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Stevens 2013
Stevens 2013
Description: The Kidney Disease: Improving Global Outcomes KDIGO Board of Directors and a public review process involving
(KDIGO) organization developed clinical practice guidelines in 2012 registered stakeholders.
to provide guidance on the evaluation, management, and treat-
ment of chronic kidney disease (CKD) in adults and children who Recommendations: The full guideline included 110 recommenda-
are not receiving renal replacement therapy. tions. This synopsis focuses on 10 key recommendations pertinent
to definition, classification, monitoring, and management of CKD in
Methods: The KDIGO CKD Guideline Development Work Group adults.
defined the scope of the guideline, gathered evidence, determined
topics for systematic review, and graded the quality of evidence Ann Intern Med. 2013;158:825-830. www.annals.org
that had been summarized by an evidence review team. Searches For author affiliations, see end of text.
of the English-language literature were conducted through Novem- * For a list of the members of the KDIGO CKD Guideline Development Work
ber 2012. Final modification of the guidelines was informed by the Group, see the Appendix (available at www.annals.org).
back from this was reviewed by the work group, and final The classification system has been revised to encom-
revisions were incorporated before publication of the pass cause and severity. Identifying cause is emphasized
guideline. because of its fundamental importance in predicting out-
come and guiding choice of cause-specific treatments. Se-
RECOMMENDATIONS RELATING TO THE DEFINITION AND verity is expressed by level of GFR and albuminuria (Table
CLASSIFICATION OF CKD 2). Severity is linked to risks for adverse outcomes, includ-
ing death and kidney outcomes.
1.1.1. CKD is defined as abnormalities of kidney struc-
The GFR categories mapping to the previous 5-stage
ture or function, present for ⬎3 months, with implica-
classification have been retained but with subdivision of
tions for health. (Not Graded)
the G3 category of 30 to 59 mL/min per 1.73 m2 into
Criteria for CKD are shown in Table 1. Diagnostic categories G3a (45 to 59 mL/min per 1.73 m2) and G3b
thresholds for glomerular filtration rate (GFR) of less than (30 to 44 mL/min per 1.73 m2). This was driven by data
60 mL/min per 1.73 m2 and an albumin– creatinine ratio supporting different outcomes and risk profiles in these
(ACR) of 30 mg/g or greater were retained. This was categories (6 –10). Many other concurrent complications
driven by studies examining risk for all-cause and cardio- are associated with decreased categories of GFR, including
vascular mortality, AKI, CKD progression, and kidney fail- infection, impaired cognitive and physical function, and
ure in the general population and populations with in- threats to patient safety.
creased risk for cardiovascular disease (6 –9). However, the Three albuminuria categories were proposed both for
addition of “with implications for health” reflects the no- simplification and initial assessment and prognostication.
tion that although various abnormalities of kidney struc- Further classification into higher and nephrotic ranges
ture or function exist, not all have implications for a per- (ACR ⬎2220 mg/g) may be appropriate for specific cir-
son’s health. For example, although age-associated GFR cumstances in specialist centers.
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 RECOMMENDATIONS FOR EVALUATION OF GFR AND
adult men and women (which is approximately 125 mL/ URINARY ALBUMIN EXCRETION
min per 1.73 m2) and is associated with a higher risk for The Chronic Kidney Disease Epidemiology Collabo-
complications of CKD than in persons with CKD and ration (CKD-EPI) equation was recommended for report-
conserved GFR. The mechanisms underlying these associ- ing estimated GFR (eGFR) in adults from serum creatinine
ations are not fully understood, but there is a clinically levels measured by an assay calibrated to the isotope-
significant effect of reduced GFR on drug toxicity, endo- dilution mass spectrometry reference method. Systematic
crine and metabolic complications, and risk for cardiovas- review supported the strength of this recommendation
cular disease and death. These are relevant to all patients (evidence level 1B). The CKD-EPI equation had less bias
with reduced GFR, regardless of country, age, or cause. An than the MDRD (Modification of Diet in Renal Disease)
ACR of 30 mg/g is greater than 3 times the normal value Study equation, especially at a GFR of 60 mL/min per
in young adult men and women (which is approximately 1.73 m2 or greater; a small improvement in precision; and
10 mg/g) and is associated with an increased risk for com- greater accuracy (11). Most but not all studies from North
plications of CKD. America, Europe, and Australia show that the CKD-EPI
1.2.1. We recommend that CKD is classified based on
equation is more accurate than the MDRD Study equa-
cause, GFR category, and albuminuria category (CGA). tion, especially at greater GFR, enabling reporting of nu-
(1B) merical values across the range of GFRs. Selection of a
single equation for use should facilitate communication
among providers, patients, researchers, and public health
Table 1. Criteria for Chronic Kidney Disease* officials. However, where CKD-EPI has been modified for
use in other racial and ethnic groups, and where validated
Markers of kidney damage (>1 for >3 mo) country- or region-specific equations have been developed,
Albuminuria (AER ⱖ30 mg/d; ACR ⱖ30 mg/g) these should be used in preference to unmodified equations.
