CLINICAL GUIDELINE

Evaluation and Management of Chronic Kidney Disease: Synopsis ofthe Kidney Disease: Improving Global Dutcomes 2012 ClinicalPractice GuidelinePaul 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 2012to provide guidance on the evaluation, management, and treat-ment of chronic kidney disease (CKD) in adults and children whoare not receiving renal replacement therapy.

Methods: The KDIGO CKD Guideline Development Work Groupdefined the scope of the guideline, gathered evidence, determinedtopics for systematic review, and graded the quality of evidencethat had been summarized by an evidence review team. Searchesof the English-language literature were conducted through Novem-ber 2012. Final modification of the guidelines was informed by the

KDIGO Board of Directors and a public review process involvingregistered stakeholders.

Recommendations: The full guideline included 110 recommenda-tions. This synopsis focuses on 10 key recommendations pertinentto definition, classification, monitoring, and management of CKD inadults.

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 WorkGroup, see the Appendix (available at www.annals.org).

A decade of research after the publication of the firstinternationally accepted definition and classification

of CKD (1) led the Kidney Disease: Improving ClobalOutcomes (KDICO) organization to develop an updatedClinical Practice Guideline for the Evaluation and Man-agement of Chronic Kidney Disease (2). The updatedguideline applied to all persons with chronic kidney disease(CKD) who were not receiving renal replacement therapyand included aspects related to both adults and children.Within the guideline, implications for clinical practice,public policy, and international considerations were high-lighted, along with areas of controversy, confusion, or non-consensus. The detailed work-up for specific causes ofCKD was beyond the scope of the guideline, as were spe-cific approaches to acute kidney injury (AKI) and otheracute kidney diseases, diagnostic work-up or treatment ofspecific causes of CKD, management of CKD in preg-nancy, detailed management of endocrine and metaboliccomplications, and detailed drug dosing.

The guideline sought to provide comprehensive guid-ance encompassing the whole CKD pathway, from earlyidentification and diagnosis throtigh initiation of renal re-placement therapy for end-stage renal disease or end-of-lifecare. The recognition of the importance of patient safetyand inclusion of caveats in the tise and interpretation ofcommonly used tests was unique and highly practical.These details can be found in the full guideline (2), andrecommendations are listed in the Supplement (availableat www.annals.org). This synopsis focuses on the evalua-tion and classification of CKD, areas that have generatedsubstantial controversy. We also discuss some key recom-mendations, including the management of CKD progres-sion and complications, and the relationship between AKIand CKD.

GuiDEUNE DEVELOPMENT PROCESS, EVIDENCE

GRADING, AND STAKEHOLDER AND PUBLIC

CONSULTATION

The work group consisted of an international groupof clinicians and researchers, including kidney specialists,primary care physicians, a diabetologist, an epidemiologist,a clinical chemist, administrators, and a professional evi-dence review team. The work group formulated the scopeof the guideline, graded evidence on the basis of theCRADE (Grading of Recommendations Assessment, De-velopment and Evaluation) system (3-5) (Appendix Ta-bles 1 and 2, available at www.annals.org), and made con-sensus recommendations even when the quality of evidencewas low to highlight key concepts and areas of confusion inclinical practice. In addition, the evidence review team didsystematic reviews for 8 topics of interest (Appendix Table3, available at www.annals.org), and searches were last con-ducted in June 2011 and supplemented with additionalevidence through November 2012. Further guideline de-velopment, evidence synthesis, and writing of the guidelineitself was done by the work group. Full details of the guide-line development process, topic discussion, and consensusdevelopment can be found in the published guideline (2).

The draft guideline was reviewed by the KDIGOBoard of Directors, and revisions were incorporated beforea structured, Internet-based public review process. Feed-

See also:

Web-OnlyCME quizSupplement

© 2013 American College of Physicians 825

i^ LIN ICA L LrUIDELINE Synopsis of ClinicaJ Practice Guideline on Evaluation and Management of CKD

back from this was reviewed by the work group, and finaJrevisions were incorporated before pubhcation of theguideline.

