Annals of Internal Medicine

Clinical Guideline

Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline
Paul E. Stevens, MBBS, BSc, and Adeera Levin, MD, BSc, for the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members*

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of chronic kidney disease (CKD) in adults and children who are not receiving renal replacement therapy. Methods: The KDIGO CKD Guideline Development Work Group defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence that had been summarized by an evidence review team. Searches of the English-language literature were conducted through November 2012. Final modification of the guidelines was informed by the

KDIGO Board of Directors and a public review process involving registered stakeholders. Recommendations: The full guideline included 110 recommendations. This synopsis focuses on 10 key recommendations pertinent to definition, classification, monitoring, and management of CKD in adults.
Ann Intern Med. 2013;158:825-830. www.annals.org For author affiliations, see end of text. * For a list of the members of the KDIGO CKD Guideline Development Work Group, see the Appendix (available at www.annals.org).

decade of research after the publication of the rst internationally accepted denition and classication of CKD (1) led the Kidney Disease: Improving Global Outcomes (KDIGO) organization to develop an updated Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (2). The updated guideline applied to all persons with chronic kidney disease (CKD) who were not receiving renal replacement therapy and included aspects related to both adults and children. Within the guideline, implications for clinical practice, public policy, and international considerations were highlighted, along with areas of controversy, confusion, or nonconsensus. The detailed work-up for specic causes of CKD was beyond the scope of the guideline, as were specic approaches to acute kidney injury (AKI) and other acute kidney diseases, diagnostic work-up or treatment of specic causes of CKD, management of CKD in pregnancy, detailed management of endocrine and metabolic complications, and detailed drug dosing. The guideline sought to provide comprehensive guidance encompassing the whole CKD pathway, from early identication and diagnosis through initiation of renal replacement therapy for end-stage renal disease or end-of-life care. The recognition of the importance of patient safety and inclusion of caveats in the use and interpretation of commonly used tests was unique and highly practical. These details can be found in the full guideline (2), and recommendations are listed in the Supplement (available at www.annals.org). This synopsis focuses on the evaluation and classication of CKD, areas that have generated substantial controversy. We also discuss some key recommendations, including the management of CKD progression and complications, and the relationship between AKI and CKD.
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GUIDELINE DEVELOPMENT PROCESS, EVIDENCE GRADING, AND STAKEHOLDER AND PUBLIC CONSULTATION
The work group consisted of an international group of clinicians and researchers, including kidney specialists, primary care physicians, a diabetologist, an epidemiologist, a clinical chemist, administrators, and a professional evidence review team. The work group formulated the scope of the guideline, graded evidence on the basis of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system (35) (Appendix Tables 1 and 2, available at www.annals.org), and made consensus recommendations even when the quality of evidence was low to highlight key concepts and areas of confusion in clinical practice. In addition, the evidence review team did systematic reviews for 8 topics of interest (Appendix Table 3, available at www.annals.org), and searches were last conducted in June 2011 and supplemented with additional evidence through November 2012. Further guideline development, evidence synthesis, and writing of the guideline itself was done by the work group. Full details of the guideline development process, topic discussion, and consensus development can be found in the published guideline (2). The draft guideline was reviewed by the KDIGO Board of Directors, and revisions were incorporated before a structured, Internet-based public review process. Feed-

See also: Web-Only CME quiz Supplement

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Synopsis of Clinical Practice Guideline on Evaluation and Management of CKD

back from this was reviewed by the work group, and nal revisions were incorporated before publication of the guideline.

