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CLINICAL GUIDELINE

E v a l u a t i o n a n d M a n a g e m e n t o f C h r o n i c K i d n e y D i s e a s e : S y n o p s i s o f
t h e K id n e y D i s e a s e : I m p r o v i n g G l o b a l D u t c o m e s 2 0 1 2 C l i n i c a l
P r a c t i c e G u i d e l i n e
P a u l E. S t e v e n s , M BBS , BS c , a n d Ad e e r a Le v i n , M D , BS c , f o r t h e K i d n e y D i s e a s e : I m p r o v i n g G l o b a l Ou t c o m e s C h r o n i c K i d n e y D i s e a s e
G u i d e l i n e D e v e l o p m e n t Wo r k G r o u p M e m b e r s *
D e s c r i p t i o n : The Kidney Disease: Improving Global Outcomes
(KDIGO) organization developed clinical practice guidelines in 2012
to provide guidance on the evaluation, management, and treat-
ment of chronic kidney disease (CKD) in adults and children who
are not receiving renal replacement therapy.
M e t h o d s : 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 Novem-
ber 2012. Final modification of the guidelines was informed by the
KDIGO Board of Directors and a public review process involving
registered stakeholders.
Re c o m m e n d a t i o n s : The full guideline included 110 recommenda-
tions. This synopsis focuses on 10 key recommendations pertinent
to definition, classification, monitoring, and management of CKD in
adults.
A n n In tern 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 Ap p e n d i x (available at www.annals.org).
A
decade of research after the publication of the first
internationally accepted definition and classification
of CKD (1) led the Kidney Disease: Improving Clobal
Outcomes (KDICO) organization to develop an updated
Clinical Practice Guideline for the Evaluation and Man-
agement 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 high-
lighted, along with areas of controversy, confusion, or non-
consensus. The detailed work-up for specific causes of
CKD was beyond the scope of the guideline, as were spe-
cific 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 preg-
nancy, detailed management of endocrine and metabolic
complications, and detailed drug dosing.
The guideline sought to provide comprehensive guid-
ance encompassing the whole CKD pathway, from early
identification and diagnosis throtigh initiation of renal re-
placement 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 tise 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 evalua-
tion and classification of CKD, areas that have generated
substantial controversy. We also discuss some key recom-
mendations, including the management of CKD progres-
sion and complications, and the relationship between AKI
and CKD.
GuiDEUNE 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 evi-
dence review team. The work group formulated the scope
of the guideline, graded evidence on the basis of the
CRADE (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 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 con-
ducted in June 2011 and supplemented with additional
evidence through November 2012. Further guideline de-
velopment, evidence synthesis, and writing of the guideline
itself was done by the work group. Full details of the guide-
line 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:
We b -On l y
CME quiz
Supplement
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 finaJ
revisions were incorporated before pubhcation of the
guideline.
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. Diagnostic
thresholds for glomerular filtration rate (GFR) of less than
60 mL/min per 1.73 m and an albumincreatinine ratio
(ACR) of 30 mg/g or greater were retained. This was
driven 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, the
addition 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 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 m is less than half of the normal value in young
adult men and women (which is approximately 125 mL/
min per 1.73 m^) and is associated with a higher risk for
complications of CKD than in persons with GKD and
conserved GFR. The mechanisms underlying these associ-
ations are not fully understood, but there is a clinically
significant 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 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 com-
plications of CKD.
1.2.1. We recommend that CKD is classified based on
cause, 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 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)
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.
826 4June2013 Antialsof Internal Medicine Volume 158*Numbcr 1)
The classification system has been revised to encom-
pass cause and severity. Identifying cause is emphasized
because 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 (Table
2). Severity is linked to risks for adverse outcomes, includ-
ing death and kidney outcomes.
The GFR categories mapping to the previous 3-stage
classification have been retained but with subdivision of
the G3 category of 30 to 59 mL/min per 1.73 m^ into
categories 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 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 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 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 IB). 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
L73 m 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 equa-
tion, especially at greater GFR, enabling reporting of nu-
merical 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.
1.4.3.5- We suggest measuring cystatin C in adults
with eGFRcreat [creatinine-based eGFR] 45-59 ml/
min/1.73 m 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
www.annals.ore
Synopsis of Clinical Practice Guideline on Evaluation and Management of CKD Ci LINICAL LrUIDELINE
Table 2. GFR
Category
CFR
' 0 1
G2
' 03a
03b
04
05
Albuminuria
L Al
A2
A3
and Albuminuria Categories in the
GFR, mL/min per 1.73 m^
S90
60-89
45-59
30-44
15-29
<15
_
-
-
New Classification
AER, mg/d
-
-
-
-
-
<30
30-300
>300
ACR Equivalent, mg/g
-
-
-
-
-
<30
30-300
>300
Descriptor
Normal or high
Mildly decreased't
Mildly to moderately decreased
Moderately to severely decreased
Severely decreased |
Kidney failure
Normal to mildiy increased
Moderately 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-based
eGFR (eGFRcys) in persons without albuminuria (cate-
gory Al) or other markers of kidney damage, especially
those with an eGFRcreat of 45 to 59 mL/min per 1.73 m^
(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 GKD on the basis of eGFRcreat and
urinary AGR alone. Because the diagnosis of GKD 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 con-
firm GKD in populations has shown that two thirds of
persons with eGFRcreat less than 60 mL/min per 1.73 m^
have a diagnosis of GKD confirmed by eGFRcys less than
60 mL/min per 1.73 m'^ and had markedly elevated risks
for death, cardiovascular disease, and end-stage renal dis-
ease compared with those with eGFRcys greater than 60
mL/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 in
addition to albumin concentration or proteinuria con-
centrations rather than the concentrations alone. (IB)
Measurement of urinary AGR was recommended for
evaluation 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 population
studies, 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) reduction
or renin-angiotensin blockade has shown benefit for pro-
gression of GKD. Urinary AGR has greater sensitivity for
detecting low-grade but clinically important albuminuria
and is more precise at low but diagnostically important
concentrations (20).
www. annals. org
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 with
diabetes 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 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
Persons with GKD should be assessed at least annu-
ally. The exact frequency of GFR and AGR monitoring
will depend on the severity of GKD (Figure) and the risk
for 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 of
cardiovascular disease, ongoing exposure to nephrotoxic
agents, and others.
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 examin-
ing progression have assumed that progression is linear,
this is often not the case. The greater the fiuctuation 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 per-
centage of change would ensure that small changes in GFR
(from 61 to 59 mL/min per 1.73 m^, for example, which
4J une 2013 I Annals of Internal Medicine Volume 1 5 8 ' Nu mb e r l l | 8 2 7
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
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e
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R
a
n
g
e
G1
G2
G3a
G3b
G4
G5
Normal or high
Mddty decreased
Mildly to moderately
decreased
Moderately to
severely decreased
Severely decreased
Kidney failure
90
60-89
45-59
30-44
15-29
<15
Persistent Albuminuria Categories
Description and Range
Al
Normal to
mildly
increased
ACR <30 mg/g
1 if CKD
1 if CKD
1
2