Urinary sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology 1.4.3.5. We suggest measuring cystatin C in adults
Structural abnormalities detected by imaging with eGFRcreat [creatinine-based eGFR] 45-59 ml/
History of kidney transplantation min/1.73 m2 who do not have other markers of kidney
Decreased GFR (for >3 mo)
damage if confirmation of CKD is required. (2C)
GFR ⬍60 mL/min per 1.73 m2 (GFR categories G3a–G5)
The guideline acknowledged that this is a contentious
ACR ⫽ albumin– creatinine ratio; AER ⫽ albumin excretion rate; GFR ⫽ glo-
merular filtration rate.
area with potential health economics consequences and
* Reproduced from reference 2. that not all laboratories internationally will be able to assay
826 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 www.annals.org
Category GFR, mL/min per 1.73 m2 AER, mg/d ACR Equivalent, mg/g Descriptor
GFR – –
G1 ⱖ90 – – Normal or high
G2 60–89 – – Mildly decreased*†
G3a 45–59 – – Mildly to moderately decreased
G3b 30–44 – – Moderately to severely decreased
G4 15–29 – – Severely decreased
G5 ⬍15 – – Kidney failure
Albuminuria
A1 – ⬍30 ⬍30 Normal to mildly increased
A2 – 30–300 30–300 Moderately increased*
A3 – ⬎300 ⬎300 Severely increased‡
ACR ⫽ albumin– creatinine ratio; AER ⫽ albumin excretion rate; GFR ⫽ glomerular filtration rate.
* Relative to young adult level.
† In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill 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 1.4.4.2.1. The term microalbuminuria should no lon-
eGFR (eGFRcys) in persons without albuminuria (cate- ger be used by laboratories. (Not Graded)
gory A1) or other markers of kidney damage, especially
those with an eGFRcreat of 45 to 59 mL/min per 1.73 m2 Although the significance of the A2 category of ACR
(category G3a) (12, 13). This group represents 3.6% of the (30 to 300 mg/g) has been understood in persons with
U.S. population and 41% of persons in the United States diabetes for decades, use of this category to denote CKD,
estimated to have CKD on the basis of eGFRcreat and especially in those with higher GFRs, remains controver-
urinary ACR alone. Because the diagnosis of CKD in these sial. However, data demonstrate that, at any level of GFR,
persons is an area of substantial controversy with potential an ACR increase above normal is associated with increased
implications from disease labeling, the potential utility of a risk for adverse outcomes and that this increased risk is a
confirmatory marker is important. Use of eGFRcys to con- continuum (6 –9). It was, therefore, suggested that the
firm CKD in populations has shown that two thirds of term “microalbuminuria” no longer be used.
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 RECOMMENDATIONS FOR MONITORING CKD
for death, cardiovascular disease, and end-stage renal dis- Persons with CKD should be assessed at least annu-
ease compared with those with eGFRcys greater than 60 ally. The exact frequency of GFR and ACR monitoring
mL/min per 1.73 m2. will depend on the severity of CKD (Figure) and the risk
for and rate of progression. Factors associated with pro-
1.4.4.2. We recommend that clinical laboratories re- gression include cause of CKD, level of GFR, level of al-
port albumin:creatinine ratios (ACR) and protein:crea- buminuria, AKI, age, sex, race or ethnicity, elevated BP,
tinine ratios (PCR) in untimed urine samples in hyperglycemia, dyslipidemia, smoking, obesity, history of
addition to albumin concentration or proteinuria con- cardiovascular disease, ongoing exposure to nephrotoxic
centrations rather than the concentrations alone. (1B) agents, and others.
Small fluctuations in GFR are common and do not
Measurement of urinary ACR was recommended for necessarily indicate progression. An approach involving an
evaluation of proteinuria in preference to urinary total pro- assessment of change in eGFR category confirmed by a
tein for many reasons. Albumin is the most important pro- minimal percentage of change in eGFR (25% or greater)
tein lost in the urine in most cases of CKD. In population was recommended to define progression. The reasoning for
studies, urinary ACR accurately predicts kidney and car- this was that although longitudinal cohort studies examin-
diovascular risks (6 –9, 14 –19). Reduction in ACR in in- ing progression have assumed that progression is linear,
tervention trials targeted at blood pressure (BP) reduction this is often not the case. The greater the fluctuation in
or renin–angiotensin blockade has shown benefit for pro- kidney function, the higher the probability of nonlinear
gression of CKD. Urinary ACR has greater sensitivity for progression (21, 22). A criterion requiring both a change in
detecting low-grade but clinically important albuminuria GFR category (that is, from category G2 to G3a) and per-
and is more precise at low but diagnostically important centage of change would ensure that small changes in GFR
concentrations (20). (from 61 to 59 mL/min per 1.73 m2, for example, which
www.annals.org 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 827
A1 A2 A3
Normal to
mildly Moderately Severely
increased increased increased
Mildly to moderately
G3a decreased 45–59 1 2 3
Moderately to
G3b 30–44 2 3 3
severely decreased
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.