RECOMMENDATIONS RELATING CLASSIFICATION OF CKD

TO THE

DEFINITION

AND

1.1.1. CKD is dened as abnormalities of kidney structure or function, present for 3 months, with implications for health. (Not Graded)

Criteria for CKD are shown in Table 1. Diagnostic thresholds for glomerular ltration rate (GFR) of less than 60 mL/min per 1.73 m2 and an albumin creatinine ratio (ACR) of 30 mg/g or greater were retained. This was driven by studies examining risk for all-cause and cardiovascular mortality, AKI, CKD progression, and kidney failure in the general population and populations with increased risk for cardiovascular disease (6 9). However, the addition of with implications for health reects the notion that although various abnormalities of kidney structure or function exist, not all have implications for a persons health. For example, although age-associated GFR decline is seen in longitudinal as well as cross-sectional studies, it varies substantially. A GFR less than 60 mL/min per 1.73 m2 is less than half of the normal value in young adult men and women (which is approximately 125 mL/ min per 1.73 m2) and is associated with a higher risk for complications of CKD than in persons with CKD and conserved GFR. The mechanisms underlying these associations are not fully understood, but there is a clinically signicant effect of reduced GFR on drug toxicity, endocrine and metabolic complications, and risk for cardiovascular disease and death. These are relevant to all patients with reduced GFR, regardless of country, age, or cause. An ACR of 30 mg/g is greater than 3 times the normal value in young adult men and women (which is approximately 10 mg/g) and is associated with an increased risk for complications of CKD.
1.2.1. We recommend that CKD is classied based on cause, GFR category, and albuminuria category (CGA). (1B)

The classication system has been revised to encompass cause and severity. Identifying cause is emphasized because of its fundamental importance in predicting outcome and guiding choice of cause-specic treatments. Severity is expressed by level of GFR and albuminuria (Table 2). Severity is linked to risks for adverse outcomes, including death and kidney outcomes. The GFR categories mapping to the previous 5-stage classication have been retained but with subdivision of the G3 category of 30 to 59 mL/min per 1.73 m2 into categories G3a (45 to 59 mL/min per 1.73 m2) and G3b (30 to 44 mL/min per 1.73 m2). This was driven by data supporting different outcomes and risk proles in these categories (6 10). Many other concurrent complications are associated with decreased categories of GFR, including infection, impaired cognitive and physical function, and threats to patient safety. Three albuminuria categories were proposed both for simplication and initial assessment and prognostication. Further classication into higher and nephrotic ranges (ACR 2220 mg/g) may be appropriate for specic circumstances in specialist centers.

RECOMMENDATIONS FOR EVALUATION URINARY ALBUMIN EXCRETION

OF

GFR

AND

Table 1. Criteria for Chronic Kidney Disease*

Markers of kidney damage (>1 for >3 mo) Albuminuria (AER 30 mg/d; ACR 30 mg/g) Urinary sediment abnormalities Electrolyte and other abnormalities due to tubular disorders Abnormalities detected by histology Structural abnormalities detected by imaging History of kidney transplantation Decreased GFR (for >3 mo) GFR 60 mL/min per 1.73 m2 (GFR categories G3aG5)

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was recommended for reporting estimated GFR (eGFR) in adults from serum creatinine levels measured by an assay calibrated to the isotopedilution mass spectrometry reference method. Systematic review supported the strength of this recommendation (evidence level 1B). The CKD-EPI equation had less bias than the MDRD (Modication of Diet in Renal Disease) Study equation, especially at a GFR of 60 mL/min per 1.73 m2 or greater; a small improvement in precision; and greater accuracy (11). Most but not all studies from North America, Europe, and Australia show that the CKD-EPI equation is more accurate than the MDRD Study equation, especially at greater GFR, enabling reporting of numerical values across the range of GFRs. Selection of a single equation for use should facilitate communication among providers, patients, researchers, and public health ofcials. However, where CKD-EPI has been modied for use in other racial and ethnic groups, and where validated country- or region-specic equations have been developed, these should be used in preference to unmodied equations.
1.4.3.5. We suggest measuring cystatin C in adults with eGFRcreat [creatinine-based eGFR] 45-59 ml/ min/1.73 m2 who do not have other markers of kidney damage if conrmation of CKD is required. (2C)

ACR albumin creatinine ratio; AER albumin excretion rate; GFR glomerular ltration rate. * Reproduced from reference 2.
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The guideline acknowledged that this is a contentious area with potential health economics consequences and that not all laboratories internationally will be able to assay
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Clinical Guideline

