor of

nephrology, and director of the

nephrology research program and se-

nior consultant at the Intensive Care

Medicine and Vascular Medicine, VU

U niversity Medical Center , Amsterdam,

Netherlands. He is program leader at the

Institute of Cardiovascular Rese arch VU

(ICaR-VU), secretary of the CKD-MBD

working group of the Eur opean Renal

Association–E ur opean Dialysis and Transplant Association, and a

member of the scientiﬁc committee of the Dutch Kidney Foun-

dation. Dr . Vervloet obtained his medical degree in 1989, and

graduated as internist in 1997 and as nephrologist in 1999. His

current resear ch interests encompass research on the deranged

bone and metabolism in CKD . Dr. Vervloet currently heads the

hemodialysis unit at his hospital, where he performs instructional

duties to medical students, residents, and nephrology fellows, and

guides several PhD students. He has gained numerous research

grants, mainly covering topics related to CKD-MBD, in particular

on the role of FGF23 and Klotho, and the clinical use of calci-

mimetic therapy . In addition, his laboratory research comprises

severalanimalmodelsofCKDandvitaminDdeﬁciency, exam-

ining mainly cardiovascular endpoints as assessed by imaging

and functional testing in vivo.

Advisory board: Amgen, Fresenius Medical Care

Consultant: Amgen, Fresenius Medical Care, Otsuk a

Grants/research support: AbbVie*, Fresenius Medical Care*,

Sanoﬁ*, Shire*

Speaker: Amgen, Baxter

*Monies paid to institution.

KDIGO Chairs

web 4C=FPOweb 4C=FPO

David C. Wheeler, MD, FRCP, is

professor of kidney medicine at Uni-

versity College London, UK, and

honorary consultant nep hrologist at

the Royal Free London NHS Foun-

dation Trust. He is a clinician scientist

with an interest in the complications

of CKD, speciﬁcally those that in-

crease the burden of cardiovascular

disease and/or accelerate progression

of kidney failure. He has participated

in the design, roll-out, and monitoring of several large-scale

clinical trials . He was a member of the steering committee

of the Study of Heart and Renal Protection (SHARP) and the

EValuation Of Cinacalcet HCl Therapy to Lower CardioVas-

cular Events (EVOLVE). He currently sits on the steering

committee of Canaglifozin and Renal Events in Diabetes with

Established Nephropathy Clinical Evaluation (CREDENCE),

acting as UK principal investigator for this study. He is clinical

lead for Division 2 of the North Thame s Clinical Research

Network and heads a team of eight clinical trial nurses and

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Kidney International Supplements (2017) 7, 1–59

practitioners at the Centre for Nephrology, Royal Free

Hospital in London. He is past president of the UK Renal

Association and past chair of the UK Renal Registry. His

other responsibilities include serving as associate editor

of Nephrology Dialysis Transplantation and member of the

editorial board of Journal of the American Society of

Nephrology.

Consultant: Akebia, Alberta Innovates Health Solutions,

Amgen, AstraZeneca, Bio Nano Consulting, Boehringer

Ingelheim, Bristol-Myers Squibb, Fresenius, GSK, Janssen*,

Otsuka, UCB Celltech, Vifor

Speaker: Amgen, Fresenius Medical Care, Janssen, Vifor

Fresenius Medical Care Renal Pharma, ZS Pharma

*Monies paid to institution.

web 4C=FPOweb 4C=FPO

Wolfgang C. Winkelmayer, MD,

MPH, ScD, is the Gordon A. Cain

Chair of Nephrology and professor of

medicine at Baylor College of Medi-

cine in Houston, TX. Dr. Winkel-

mayer received his medical degree

(1990) from the University of Vienna,

Austria, and later earned a Master of

Public Health degree in health care

management (1999) and a Doctor of

Science degree in health policy (2001)

from Harvard University. He then spent 8 years on the faculty

of Brigham and Women’s Hospital and Harvard Medical

School, where he established himself as a proliﬁc investigator

and leader in the discipline of comparative-effectiveness

research as it pe rtains to patients with kidney disease. From

2009 to 2014, he was the director of clinical research in the

Division of Nephrology at Stan ford University School of

Medicine, Palo Alto, CA. He assumed his current position as

chief of nephrology at Baylor College of Medicine in

September 2014. His main areas of research interest include

comparative effectiveness and safety research of treatment

strategies in anemia as well as of various interventions for

cardiovascular disease in patient s with kidney disease. His

clinical passion lies in providing quality kidney care to the

predominantly disadvantaged and un(der)insured population

in the public safety net health system of Harris County, TX.