represents a change in category but a minimal change in diastolic be treated with BP-lowering drugs to maintain
GFR) would not be misinterpreted to represent progres- a BP that is consistently ⱕ140 mm Hg systolic and
sion. Preliminary studies have indicated that this approach ⱕ90 mm Hg diastolic. (1B)
identifies those at increased risk (23–25).
Data were insufficient to inform recommendations de- 3.1.5 We suggest that both diabetic and non-diabetic
fining albuminuria progression, although increasing levels adults with CKD and with urine albumin excretion of
of albuminuria suggest progression and has been shown to ⱖ30 mg/24 hours (or equivalent) whose office BP is
be associated with increased risk for adverse outcomes. consistently ⬎130 mm Hg systolic or ⬎80 mm Hg
diastolic be treated with BP-lowering drugs to maintain
MANAGEMENT OF CKD a BP that is consistently ⱕ130 mm Hg systolic and
Detailed within the guideline were many management ⱕ80 mm Hg diastolic. (2D)
recommendations for prevention of CKD progression and
management of specific complications of CKD (see Sup- 3.1.7 We recommend that an ARB [angiotensin-
plement). Key recommendations relating to BP control, receptor blocker] or ACE-I [angiotensin-converting en-
proteinuria reduction, AKI, and cardiovascular disease are zyme inhibitor] be used in both diabetic and non-
summarized. diabetic adults with CKD and urine albumin excretion
⬎300 mg/24 hours (or equivalent). (1B)
3.1.4 We recommend that both diabetic and non-
diabetic adults with CKD and urine albumin excretion Control of blood pressure and reduction of proteinuria
⬍30 mg/24 hours (or equivalent) whose office BP is are critical in preventing CKD progression. Studies have
consistently ⬎140 mm Hg systolic or ⬎90 mm Hg consistently shown that reduction of proteinuria using
828 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 www.annals.org
renin–angiotensin–aldosterone system (RAAS) interrup- fore, we chose to include only kidney-related measures, and
tion slows progression of both diabetic and nondiabetic by including cause of CKD, we acknowledge the true dif-
nephropathy. Lowering blood pressure also slows CKD ferences in the natural history of kidney disease of different
progression, breaking a potentially vicious cycle associating causes. The revised classification provides a framework for
hypertension and CKD. Evidence is insufficient to recom- the next decade of reporting and research in CKD.
mend combining an angiotensin-converting enzyme inhib- Whether decreased GFR or increased ACR in older
itor with angiotensin-receptor blockers to prevent CKD persons represents a disease or “normal aging” will always
progression. In formulating statements about blood pres- be debatable, and disease labeling will continue to provoke
sure control and RAAS interruption, the recommendations controversy in an aging society. Persons older than 75 years
in the KDIGO guidance on blood pressure control in have a spectrum of GFRs exceeding 60 mL/min per
CKD were followed to maintain consistency (26). 1.73 m2 with and without albuminuria, as well as values
Lifestyle interventions (reduced sodium intake to ⬍2 g less than 60 mL/min per 1.73 m2. Aging is associated with
per day, achieving a healthy body mass index of 20 to 25 accruing comorbid conditions and the use of medications
kg/m2, smoking cessation, and exercising for 30 minutes 5 that may result in reductions in GFR and albuminuria, and
times per week) and good diabetes control (target hemo- that is an underappreciated aspect of the argument about
globin A1c level of 7%) are also linked to reduction of aging and eGFR.