Table 2. GFR and Albuminuria Categories in the New Classification

Category GFR G1 G2 G3a G3b G4 G5 Albuminuria A1 A2 A3 GFR, mL/min per 1.73 m2 90 6089 4559 3044 1529 15 AER, mg/d ACR Equivalent, mg/g Descriptor Normal or high Mildly decreased* Mildly to moderately decreased Moderately to severely decreased Severely decreased Kidney failure

30 30300 300

30 30300 300

Normal to mildly increased Moderately increased* Severely increased

ACR albumin creatinine ratio; AER albumin excretion rate; GFR glomerular ltration rate. * Relative to young adult level. In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulll the criteria for chronic kidney disease. Including the nephrotic syndrome (AER usually 2200 mg/d [ACR 2220 mg/g]).

cystatin C. Evidence supports the use of cystatin C based eGFR (eGFRcys) in persons without albuminuria (category A1) or other markers of kidney damage, especially those with an eGFRcreat of 45 to 59 mL/min per 1.73 m2 (category G3a) (12, 13). This group represents 3.6% of the U.S. population and 41% of persons in the United States estimated to have CKD on the basis of eGFRcreat and urinary ACR alone. Because the diagnosis of CKD in these persons is an area of substantial controversy with potential implications from disease labeling, the potential utility of a conrmatory marker is important. Use of eGFRcys to conrm CKD in populations has shown that two thirds of persons with eGFRcreat less than 60 mL/min per 1.73 m2 have a diagnosis of CKD conrmed by eGFRcys less than 60 mL/min per 1.73 m2 and had markedly elevated risks for death, cardiovascular disease, and end-stage renal disease compared with those with eGFRcys greater than 60 mL/min per 1.73 m2.
1.4.4.2. We recommend that clinical laboratories report albumin:creatinine ratios (ACR) and protein:creatinine ratios (PCR) in untimed urine samples in addition to albumin concentration or proteinuria concentrations rather than the concentrations alone. (1B)

1.4.4.2.1. The term microalbuminuria should no longer be used by laboratories. (Not Graded)

Although the signicance of the A2 category of ACR (30 to 300 mg/g) has been understood in persons with diabetes for decades, use of this category to denote CKD, especially in those with higher GFRs, remains controversial. However, data demonstrate that, at any level of GFR, an ACR increase above normal is associated with increased risk for adverse outcomes and that this increased risk is a continuum (6 9). It was, therefore, suggested that the term microalbuminuria no longer be used.

RECOMMENDATIONS

FOR

MONITORING CKD

Measurement of urinary ACR was recommended for evaluation of proteinuria in preference to urinary total protein for many reasons. Albumin is the most important protein lost in the urine in most cases of CKD. In population studies, urinary ACR accurately predicts kidney and cardiovascular risks (6 9, 14 19). Reduction in ACR in intervention trials targeted at blood pressure (BP) reduction or reninangiotensin blockade has shown benet for progression of CKD. Urinary ACR has greater sensitivity for detecting low-grade but clinically important albuminuria and is more precise at low but diagnostically important concentrations (20).
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Persons with CKD should be assessed at least annually. The exact frequency of GFR and ACR monitoring will depend on the severity of CKD (Figure) and the risk for and rate of progression. Factors associated with progression include cause of CKD, level of GFR, level of albuminuria, AKI, age, sex, race or ethnicity, elevated BP, hyperglycemia, dyslipidemia, smoking, obesity, history of cardiovascular disease, ongoing exposure to nephrotoxic agents, and others. Small uctuations in GFR are common and do not necessarily indicate progression. An approach involving an assessment of change in eGFR category conrmed by a minimal percentage of change in eGFR (25% or greater) was recommended to dene progression. The reasoning for this was that although longitudinal cohort studies examining progression have assumed that progression is linear, this is often not the case. The greater the uctuation in kidney function, the higher the probability of nonlinear progression (21, 22). A criterion requiring both a change in GFR category (that is, from category G2 to G3a) and percentage of change would ensure that small changes in GFR (from 61 to 59 mL/min per 1.73 m2, for example, which
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Figure. Guide to frequency of monitoring by GFR and albuminuria categories.