RECOMMENDATIONS RELATING TO THE DEFINITION AND

CLASSIFICATION OF CKD

1.1.1. CKD is defined as abnormalities of kidney struc-ture or function, present for >3 months, with implica-tions for health. (Not Graded)

Criteria for CKD are shown in Table 1. Diagnosticthresholds for glomerular filtration rate (GFR) of less than60 mL/min per 1.73 m and an albumin—creatinine ratio(ACR) of 30 mg/g or greater were retained. This wasdriven by studies examining risk for all-cause and cardio-vascular mortality, AKI, CKD progression, and kidney fail-ure in the general population and populations with in-creased risk for cardiovascular disease (6-9). However, theaddition of "with implications for health" reflects the no-tion that although various abnormalities of kidney struc-ture or function exist, not all have implications for a per-son's health. For example, although age-associated GFRdecline is seen in longitudinal as well as cross-sectionalstudies, it varies substantially. A GFR less than 60 mL/minper 1.73 m is less than half of the normal value in youngadult men and women (which is approximately 125 mL/min per 1.73 m^) and is associated with a higher risk forcomplications of CKD than in persons with GKD andconserved GFR. The mechanisms underlying these associ-ations are not fully understood, but there is a clinicallysignificant effect of reduced GFR on drug toxicity, endo-crine and metabolic complications, and risk for cardiovas-cular disease and death. These are relevant to all patientswith reduced GFR, regardless of country, age, or cause. AnACR of 30 mg/g is greater than 3 times the normal valuein young adult men and women (which is approximately10 mg/g) and is associated with an increased risk for com-plications of CKD.

1.2.1. We recommend that CKD is classified based oncause, CFR category, and albuminuria category (CGA).OB)

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 abnormalitiesElectrolyte and other abnormalities due to tubular disordersAbnormalities detected by histologyStructural abnormalities detected by imagingHistory of kidney transplantation

Decreased GFR (for >3 mo)CFR <60 mL/min per 1.73 m^ (GFR categories C3a-G5)

ACR = albumin-creatinine ratio; AER = albumin excretion rate; GFR = glo-merular filtration rate.* Reproduced from reference 2.

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The classification system has been revised to encom-pass cause and severity. Identifying cause is emphasizedbecause of its fundamental importance in predicting out-come and guiding choice of cause-specific treatments. Se-verity is expressed by level of GFR and albuminuria (Table2). Severity is linked to risks for adverse outcomes, includ-ing death and kidney outcomes.

The GFR categories mapping to the previous 3-stageclassification have been retained but with subdivision ofthe G3 category of 30 to 59 mL/min per 1.73 m^ intocategories G3a (45 to 59 mL/min per 1.73 m^) and G3b(30 to AA mL/min per 1.73 m^). This was driven by datasupporting different outcomes and risk profiles in thesecategories (6-10). Many other concurrent complicationsare associated with decreased categories of GFR, includinginfection, impaired cognitive and physical function, andthreats to patient safety.

Three albuminuria categories were proposed both forsimplification and initial assessment and prognostication.Further classification into higher and nephrotic ranges(ACR >2220 mg/g) may be appropriate for specific cir-cumstances in specialist centers.

RECOMMENDATIONS FOR EVALUATION OF GFR AND

URINARY ALBUMIN EXCRETION

The Chronic Kidney Disease Epidemiology Collabo-ration (CKD-EPI) equation was recommended for report-ing estimated GFR (eGFR) in adults from serum creatininelevels measured by an assay calibrated to the isotope-dilution mass spectrometry reference method. Systematicreview supported the strength of this recommendation(evidence level IB). The CKD-EPI equation had less biasthan the MDRD (Modification of Diet in Renal Disease)Study equation, especially at a GFR of 60 mL/min perL73 m or greater; a small improvement in precision; andgreater accuracy (11). Most but not all studies from NorthAmerica, Europe, and Australia show that the CKD-EPIequation is more accurate than the MDRD Study equa-tion, especially at greater GFR, enabling reporting of nu-merical values across the range of GFRs. Selection of asingle equation for use should facilitate communicationamong providers, patients, researchers, and public healthofficials. However, where CKD-EPI has been modified foruse in other racial and ethnic groups, and where validatedcountry- or region-specific equations have been developed,these should be used in preference to unmodified equations.

