Paul E. Stevens, MBBS, BSc; Adeera Levin, MD, BSc; for the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members*
* For a list of the members of the KDIGO CKD Guideline Development Work Group, see the Appendix.
Acknowledgment: The authors thank the KDIGO co-chairs Bertram L. 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 institution): 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/ConflictOfInterestForms.do?msNum=M13-0034.
Requests for Single Reprints: Paul E. Stevens, MBBS, BSc, Kent Kidney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, United Kingdom; e-mail, email@example.com.
Current Author Addresses: Dr. Stevens: Kent Kidney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, United Kingdom.
Dr. Levin: St. Paul's Hospital, Providence Wing, Room 6010A, 1160 Burrard Street, Vancouver, British Columbia V6Z 1Y8, Canada.
Author Contributions: Conception and design: A. Levin.
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.
Administrative, technical, or logistic support: A. Levin.
Collection and assembly of data: A. Levin.
Stevens P., Levin A., ; Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline. Ann Intern Med. 2013;158:825-830. doi: 10.7326/0003-4819-158-11-201306040-00007
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Published: Ann Intern Med. 2013;158(11):825-830.
Appendix: KDIGO CKD Guideline Development Work Group Members
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.
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.
The full guideline included 110 recommendations. This synopsis focuses on 10 key recommendations pertinent to definition, classification, monitoring, and management of CKD in adults.
A decade of research after the publication of the first internationally accepted definition and classification 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 specific causes of CKD was beyond the scope of the guideline, as were specific approaches to acute kidney injury (AKI) and other acute kidney diseases, diagnostic work-up or treatment of specific 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 identification 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. This synopsis focuses on the evaluation and classification 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.
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 (3–5) (Appendix Tables 1 and 2), 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), 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).
Appendix Table 1. GRADE Criteria Used for Grade Levels in the KDIGO CKD Guideline
Appendix Table 2. GRADE Criteria Used for Letter Grades in the KDIGO CKD Guideline
Appendix Table 3. Topics Chosen for Systematic Review
The draft guideline was reviewed by the KDIGO Board of Directors, and revisions were incorporated before a structured, Internet-based public review process. Feedback from this was reviewed by the work group, and final revisions were incorporated before publication of the guideline.
1.1.1. CKD is defined 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 filtration 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” reflects the notion that although various abnormalities of kidney structure or function exist, not all have implications for a person's 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 significant 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.
Table 1. Criteria for Chronic Kidney Disease
1.2.1. We recommend that CKD is classified based on cause, GFR category, and albuminuria category (CGA). (1B)
The classification 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-specific 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.
Table 2. GFR and Albuminuria Categories in the New Classification
The GFR categories mapping to the previous 5-stage classification 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 profiles 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 simplification and initial assessment and prognostication. Further classification into higher and nephrotic ranges (ACR >2220 mg/g) may be appropriate for specific circumstances in specialist centers.
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 isotope-dilution 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 (Modification 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 officials. However, where CKD-EPI has been modified for use in other racial and ethnic groups, and where validated country- or region-specific equations have been developed, these should be used in preference to unmodified equations.
184.108.40.206. 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 confirmation of CKD is required. (2C)
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 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 confirmatory marker is important. Use of eGFRcys to confirm 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 confirmed 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.
220.127.116.11. 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)
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 renin–angiotensin blockade has shown benefit 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).
18.104.22.168.1. The term microalbuminuria should no longer be used by laboratories. (Not Graded)
Although the significance 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.
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.
Guide to frequency of monitoring by GFR and albuminuria categories.
This GFR and albuminuria grid reflects 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 filtration rate.
Small fluctuations in GFR are common and do not necessarily indicate progression. An approach involving an assessment of change in eGFR category confirmed by a minimal percentage of change in eGFR (25% or greater) was recommended to define 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 fluctuation 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 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 identifies those at increased risk (23–25).
Data were insufficient to inform recommendations defining albuminuria progression, although increasing levels of albuminuria suggest progression and has been shown to be associated with increased risk for adverse outcomes.
Detailed within the guideline were many management recommendations for prevention of CKD progression and management of specific 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 non-diabetic adults with CKD and urine albumin excretion <30 mg/24 hours (or equivalent) whose office BP is consistently >140 mm Hg systolic or >90 mm Hg 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 office 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 [angiotensin-receptor blocker] or ACE-I [angiotensin-converting enzyme inhibitor] be used in both diabetic and non-diabetic adults with CKD and urine albumin excretion >300 mg/24 hours (or equivalent). (1B)
Control of blood pressure and reduction of proteinuria are critical in preventing CKD progression. Studies have consistently shown that reduction of proteinuria using renin–angiotensin–aldosterone 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 insufficient 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 (27–30).
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.
The CKD classification 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 classification (33); however, while refining the existing staging system, we also wanted to retain the simplicity and easy applicability of a classification system in clinical, research, and public health practice. Therefore, 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 classification 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 definition and evaluation of CKD, together with identification 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 beneficial 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 beneficial may actually cause harm. For example, indiscriminate use of RAAS blockade in those with lower GFR and no specific indication other than hypertension may expose persons to additional risk for AKI with no benefit. Allied to these areas, we need a much better understanding of definitions 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 influence this relationship.
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