REVIEWS

Early detection of CKD: the benefits,

limitations and effects on prognosis
Adeera Levin and Paul E. Stevens
Abstract | The past decade has seen an increasing focus on chronic kidney disease (CKD) and its attendant
complications, which has resulted in improved understanding of their impact on health-care resources. The
early detection of CKD has been facilitated by the implementation of routine reporting of estimated glomerular
filtration rates (eGFRs) and by education of primary care physicians on the implications of detecting a
decreased eGFR with respect to patient safety as well as to cardiovascular and renal outcomes. The goals
of early CKD detection are to prevent CKD progression and associated complications, thus improving patient
outcomes and reducing the impact of CKD on health-care resources. This Review examines the benefits of
the early detection of CKD, and describes the limitations of current knowledge with respect to screening,
early detection and treatment, as well as the unintended consequences of detection. In addition, this article
highlights what is currently known about cardiovascular and renal outcomes and the effects of intervention in
patients with CKD.
Levin, A. & Stevens, P. E. Nat. Rev. Nephrol. 7, 446–457 (2011); published online 28 June 2011; doi:10.1038/nrneph.2011.86

Introduction
In the past decade, increased recognition of chronic
kidney disease (CKD) and its attendant complications
has led to an improved understanding of their health-
care burden. Given the growing awareness of the increas-
ing prevalence of CKD in developed and developing
countries, and its strong association with diabetes and
hypertension, the World Health Organization (WHO)
has highlighted CKD as an important component of its
strategy for noncommunicable diseases.1
CKD has been defined as evidence of functional
impairment or structural damage to the kidney and/or
reduced kidney function, as manifested by a reduction
of estimated glomerular filtration rate (eGFR) sustained
for at least 3 months. Such evidence includes persistent
proteinuria or albuminuria, hematuria, biopsy samples
showing characteristic features of renal disease, or
ultrasonographic and other imaging findings indica-
tive of scarring or pathology (such as polycystic kidney
disease). 2 The International Classification of CKD
Division of Nephrology, identifies five stages, and includes patients receiving
University of British renal replacement therapy (RRT) through either dialy-
Columbia, 1081
Burrard Street, Room
sis or functioning kidney transplant.2 Others have since
60101A, Vancouver, updated this classification to underline the importance of
BC V6Z1Y8, Canada proteinuria and lower levels of glomerular filtration rate
(A. Levin). Kent Kidney
Care Center, East Kent (GFR) (Table 1).3 For the purpose of this Review, which
Hospitals University is focused on early detection, we have excluded patients
National Health Service
Foundation Trust,
receiving RRT. An important caveat is that CKD is defined
Ethelbert Road, solely by eGFR in the majority of the available literature,
Canterbury, Kent CT1 which confines a great deal of the evidence to an eGFR
3NG, UK (P. E. Stevens).
<60 ml/min/1.73 m2. Thus, by necessity, the majority of
Correspondence to:
A. Levin
alevin@ Competing interests
providencehealth.bc.ca The authors declare no competing interests.
this Review deals with stages 3–5 CKD. Statements in this
article that refer to the entire spectrum of CKD (that is,
stages 1–5) are clearly mentioned as such.
In this Review, we will examine the benefits associ-
ated with early detection of CKD, as well as the limita-
tions of our current knowledge with respect to screening,
early detection and treatment. We will also consider the
unintended consequences of early detection, and discuss
what is currently known about outcomes and the effects
of intervention in patients with CKD.
Rationale for early detection of CKD
The WHO principles for early disease detection require a
number of conditions to be met.4 In many respects CKD
does meet these criteria (Box 1).