1.4.3.5- We suggest measuring cystatin C in adultswith eGFRcreat [creatinine-based eGFR] 45-59 ml/min/1.73 m who do not have other markers of kidneydamage if confirmation of CKD is required. (2C)

The guideline acknowledged that this is a contentiousarea with potential health economics consequences andthat not all laboratories internationally will be able to assay

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Synopsis of Clinical Practice Guideline on Evaluation and Management of CKD CiLINICAL LrUIDELINE

Table 2. GFR

Category

CFR' 0 1

G2' 03a

03b0405

AlbuminuriaL Al

A2A3

and Albuminuria Categories in the

GFR, mL/min per 1.73 m^

S9060-8945-5930-4415-29<15

_-

-

New Classification

AER, mg/d

-----

<3030-300>300

ACR Equivalent, mg/g

-----

<3030-300>300

Descriptor

Normal or highMildly decreased'tMildly to moderately decreasedModerately to severely decreasedSeverely decreased |Kidney failure

Normal to mildiy increasedModerately increased*Severely increased*

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

cystatin G. Evidence supports the use of cystatin G-basedeGFR (eGFRcys) in persons without albuminuria (cate-gory Al) or other markers of kidney damage, especiallythose with an eGFRcreat of 45 to 59 mL/min per 1.73 m^(category G3a) (12, 13). This group represents 3.6% of theU.S. population and 41% of persons in the United Statesestimated to have GKD on the basis of eGFRcreat andurinary AGR alone. Because the diagnosis of GKD in thesepersons is an area of substantial controversy with potentialimplications from disease labeling, the potential utility of aconfirmatory marker is important. Use of eGFRcys to con-firm GKD in populations has shown that two thirds ofpersons with eGFRcreat less than 60 mL/min per 1.73 m^have a diagnosis of GKD confirmed by eGFRcys less than60 mL/min per 1.73 m'̂ and had markedly elevated risksfor death, cardiovascular disease, and end-stage renal dis-ease compared with those with eGFRcys greater than 60mL/min per 1.73 m'̂ .

1.4.4.2. We recommend that clinical laboratories re-port albuminxreatinine ratios (ACR) and proteinxrea-tinine ratios (PCR) in untimed urine samples inaddition to albumin concentration or proteinuria con-centrations rather than the concentrations alone. (IB)

Measurement of urinary AGR was recommended forevaluation of proteinuria in preference to urinary total pro-tein for many reasons. Albumin is the most important pro-tein lost in the urine in most cases of GKD. In populationstudies, urinary AGR accurately predicts kidney and car-diovascular risks (6-9, 14-19). Reduction in AGR in in-tervention trials targeted at blood pressure (BP) reductionor renin-angiotensin blockade has shown benefit for pro-gression of GKD. Urinary AGR has greater sensitivity fordetecting low-grade but clinically important albuminuriaand is more precise at low but diagnostically importantconcentrations (20).

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1.4.4.2.1. The term microalbuminuria should no lon-ger be used by laboratories. (Not Graded)

Although the significance of the A2 category of AGR(30 to 300 mg/g) has been understood in persons withdiabetes for decades, use of this category to denote GKD,especially in those with higher GFRs, remains controver-sial. However, data demonstrate that, at any level of GFR,an AGR increase above normal is associated with increasedrisk for adverse outcomes and that this increased risk is acontinuum (6-9). It was, therefore, suggested that theterm "microalbuminuria" no longer be used.

RECOMMENDATIONS FOR MONITORING CKD

Persons with GKD should be assessed at least annu-ally. The exact frequency of GFR and AGR monitoringwill depend on the severity of GKD (Figure) and the riskfor and rate of progression. Factors associated with pro-gression include cause of GKD, level of GFR, level of al-buminuria, AKI, age, sex, race or ethnicity, elevated BP,hyperglycemia, dyslipidemia, smoking, obesity, history ofcardiovascular disease, ongoing exposure to nephrotoxicagents, and others.