Dr. Winkelmayer has authored over 270 peer-reviewed pub-

lications, and he has a particular interest in medical pub-

lishing. He currently serves as an associate editor for The

Journal of the American Medical Association, was a co-editor of

the American Journal of Kidney Diseases from 2007 to 2016,

and has been appointed to several other editorial boards of

leading nephrology and epidemiology journals. He also vol-

unteers his time toward important initiatives of the American

Society of Nephrology (e.g., public policy board). He joined

KDIGO volunteer leadership as an executive committee

member in 2015 and has served as its co-chair since 2016.

Advisory board: Akebia, AMAG Pharmaceuticals, Amgen,

AstraZeneca, Bayer, Daichi Sankyo, Medtronic, Relypsa,

Vifor Fresensius Medical Care Renal Pharma

Consultant: Akebia, AMAG Pharmaceuticals, Amgen,

AstraZeneca, Bayer, Daichi Sankyo, Medtronic, Relypsa,

Vifor Fresensius Medical Care Renal Pharma

Evidence review team

Karen A. Robinson, PhD, is associate professor of medicine,

epidemiolog y and health policy & management, and director

of the Evidence-Based Practice Center at Johns Hopkins

University, serving as the project director. She provided

methodological expertise in the conduct of the systematic

review and guideline development processes, and oversaw and

participated in all aspects of the project, including topic

reﬁnement, abstract and full-text screening, data extraction,

study assessment, evidence grading, and recommendation

formulation.

Dr. Robinson declared no competing interests.

Casey M. Rebholz, PhD, MPH, MS, is assistant professor

of epidemiology at Johns Hopkins Bloomberg School of

Public Health and Core Faculty at the Welch Center for

Prevention, Epidemiology, and Clinical Research. She guided

the team through all phases of the project, includin g reﬁning

the questions, conducting literature searches, screening ab-

stracts and full-text articles, abstracting data, drafting and

ﬁnalizing the evidence tables, and synthesizing the results.

Dr. Rebholz declared no competing interests.

Lisa M. Wilso n, ScM, is a research associate at the

Johns Hopkins University Bloomberg School of Public

Health. As the project coordinator for the evidence review

team, Ms. Wilson managed and participated in all phases

of the project, including conducting literature se arches,

screening abstracts and full-text ar ticles, abstracting data,

drafting and ﬁnalizing the ev idence tables, and synthesizing

the results.

Ms. Wilson declared no competing interests.

Ermias Jirru, MD, MPH, is currently an internal medicine

resident at Mount Sinai St. Luke’s and Mount Sinai West. He

completed his MPH at the Johns Hopkins University

Bloomberg School of Public Health. For this project, he

participated in screening abstracts and full-text articles, and

abstracting data.

Dr. Jirru declared no competing interests.

Marisa Chi Liu, MD, MPH, is currently a resident

physician at University of California, Irvine, in obstetrics and

gynecology. She completed her MPH at Johns Hopkins Uni-

versity Bloomberg School of Public Health and graduated

from the University of Vermont Colleg e of Medicine. For this

project, she participated in screening abstracts and articles,

and abstracting data.

Dr. Liu declared no competing interests.

Jessica Gayleard, BS, is a research assistant within the

Johns Hopkins University Evidence-Based Practice Center.

She participated in all phases of the project, including con-

ducting literature searches, screening abstracts and full-text

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Kidney International Supplements (2017) 7, 1–59 53

articles, abstracting data, and drafting and ﬁnalizing the evi-

dence tables.

Ms. Gayleard declared no competing interests.

Allen Zhang, BS, is a research data analyst at the Johns

Hopkins University Evidence-Based Practice Center. He has a

degree in microbiology from the Virginia Polytechnic

Institute and University. Mr. Zhang participated in the sys-

tematic review development, including search string creation,

screening, data cleaning, data manage ment, and writing. In

addition, he supplied the necessary statistical analysis,

including meta-analyses and meta-regression calculations.