The rationale for early detection of CKD was that
patient outcomes could be improved by identifying high-
risk groups, thereby permitting targeted therapy to be
implemented to reduce the incidence of adverse effects
such as progression to end-stage renal disease (ESRD),
cardiovascular events and mortality (Figure 1). In devel-
oping countries where dialysis and transplant facilities are
limited, early detection of CKD may have an especially
profound effect on the progression of renal disease, and on
the health of populations as a whole. Drug safety and
appropriate monitoring of toxic effects are also enhanced
with early identification of renal impairment. In addition,
potential savings to the health-care system and individuals
may be made. The increased costs associated with treat-
ment of the CKD population are largely a result of the
high rates of comorbidity-driven admission and extended
hospital stays that are required as CKD progresses. Thus,
the costs incurred during early stages of CKD increase

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Table 1 | Updated CKD classification
Stage* GFR (ml/ Description
min/1.73 m2)
1 ≥90 Normal or increased GFR, with
other evidence of kidney damage‡
present for ≥3 months
2 60–89 Slight decrease in GFR, with other
evidence of kidney damage‡
present for ≥3 months
3a 45–59 Moderate decrease in GFR for
3b 30–44 ≥3 months, with or without other
evidence of kidney damage
4 15–29 Severe decrease in GFR, with or
without other evidence of kidney
damage
5 <15 Established renal failure
*Use the suffix (p) to denote the presence of significant proteinuria when
staging CKD (ACR ≥30 mg/mmol, or PCR ≥50 mg/mmol). ‡Kidney damage
refers to the presence of structural abnormalities and/or persistent
hematuria, proteinuria or microalbuminuria. Abbreviations: ACR,
albumin:creatinine ratio; CKD, chronic kidney disease; GFR, glomerular
filtration rate; PCR, protein:creatinine ratio. Permission obtained from the
Royal College of Physicians © The National Collaborating Center for Chronic
Conditions. Chronic kidney disease: national clinical guideline for early
identification and management in adults in primary and secondary care
[online], http://www.nice.org.uk/nicemedia/live/12069/42116/42116.
pdf (2008).3
markedly with progression to ESRD and remain elevated
thereafter. Increased awareness of CKD among health-
care providers, leading to its early identification, might
then result in timely interventions, as well as improved
clinical and economic outcomes. Moreover, renewed
interest in acute kidney injury (AKI), and the recogni-
tion that CKD is an important modifier of outcomes, has
led to increased opportunities for peer-reviewed funding
support of research in both AKI and CKD.
Various publications have attempted to quantify the
potential cost savings of early CKD detection.5–12 However,
relatively few such studies have established definitively
that early implementation of care strategies results in
improved outcomes. Nonetheless, extrapolation from
other screening programs for chronic conditions (dia-
betes, cardiovascular disease [CVD] and cancer) suggests
that prompt treatment is a prudent strategy.
The role of routine eGFR reporting
The early identification of CKD has been greatly simpli-
fied by the advent of automatic reporting of an eGFR by
laboratories whenever a request for serum creatinine is
made, by publication of the Kidney Disease Outcomes
Quality Initiative (KDOQI) Guidelines for CKD in 2002
(Table 2), and by adoption of the CKD staging system.2
For the purposes of early detection and prevention strat-
egies conducted in accordance with WHO principles, it is
important to clarify what is truly meant by early identifica-
tion. Unlike the situation when seeking to identify CKD
in a high-risk population, an ‘incidental’ or unanticipated
finding of reduced eGFR in an individual patient may lead
to clinical confusion. Although the difference between
these circumstances may seem to be semantic, it does have
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Key points
■ Chronic kidney disease (CKD) is prevalent worldwide and occurs in conjunction
with cardiovascular disease and diabetes
■ CKD should be defined in terms of both estimated glomerular filtration rates
and albuminuria, as each is an independent predictor of prognosis with respect
to renal and cardiovascular outcomes
■ Early detection of CKD allows implementation of treatments and strategies that
can influence both progression of kidney disease and cardiovascular health
■ Detection and identification of CKD facilitates avoidance of drugs and
situations that may cause worsening of kidney function and acute kidney injury
■ CKD is recognized to have widely varying outcomes, which makes predicting the
prognosis of individual patients difficult
■ Improved prediction of renal and other risks in patients with CKD is a focus for
research
Box 1 | WHO Screening Criteria4
■ Is the disease a major health problem?
■ Is the natural history (including development from
latent to overt disease) adequately understood?
■ Is there a recognizable latent or early symptomatic
stage?
■ Does early detection extend life?
■ Is there an efficient screening test that is acceptable
to the population?
■ Is there evidence of screening for the disease from
other countries?
■ Is the test(s) for the disease free of complications? Are
there any harms associated with the test(s)?
■ What quality of life is associated with screening?
■ Is there an accepted and effective treatment for
patients with the recognized disease?