Small fluctuations in GFR are common and do notnecessarily indicate progression. An approach involving anassessment of change in eGFR category confirmed by aminimal percentage of change in eGFR (25% or greater)was recommended to define progression. The reasoning forthis was that although longitudinal cohort studies examin-ing progression have assumed that progression is linear,this is often not the case. The greater the fiuctuation inkidney function, the higher the probability of nonlinearprogression (21, 22). A criterion requiring both a change inGFR category (that is, from category G2 to G3a) and per-centage of change would ensure that small changes in GFR(from 61 to 59 mL/min per 1.73 m^, for example, which

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L-'LINICAL V J U I D E L I N E Synopsis of Ciinical Practice Guideline on Evaluation and Management of CKD

Figure. Guide to frequency of monitoring by GFR and albuminuria categories.G

FR C

ateg

ori

es (

mL

/min

per

1.7

3 m

')D

escr

ipti

on

and

Ran

ge

G1

G2

G3a

G3b

G4

G5

Normal or high

Mddty decreased

Mildly to moderatelydecreased

Moderately toseverely decreased

Severely decreased

Kidney failure

£90

60-89

45-59

30-44

15-29

<15

Persistent Albuminuria CategoriesDescription and Range

Al

Normal tomildly

increased

ACR <30 mg/g

1 if CKD

1 if CKD

1

2•

A2

Moderatelyincreased

ACR of 30-300 mg/g

1

1

2•A3

Severelyincreased

ACR >300 mg/g

2

2

1This GFR and albuminuria grid reflects the risk for progression by intensity of coloring. The numbers in the boxes are a guide to the frequency ofmonitoring (number of times per year). Reproduced from reference 2. ACR = albumin-creatinine ratio; CKD = chronic kidney disease; GFR =glomerular filtration rate.

represents a change in category but a minimal change inGFR) would not be misinterpreted to represent progres-sion. Preliminary studies have indicated that this approachidentifies those at increased risk (23-25).

Data were insufficient to inform recommendations de-fining albuminuria progression, although increasing levelsof albuminuria suggest progression and has been shown tobe associated with increased risk for adverse outcomes.

MANAGEMENT OF CKD

Detailed within the guideline were many managementrecommendations for prevention of CKD progression andmanagement of specific complications of CKD (see Sup-plement). Key recommendations relating to BP control,proteinuria reduction, AKI, and cardiovascular disease aresummarized.

3.1.4 We recommend that both diabetic and non-diabetic adults with CKD and urine albumin excretion<30 mg/24 hours (or equivalent) whose office BP isconsistently >14O mm Hg systolic or >90 mm Hg

828 4Junc2013 Annals of Internal Medicine Volume 158 • Number 11

diastolic be treated with BP-lowering drugs to maintaina BP that is consistently <14O mm Hg systolic and<90 mm Hg diastolic. (IB)

3.1.5 We suggest that both diabetic and non-diabeticadults with CKD and with urine albumin excretion of^ 3 0 mg/24 hours (or equivalent) whose office BP isconsistently >130 mm Hg systolic or >80 mm Hgdiastolic be treated with BP-lowering drugs to maintaina BP that is consistently £130 mm Hg systolic and<80 mm Hg diastoiic. (2D)

3.1.7 We recommend chat an ARB [angiotensin-receptor blocker] or ACE-I [angiotensin-converting en-zyme inhibitor] be used in both diabetic and non-diabetic adults with CKD and urine albumin excretion>300 mg/24 hours (or equivalent). (IB)

Control of blood pressure and reduction of proteinuriaare critical in preventing CKD progression. Studies haveconsistendy shown that reduction of proteinuria using

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Synopsis of Clinical Praccice Guideline on Evaluation and Management of CKD L^LINICAL vjUIDELINE

renin-angiotensin-aldosterone system (RAAS) interrup-tion slows progression of both diabetic and nondiabeticnephropathy. Lowering blood pressure also slows GKDprogression, breaking a potentially vicious cycle associatinghypertension and GKD. Evidence is insufficient to recom-mend combining an angiotensin-converting enzyme inhib-itor with angiotensin-receptor blockers to prevent GKDprogression. In formulating statements about blood pres-sure control and RAAS interruption, the recommendationsin the KDIGO guidance on blood pressure control inGKD were followed to maintain consistency (26).

Lifestyle interventions (reduced sodium intake to <2 gper day, achieving a healthy body mass index of 20 to 25kg/m'^, smoking cessation, and exercising for 30 minutes 5times per week) and good diabetes control (target hemo-globin Ai^ level of 7%) are also linked to reduction ofproteinuria and alleviation of GKD progression (27-30).