A2
Moderately
increased
ACR of 30-300 mg/g
1
1
2

A3
Severely
increased
ACR >300 mg/g
2
2
1
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
GFR) would not be misinterpreted to represent progres-
sion. Preliminary studies have indicated that this approach
identifies those at increased risk (23-25).
Data were insufficient to inform recommendations de-
fining albuminuria progression, although increasing levels
of albuminuria suggest progression and has been shown to
be associated with increased risk for adverse outcomes.
MANAGEMENT OF CKD
Detailed within the guideline were many management
recommendations for prevention of CKD progression and
management of specific complications of CKD (see Sup-
plement). 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 >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 maintain
a BP that is consistently <14O mm Hg systolic and
<90 mm Hg diastolic. (IB)
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 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 proteinuria
are critical in preventing CKD progression. Studies have
consistendy shown that reduction of proteinuria using
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Synopsis of Clinical Praccice Guideline on Evaluation and Management of CKD L^LINICAL vj UIDELINE
renin-angiotensin-aldosterone system (RAAS) interrup-
tion slows progression of both diabetic and nondiabetic
nephropathy. Lowering blood pressure also slows GKD
progression, breaking a potentially vicious cycle associating
hypertension and GKD. Evidence is insufficient to recom-
mend combining an angiotensin-converting enzyme inhib-
itor with angiotensin-receptor blockers to prevent GKD
progression. In formulating statements about blood pres-
sure control and RAAS interruption, the recommendations
in the KDIGO guidance on blood pressure control in
GKD 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/m'^, smoking cessation, and exercising for 30 minutes 5
times per week) and good diabetes control (target hemo-
globin Ai^ level of 7%) are also linked to reduction of
proteinuria and alleviation of GKD progression (27-30).
3.L12. We recommend that all people with CKD are
considered to be at increased risk of AKI. (IA)
The goal of this recommendation was to promote
awareness of the complex relationship between GKD and
AKI. Evidence demonstrates that GKD remains an inde-
pendent risk factor for AKI, even after multivariate adjust-
ment for comorbid conditions (31). Mounting evidence
suggests that AKI is a risk factor for both incident GKD
and progression of GKD. Both GKD and AKI increase in
prevalence with age, and we are an aging population.
4.L2 We recommend that the level of care for ischmie
heart disease offered to people with CKD should not be
prejudiced 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 acute
myocardial 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 with
GKD is still frequently suboptimal.
DiSCUSSION
The GKD classification system now encompasses
cause of GKD, 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 misun-
derstandings in a systematic manner. It has been argued
that additional factors, such as blood pressure, should be
included within the classification (33); however, while re-
fining the existing staging system, we also wanted to retain
the simplicity and easy applicability of a classification sys-
tem in clinical, research, and public health practice. There-
v m w . a n n a l s . o r g
fore, we chose to include only kidney-related measures, and
by including cause of GKD, we acknowledge the true dif-
ferences 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 GKD.
Whether decreased GFR or increased AGR 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 yeats
have a spectrum of GFRs- exceeding 60 mL/min per
1.73 m^ with and without albuminuria, as well as values
less than 60 mL/min per 1.73 m^. 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 gen-
erated in the past decade has been aimed at definition and
evaluation of GKD, together with identification of persons
with 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 and
use of statin therapy for GKD (34, 35), and limited trial
data 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 ate
beneficial in prevention or alleviation of both GKD pro-
gression 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 bene-
ficial 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 defi-
nitions of GKD progression and how they affect clinical
practice and trials, how the relationship between AKI and
GKD relates to progression, and whether we can positively
influence this relationship.
From Kent Kidney Care Centre, East Kent Hospitals University NHS
Foundation Trust, Canterbury, United Kingdotn, and University of
British 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, Michael
Cheung); and all those who provided feedback during the public review
of the draft guideline.
Potential Confiicts of interest: Dr. Levin: Consultancy (money to insti-
tution): Abbott Laboratoties, Merck & Co; Grants/grants pending (money
to institution): Canadian Institutes of Health Research (CIHR), Kidney
Foundation, Merck & Co, Ortho. Dr. Stevens: None disclosed. Disclo-
sures can also be viewed at www.acponline.org/authors/icmje/ConflictOf
In teres tForms.do?msNtim=M13-0034.
4 June 2013|AnnalsofInternal Medicine Volume 158' Number 11 829
LrUIDELINE 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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