Persistent Albuminuria Categories Description and Range

A1

A2

A3

Normal to mildly increased

Moderately increased

Severely increased

ACR <30 mg/g

ACR of 30300 mg/g

ACR >300 mg/g

G1

Normal or high

90

1 if CKD

GFR Categories (mL/min per 1.73 m2) Description and Range

G2

Mildly decreased

6089

1 if CKD

G3a

Mildly to moderately decreased

4559

G3b

Moderately to severely decreased

3044

G4

Severely decreased

1529

4+

G5

Kidney failure

<15

4+

4+

4+

This GFR and albuminuria grid reects the risk for progression by intensity of coloring. The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). Reproduced from reference 2. ACR albumin creatinine ratio; CKD chronic kidney disease; GFR glomerular ltration rate.

represents a change in category but a minimal change in GFR) would not be misinterpreted to represent progression. Preliminary studies have indicated that this approach identies those at increased risk (2325). Data were insufcient to inform recommendations dening albuminuria progression, although increasing levels of albuminuria suggest progression and has been shown to be associated with increased risk for adverse outcomes.

diastolic be treated with BP-lowering drugs to maintain a BP that is consistently 140 mm Hg systolic and 90 mm Hg diastolic. (1B) 3.1.5 We suggest that both diabetic and non-diabetic adults with CKD and with urine albumin excretion of 30 mg/24 hours (or equivalent) whose ofce BP is consistently 130 mm Hg systolic or 80 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently 130 mm Hg systolic and 80 mm Hg diastolic. (2D) 3.1.7 We recommend that an ARB [angiotensinreceptor blocker] or ACE-I [angiotensin-converting enzyme inhibitor] be used in both diabetic and nondiabetic adults with CKD and urine albumin excretion 300 mg/24 hours (or equivalent). (1B)

MANAGEMENT

OF

CKD

Detailed within the guideline were many management recommendations for prevention of CKD progression and management of specic complications of CKD (see Supplement). Key recommendations relating to BP control, proteinuria reduction, AKI, and cardiovascular disease are summarized.
3.1.4 We recommend that both diabetic and nondiabetic adults with CKD and urine albumin excretion 30 mg/24 hours (or equivalent) whose ofce BP is consistently 140 mm Hg systolic or 90 mm Hg
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Control of blood pressure and reduction of proteinuria are critical in preventing CKD progression. Studies have consistently shown that reduction of proteinuria using
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Clinical Guideline

reninangiotensinaldosterone system (RAAS) interruption slows progression of both diabetic and nondiabetic nephropathy. Lowering blood pressure also slows CKD progression, breaking a potentially vicious cycle associating hypertension and CKD. Evidence is insufcient to recommend combining an angiotensin-converting enzyme inhibitor with angiotensin-receptor blockers to prevent CKD progression. In formulating statements about blood pressure control and RAAS interruption, the recommendations in the KDIGO guidance on blood pressure control in CKD were followed to maintain consistency (26). Lifestyle interventions (reduced sodium intake to 2 g per day, achieving a healthy body mass index of 20 to 25 kg/m2, smoking cessation, and exercising for 30 minutes 5 times per week) and good diabetes control (target hemoglobin A1c level of 7%) are also linked to reduction of proteinuria and alleviation of CKD progression (2730).
3.1.12. We recommend that all people with CKD are considered to be at increased risk of AKI. (1A)

The goal of this recommendation was to promote awareness of the complex relationship between CKD and AKI. Evidence demonstrates that CKD remains an independent risk factor for AKI, even after multivariate adjustment for comorbid conditions (31). Mounting evidence suggests that AKI is a risk factor for both incident CKD and progression of CKD. Both CKD and AKI increase in prevalence with age, and we are an aging population.
4.1.2 We recommend that the level of care for ischemic heart disease offered to people with CKD should not be prejudiced by their CKD. (1A)

Persons with CKD are more likely to have a cardiovascular event than to progress to end-stage renal disease; have worse prognosis with higher mortality rates after acute myocardial infarction; and higher risk for recurrent myocardial infarction, heart failure, and sudden cardiac death (32). Despite this, the level of care offered to persons with CKD is still frequently suboptimal.