proteinuria and alleviation of CKD progression (27–30). It is no accident that 37% of the recommendations in
the guideline were ungraded and only 10% were graded
3.1.12. We recommend that all people with CKD are “A” for quality of the evidence. Much of the research gen-
considered to be at increased risk of AKI. (1A) erated in the past decade has been aimed at definition and
evaluation of CKD, together with identification of persons
The goal of this recommendation was to promote with CKD and description of the associated adverse out-
awareness of the complex relationship between CKD and comes of CKD. We have some good trial data about inter-
AKI. Evidence demonstrates that CKD remains an inde- ventions, such as RAAS blockade in proteinuric CKD and
pendent risk factor for AKI, even after multivariate adjust- use of statin therapy for CKD (34, 35), and limited trial
ment for comorbid conditions (31). Mounting evidence data in other areas, such as bicarbonate therapy for acido-
suggests that AKI is a risk factor for both incident CKD sis. We need much more data if we want to affect out-
and progression of CKD. Both CKD and AKI increase in comes. We need to know exactly which interventions are
prevalence with age, and we are an aging population. beneficial in prevention or alleviation of both CKD pro-
gression and the associated adverse outcomes and how and
4.1.2 We recommend that the level of care for ischemic when these interventions should be applied. We also need
heart disease offered to people with CKD should not be to know when interventions that are believed to be bene-
prejudiced by their CKD. (1A) ficial may actually cause harm. For example, indiscriminate
use of RAAS blockade in those with lower GFR and no
Persons with CKD are more likely to have a cardio- specific indication other than hypertension may expose
vascular event than to progress to end-stage renal disease; persons to additional risk for AKI with no benefit. Allied to
have worse prognosis with higher mortality rates after acute these areas, we need a much better understanding of defi-
myocardial infarction; and higher risk for recurrent myo- nitions of CKD progression and how they affect clinical
cardial infarction, heart failure, and sudden cardiac death practice and trials, how the relationship between AKI and
(32). Despite this, the level of care offered to persons with CKD relates to progression, and whether we can positively
CKD is still frequently suboptimal. influence this relationship.
From Kent Kidney Care Centre, East Kent Hospitals University NHS
DISCUSSION Foundation Trust, Canterbury, United Kingdom, and University of
British Columbia, Vancouver, British Columbia, Canada.
The CKD classification system now encompasses
cause of CKD, GFR category, and albuminuria category. Acknowledgment: The authors thank the KDIGO co-chairs Bertram L.
This 3-dimensional approach builds on the simpler earlier Kasiske, Kai-Uwe Eckardt, David C. Wheeler; the evidence review team
version, and the timing of these changes is appropriate, (Katrin Uhlig, Dana C. Miskulin, Amy Earley, Shana Haynes, Michael
given the current familiarity of general physicians with the Cheung); and all those who provided feedback during the public review
simpler version and the need to address common misun- of the draft guideline.
derstandings in a systematic manner. It has been argued
Potential Conflicts of Interest: Dr. Levin: Consultancy (money to insti-
that additional factors, such as blood pressure, should be
tution): Abbott Laboratories, Merck & Co; Grants/grants pending (money
included within the classification (33); however, while re- to institution): Canadian Institutes of Health Research (CIHR), Kidney
fining the existing staging system, we also wanted to retain Foundation, Merck & Co, Ortho. Dr. Stevens: None disclosed. Disclo-
the simplicity and easy applicability of a classification sys- sures can also be viewed at www.acponline.org/authors/icmje/ConflictOf
tem in clinical, research, and public health practice. There- InterestForms.do?msNum⫽M13-0034.
www.annals.org 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 829
Requests for Single Reprints: Paul E. Stevens, MBBS, BSc, Kent Kid- 16. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M,
ney Care Centre, Kent and Canterbury Hospital, Ethelbert Road, Can- et al; ADVANCE Collaborative Group. Albuminuria and kidney function in-
terbury, Kent CT1 3NG, United Kingdom; e-mail, pstevens@nhs.net. dependently predict cardiovascular and renal outcomes in diabetes. J Am Soc
Nephrol. 2009;20:1813-21. [PMID: 19443635]
Current author addresses and author contributions are available at www 17. Viazzi F, Leoncini G, Conti N, Tomolillo C, Giachero G, Vercelli M, et al.
.annals.org. Combined effect of albuminuria and estimated glomerular filtration rate on car-
diovascular events and all-cause mortality in uncomplicated hypertensive patients.
J Hypertens. 2010;28:848-55. [PMID: 20087212]
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Appendix Table 1. GRADE Criteria Used for Grade Levels in the KDIGO CKD Guideline
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
CKD ⫽ chronic kidney disease; GRADE ⫽ Grading of Recommendations Assessment, Development, and Evaluation; KDIGO ⫽ Kidney Disease: Improving Global Outcomes.
Treatment
Treatment with bicarbonate Does treatment with bicarbonate in CKD improve clinical outcomes? Patients with a GFR ⬍60 mL/min per 1.73 m2 or KTRs
Treatment with allopurinol Does treatment with allopurinol in CKD improve clinical outcomes? Patients with a GFR ⬍60 mL/min per 1.73 m2 or KTRs
with or without hyperuricemia
Timing of initiation of RRT in When should dialysis be started (early or late)? Patients with a GFR ⬍30 mL/min per 1.73 m2
CKD
Protein restriction Should patients with CKD be on a protein-restricted diet? 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 filtration rate; KTR ⫽ kidney transplant recipient; NFD ⫽
nephrogenic fibrosing dermopathy; RRT ⫽ renal replacement therapy.
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