3.L12. We recommend that all people with CKD areconsidered to be at increased risk of AKI. (IA)

The goal of this recommendation was to promoteawareness of the complex relationship between GKD andAKI. Evidence demonstrates that GKD remains an inde-pendent risk factor for AKI, even after multivariate adjust-ment for comorbid conditions (31). Mounting evidencesuggests that AKI is a risk factor for both incident GKDand progression of GKD. Both GKD and AKI increase inprevalence with age, and we are an aging population.

4.L2 We recommend that the level of care for ischémieheart disease offered to people with CKD should not beprejudiced by their CKD. (IA)

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

DiSCUSSION

The GKD classification system now encompassescause of GKD, GFR category, and albuminuria category.This 3-dimensional approach builds on the simpler earlierversion, and the timing of these changes is appropriate,given the current familiarity of general physicians with thesimpler version and the need to address common misun-derstandings in a systematic manner. It has been arguedthat additional factors, such as blood pressure, should beincluded within the classification (33); however, while re-fining the existing staging system, we also wanted to retainthe simplicity and easy applicability of a classification sys-tem in clinical, research, and public health practice. There-

vmw.annals.org

fore, we chose to include only kidney-related measures, andby including cause of GKD, we acknowledge the true dif-ferences in the natural history of kidney disease of differentcauses. The revised classification provides a framework forthe next decade of reporting and research in GKD.

Whether decreased GFR or increased AGR in olderpersons represents a disease or "normal aging" will alwaysbe debatable, and disease labeling will continue to provokecontroversy in an aging society. Persons older than 75 yeatshave a spectrum of GFRs- exceeding 60 mL/min per1.73 m^ with and without albuminuria, as well as valuesless than 60 mL/min per 1.73 m^. Aging is associated withaccruing comorbid conditions and the use of medicationsthat may result in reductions in GFR and albuminuria, andthat is an underappreciated aspect of the argument aboutaging and eGFR.

It is no accident that 37% of the recommendations inthe guideline were ungraded and only 10% were graded"A" for quality of the evidence. Much of the research gen-erated in the past decade has been aimed at definition andevaluation of GKD, together with identification of personswith GKD and description of the associated adverse out-comes of GKD. We have some good trial data about inter-ventions, such as RAAS blockade in proteinuric GKD anduse of statin therapy for GKD (34, 35), and limited trialdata in other areas, such as bicarbonate therapy for acido-sis. We need much more data if we want to affect out-comes. We need to know exactly which interventions atebeneficial in prevention or alleviation of both GKD pro-gression and the associated adverse outcomes and how andwhen these interventions should be applied. We also needto know when interventions that are believed to be bene-ficial may actually cause harm. For example, indiscriminateuse of RAAS blockade in those with lower GFR and nospecific indication other than hypertension may exposepersons to additional risk for AKI with no benefit. Allied tothese areas, we need a much better understanding of defi-nitions of GKD progression and how they affect clinicalpractice and trials, how the relationship between AKI andGKD relates to progression, and whether we can positivelyinfluence this relationship.

From Kent Kidney Care Centre, East Kent Hospitals University NHSFoundation Trust, Canterbury, United Kingdotn, and University ofBritish Columbia, Vancouver, British Columbia, Canada.

Acknowledgment: The authots thank the KDICO co-chairs Bertram L.Kasiske, Kai-Uwe Eckardt, David C. Wheeler; the evidence review team(Katrin Uhlig, Dana C. Miskulin, Amy Earley, Shana Haynes, MichaelCheung); and all those who provided feedback during the public reviewof the draft guideline.

Potential Confiicts of interest: Dr. Levin: Consultancy (money to insti-tution): Abbott Laboratoties, Merck & Co; Grants/grants pending (moneyto institution): Canadian Institutes of Health Research (CIHR), KidneyFoundation, Merck & Co, Ortho. Dr. Stevens: None disclosed. Disclo-sures can also be viewed at www.acponline.org/authors/icmje/ConflictOfIn teres tForms.do?msNtim=M13-0034.

4 June 2013|AnnalsofInternal Medicine Volume 158'Number 11 829

L r U I D E L I N E Synopsis of Clinical Practice Guideline on Evaluation and Management of CKD

Requests for Single Reprints: Paul E. Stevens, MBBS, BSc, Kent Kid-ney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Can-terbury, Kent CTl 3NG, United Kingdom; e-mail, pstevens@nhs.net.

Current author addresses and author contributions are available at www.annals.org.

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