fore, we chose to include only kidney-related measures, and by including cause of CKD, we acknowledge the true differences in the natural history of kidney disease of different causes. The revised classication provides a framework for the next decade of reporting and research in CKD. Whether decreased GFR or increased ACR in older persons represents a disease or normal aging will always be debatable, and disease labeling will continue to provoke controversy in an aging society. Persons older than 75 years have a spectrum of GFRs exceeding 60 mL/min per 1.73 m2 with and without albuminuria, as well as values less than 60 mL/min per 1.73 m2. Aging is associated with accruing comorbid conditions and the use of medications that may result in reductions in GFR and albuminuria, and that is an underappreciated aspect of the argument about aging and eGFR. It is no accident that 37% of the recommendations in the guideline were ungraded and only 10% were graded A for quality of the evidence. Much of the research generated in the past decade has been aimed at denition and evaluation of CKD, together with identication of persons with CKD and description of the associated adverse outcomes of CKD. We have some good trial data about interventions, such as RAAS blockade in proteinuric CKD and use of statin therapy for CKD (34, 35), and limited trial data in other areas, such as bicarbonate therapy for acidosis. We need much more data if we want to affect outcomes. We need to know exactly which interventions are benecial in prevention or alleviation of both CKD progression and the associated adverse outcomes and how and when these interventions should be applied. We also need to know when interventions that are believed to be benecial may actually cause harm. For example, indiscriminate use of RAAS blockade in those with lower GFR and no specic indication other than hypertension may expose persons to additional risk for AKI with no benet. Allied to these areas, we need a much better understanding of denitions of CKD progression and how they affect clinical practice and trials, how the relationship between AKI and CKD relates to progression, and whether we can positively inuence this relationship.
From Kent Kidney Care Centre, East Kent Hospitals University NHS Foundation Trust, Canterbury, United Kingdom, and University of British Columbia, Vancouver, British Columbia, Canada.
Acknowledgment: The authors thank the KDIGO co-chairs Bertram L.

DISCUSSION
The CKD classication system now encompasses cause of CKD, GFR category, and albuminuria category. This 3-dimensional approach builds on the simpler earlier version, and the timing of these changes is appropriate, given the current familiarity of general physicians with the simpler version and the need to address common misunderstandings in a systematic manner. It has been argued that additional factors, such as blood pressure, should be included within the classication (33); however, while rening the existing staging system, we also wanted to retain the simplicity and easy applicability of a classication system in clinical, research, and public health practice. Therewww.annals.org

Kasiske, Kai-Uwe Eckardt, David C. Wheeler; the evidence review team (Katrin Uhlig, Dana C. Miskulin, Amy Earley, Shana Haynes, Michael Cheung); and all those who provided feedback during the public review of the draft guideline.
Potential Conflicts of Interest: Dr. Levin: Consultancy (money to insti-