Mr. Zhang declared no competing interests.

biographic and disclosure information www.kisupplements.org

Kidney International Supplements (2017) 7, 1–59

Acknowledgments

A special debt of gratitude is owed to the KDIGO co-chairs,

David Wheeler and Wolfgang Winkelmayer, for their invalu-

able guidance throughout the development of this guideline.

In particular, we thank Karen Robinson and her ERT mem-

bers for their substantial contribution to the rigorous

assessment of the available evidence. We are also especially

grateful to the Work Group members for their expertise

throughout the entire process of literature review, data

extraction, meeting participation, the critical writing and

editing of the statements and rationale, which made the

publication of this guideline possible. The generous gift of

their time and dedication is greatly appreciated. Finally, and

on behalf of the Work Group, we gratefully acknowledge the

careful assessment of the draft guideline by external reviewers.

The Work Group considered all of the valuable comments

made, and where appropriate, suggested changes were

incorporated into the ﬁnal publication. The following in-

dividuals provided feedback during the public review of the

draft guideline:

Patricia Abreu, Adama Lengani, Kamal Ahmed, Bülent

Altun, Luis Felipe Alva, Rui Alves, Pablo Amair, Alessandro

Amore, Andrea Angioi, Mustafa Arici, Mariano Arriola,

Rommel Bataclan, Ezequiel Bellorin-Font, Deborah Benner,

Mohammed Benyahia, Patrick Biggar, Charles Bishop, Boris

Bogov, Jordi Bover, Laura Brereton, Philippe Brunet, Rafael

Burgos-Calderon, Stephen Carrithers, Sue Cary, Rolando

Claure-Del Granado, Adrian Covic, Mario Cozzolino,

Andrew Crannage, John Cunningham, Pierre Delanaye,

Nida Dinçel, Tilman B. Drüeke, Nordin Eezsafryna Azalin,

Grahame J. Elder, Madgy ElSharkawy, Joyce Ezaki-Yamaguchi,

Toshiro Fujita, Alvaro Garc ia, Carlo Francisco Gochui co,

Heong Keong Goh, Hai An Ha Phan, Takayuki Hamano,

Ditte Hansen, Li Hao, Eero Honkanen, Alastair Hutchison ,

Atul Ingale, Joachim H. Ix, Faical Jarraya, Chandra Mauli

Jha, Kamyar Kalantar-Zadeh, Arif Khwaja, Csaba P. Kovesdy,

Holly Kramer, Craig B. Langman, Kevin V. Lemley, Edgar V.

Lerma, Nathan W. Levin, Maria Jesus Lloret, José António

Lopes, Franklin W. Maddux, Francesca Mallamaci, Sandro

Mazzaferro, Peter A. McCullough, Donald A. Molony,

Sameh Morgan, Eugen Mota, Ricardo Mouzo, Lavinia

Neg rea, Armando Negri , Michal Nowicki , Tom Nusbic kel,

Basma Osman, Susan M. Ott, Antonino Paglialunga, Saime

Paydas, Adriana Peñalba, Gerson Marques Pereir a Junior,

Eduardo Perez, Ligia Petrica, Friedrich K. Port, Pradeep

Kumar Rai, Dwarakanathan Ranganathan, Nicolas Roberto

Robles, Cibele Rodrigues, Hector Rodriguez, Guillermo

Rosa Diez, Ibrahim Saig, Deepak Sharma, Laura Sola, David

M. Spiegel, Kyriaki Stamatelou, Ekamol Tantisattamo,

Mihály Tapolyai, Francesca Tentori, Katrin Uhlig, Harun Ur

Rashid, Pablo Ureña Torres, Keth Vuthy, A ngela Yee-Moon

Wang , Talia Weinstein, Jane Wheeler, Janie Xiong, and

Xueqing Y u.

Participation in the review does not necessarily consti-

tute endorsement of the content of this report by the

above individuals, or the organization or institution they

represent.

Markus Ketteler, MD, FERA

Mary B. Leonard, MD, MSCE

Work Group Co-chairs

www.kisupplements.org acknowledgments

Kidney International Supplements (2017) 7, 1–59 55

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