tution): Abbott Laboratories, Merck & Co; Grants/grants pending (money to institution): Canadian Institutes of Health Research (CIHR), Kidney Foundation, Merck & Co, Ortho. Dr. Stevens: None disclosed. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConictOf InterestForms.do?msNumM13-0034.
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16. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al; ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813-21. [PMID: 19443635] 17. Viazzi F, Leoncini G, Conti N, Tomolillo C, Giachero G, Vercelli M, et al. Combined effect of albuminuria and estimated glomerular ltration rate on cardiovascular events and all-cause mortality in uncomplicated hypertensive patients. J Hypertens. 2010;28:848-55. [PMID: 20087212] 18. Shastri S, Katz R, Shlipak MG, Kestenbaum B, Peralta CA, Kramer H, et al. Cystatin C and albuminuria as risk factors for development of CKD stage 3: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis. 2011;57: 832-40. [PMID: 21296473] 19. Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol. 2009;20:1069-77. [PMID: 19357254] 20. Lamb EJ, MacKenzie F, Stevens PE. How should proteinuria be detected and measured? Ann Clin Biochem. 2009;46:205-17. [PMID: 19389884] 21. Li L, Astor BC, Lewis J, Hu B, Appel LJ, Lipkowitz MS, et al. Longitudinal progression trajectory of GFR among patients with CKD. Am J Kidney Dis. 2012;59:504-12. [PMID: 22284441] 22. OHare AM, Batten A, Burrows NR, Pavkov ME, Taylor L, Gupta I, et al. Trajectories of kidney function decline in the 2 years before initiation of longterm dialysis. Am J Kidney Dis. 2012;59:513-22. [PMID: 22305760] 23. Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, et al. One-year change in kidney function is associated with an increased mortality risk. Am J Nephrol. 2012;36:41-9. [PMID: 22699706] 24. Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, et al. Short-term change in kidney function and risk of end-stage renal disease. Nephrol Dial Transplant. 2012;27:3835-43. [PMID: 22764191] 25. Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, et al. Change in the estimated glomerular ltration rate over time and risk of all-cause mortality. Kidney Int. 2013. [PMID: 23344477] 26. Kidney Disease: Improving Global Outcomes (KDIGO) BP Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2:337-414. 27. Jones-Burton C, Mishra SI, Fink JC, Brown J, Gossa W, Bakris GL, et al. An in-depth review of the evidence linking dietary salt intake and progression of chronic kidney disease. Am J Nephrol. 2006;26:268-75. [PMID: 16763384] 28. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4:1565-74. [PMID: 19808241] 29. Wakasugi M, Kazama JJ, Yamamoto S, Kawamura K, Narita I. A combination of healthy lifestyle factors is associated with a decreased incidence of chronic kidney disease: a population-based cohort study. Hypertens Res. 2012. [PMID: 23171953] 30. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012;60:850-86. [PMID: 23067652] 31. Bedford M, Farmer C, Levin A, Ali T, Stevens P. Acute kidney injury and CKD: chicken or egg? [Editorial]. Am J Kidney Dis. 2012;59:485-91. [PMID: 22444492] 32. Herzog CA, Asinger RW, Berger AK, Charytan DM, D ez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80: 572-86. [PMID: 21750584] 33. Burgos-Calderon R, Depine S. Systematic approach for the management of chronic kidney disease: moving beyond chronic kidney disease classication. Curr Opin Nephrol Hypertens. 2010;19:208-13. [PMID: 19779338] 34. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006; 116:288-96. [PMID: 16453013] 35. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377: 2181-92. [PMID: 21663949]

Requests for Single Reprints: Paul E. Stevens, MBBS, BSc, Kent Kid-

ney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, United Kingdom; e-mail, pstevens@nhs.net. Current author addresses and author contributions are available at www .annals.org.

References
1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classication, and stratication. Am J Kidney Dis. 2002;39:S1-266. [PMID: 11904577] 2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150. 3. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490. [PMID: 15205295] 4. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al; GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336:1049-51. [PMID: 18467413] 5. Uhlig K, Macleod A, Craig J, Lau J, Levey AS, Levin A, 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;70:2058-65. [PMID: 17003817] 6. Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular ltration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79:1331-40. [PMID: 21289598] 7. Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80:93-104. [PMID: 21289597] 8. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular ltration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-81. [PMID: 20483451] 9. van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular ltration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 2011;79:1341-52. [PMID: 21307840] 10. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The denition, classication, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17-28. [PMID: 21150873] 11. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating equations for glomerular ltration rate in the era of creatinine standardization: a systematic review. Ann Intern Med. 2012;156:785-95. [PMID: 22312131] 12. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, et al. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA. 2011;305:1545-52. [PMID: 21482744] 13. Waheed S, Matsushita K, Sang Y, Hoogeveen R, Ballantyne C, Coresh J, et al. Combined association of albuminuria and cystatin C-based estimated GFR with mortality, coronary heart disease, and heart failure outcomes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2012;60:20716. [PMID: 22537422] 14. Rifkin DE, Katz R, Chonchol M, Fried LF, Cao J, de Boer IH, et al. Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. Nephrol Dial Transplant. 2010;25:1560-7. [PMID: 20008829] 15. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164-76. [PMID: 15616252]

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Current Author Addresses: Dr. Stevens: Kent Kidney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, United Kingdom. Dr. Levin: St. Pauls Hospital, Providence Wing, Room 6010A, 1160 Burrard Street, Vancouver, British Columbia V6Z 1Y8, Canada. Author Contributions: Conception and design: A. Levin.

Administrative, technical, or logistic support: A. Levin. Collection and assembly of data: A. Levin.

APPENDIX: KDIGO CKD GUIDELINE DEVELOPMENT WORK GROUP MEMBERS

Rudy W. Bilous, Josef Coresh, Angel L.M. de Francisco, Paul de Jong, Kathryn E. Grifth, Brenda R. Hemmelgarn, Kunitoshi Iseki, Edmund J. Lamb, Andrew S. Levey, Miguel C. Riella, Michael G. Shlipak, Haiyan Wang, Colin T. White, and Christopher G. Winearls.

Analysis and interpretation of the data: A. Levin. Drafting of the article: P.E. Stevens, A. Levin. Critical revision for important intellectual content: P.E. Stevens, A. Levin. Final approval of the article: P.E. Stevens, A. Levin.

Appendix Table 1. GRADE Criteria Used for Grade Levels in the KDIGO CKD Guideline
Grade Level* Patients 1 (We recommend) 2 (We suggest) Most persons in this situation wouldand only a small proportion would notwant the recommended course of action. Most persons in this situation wouldbut many would notwant the recommended course of action. Clinicians Most patients should receive the recommended course of action. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with his or her values and preferences. Implications Policy The recommendation can be evaluated as a candidate for developing a policy or performance measure. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.

CKD chronic kidney disease; GRADE Grading of Recommendations Assessment, Development, and Evaluation; KDIGO Kidney Disease: Improving Global Outcomes. * The additional category Not Graded was typically used to provide guidance on the basis of common sense or where the topic does not allow adequate application of evidence.

Appendix Table 2. GRADE Criteria Used for Letter Grades in the KDIGO CKD Guideline
Letter Grade A B C D Quality of Evidence High Moderate Low Very low Meaning We are confident that the true effect lies close to that of the estimate of the effect. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. The true effect may be substantially different from the estimate of the effect. The estimate of the effect is very uncertain and often will be far from the truth.

CKD chronic kidney disease; GRADE Grading of Recommendations Assessment, Development, and Evaluation; KDIGO Kidney Disease: Improving Global Outcomes.

Appendix Table 3. Topics Chosen for Systematic Review

Topic Nontreatment Prediction equations for GFR Question How do serum creatinine or cystatin Cbased prediction equations perform compared with gold standard measurement of GFR? What prediction equations predict kidney failure? What is the incidence of NFD after exposure to gadolinium? What is the incidence of AKI after taking a phosphate-containing bowel preparation? Population Patients in steady state with or without CKD and other special populations (DM, hypertension, KTRs or donors, various age groups, races, or ethnic groups) Patients with a GFR 60 mL/min per 1.73 m2 or KTRs Patients with a GFR 60 mL/min per 1.73 m2 or KTRs Patients within any GFR category; individuals without CKD

Prediction equations for risk for kidney failure Gadolinium exposure and NFD AKI and phosphate-containing bowel preparations Treatment Treatment with bicarbonate Treatment with allopurinol Timing of initiation of RRT in CKD Protein restriction

Does treatment with bicarbonate in CKD improve clinical outcomes? Does treatment with allopurinol in CKD improve clinical outcomes? When should dialysis be started (early or late)? Should patients with CKD be on a protein-restricted diet?

Patients with a GFR 60 mL/min per 1.73 m2 or KTRs Patients with a GFR 60 mL/min per 1.73 m2 or KTRs with or without hyperuricemia Patients with a GFR 30 mL/min per 1.73 m2 Patients with a GFR 60 mL/min per 1.73 m2 or KTRs

AKI acute kidney injury; CKD chronic kidney disease; DM diabetes mellitus; GFR glomerular ltration rate; KTR kidney transplant recipient; NFD nephrogenic brosing dermopathy; RRT renal replacement therapy.

W-332 4 June 2013 Annals of Internal Medicine Volume 158 Number 11

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