■ Does screening reduce mortality?
■ The screening program should involve an agreed policy
on who should be screened
■ Is screening cost effective (the cost of case finding
should be economically balanced in relation to
possible expenditure on medical care)?
■ Are the facilities for diagnosis and treatment available?
■ Case finding should be a continuing process and not a
one-time-only project
practical implications. If patients with CKD are identi-
fied by a constellation of biochemical parameters (urine
and blood analysis) in addition to clinical context, as is
proposed in the various guidelines, then early identifica-
tion has indeed been accomplished, and would not result
in any clinical confusion. Current guidelines advocate
targeted screening of high-risk populations; however, in
practice, the automatic reporting of eGFR by laborato-
ries whenever serum creatinine levels are measured has
led to de facto screening of the general population. This
approach has brought to light issues related to the sensi-
tivity and specificity of some of the currently used equa-
tions used to estimate GFR (for example, the Modification
of Diet in Renal Disease (MDRD), CKD–Epidemiology
Collaboration (CDK-EPI) and Cockcroft–Gault formu-
lae) for specific age groups and levels of kidney function,
and within certain ethnic groups.
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No disease
Prevention No prevention
No disease Early pathological changes
Early detection No early detection
Prevention of complications Progression of
and progression of disease pathological changes
Treatment No treatment
Prevention of complications Disease progression and
and progression of disease development of complications
Figure 1 | Rationale for the early detection (and ideally prevention) of disease.
The earlier in the pathway of disease progression that we are able to intervene, the
better the outcome, both for the individual and for the global health-care economy.
Mandatory eGFR testing with educational feedback
has been implemented in a number of areas. In the
UK, for example, since April 2006 all clinical chemistry
laboratories were mandated to report eGFR whenever
requests for serum creatinine were made. This initiative
was accompanied by information leaflets for laborato-
ries, primary care providers and patients together with
the publication and dissemination of clinical practice
guidelines in CKD.13 The majority of people identified
as having CKD as a result of mandatory testing will have
stage 3 disease, the first stage of CKD to be defined by
eGFR category alone, according to the internationally
accepted definition of CKD.2 In a primary care practice
looking after 10,000 adults, an estimated 144 patients will
be diagnosed as having stage 3 CKD each year, whereas
only three patients with stage 4 CKD and 0.3 patients
with stage 5 CKD will be identified.9
Despite some controversy regarding nomenclature and
‘overdiagnosis’ of some populations with CKD (primar-
ily involving the finding of reduced but stable kidney
function in older people who are otherwise well), the
benefits of eGFR reporting cannot be overstated, and
such reporting has led to increased public awareness of
CKD. Educational efforts across multiple health-care
providers (medical schools, residency programs, primary
care and specialty practice) have been refocused and
aligned, and laboratory testing has been standardized
in many countries to improve the consistency of eGFR
reporting. The International Statistical Classification of
Diseases and Related Health Problems (ICD), version 9,
has been reorganized so as to incorporate the different
stages of CKD. Although many locations are now using
more recent versions of the ICD codes (ICD-10), this
incorporation into the ICD-9 codes has established a
precedent, and the updated ICD-11 or ICD-12 codes
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© 2011 Macmillan Publishers Limited. All rights reserved
will also include the staging system. This addition into
an international coding system is seen to be a major step
forward for administrators and researchers. There are
reports indicating that mandatory eGFR testing has had
positive effects in practice.14–16 Specifically, one report
indicated that improved recognition of CKD within a
primary care practice led to changes in the prescribing of
NSAIDs and metformin, as well as an increase in eGFR
within a large population of patients in the practice over
time.14 A follow-up study from the same researchers
reported a statistically nonsignificant decrement in sub-
sequent performance, but concluded that the interven-
tion provided the education and reinforcement necessary
to effect long-term changes in patients’ management.17
The consequences of early detection
Detection of reduced kidney function often necessi-
tates additional investigations as to the etiology of the
kidney disease. Although many patients have easily
identifiable causes of CKD (such as diabetes, hyper-
tension or inherited renal disease), some do not, and
require further testing. Automatic reporting of eGFR
also requires education of primary care physicians as to
the possibly transient nature of these findings, as well
as the need to ensure that ancillary data, such as urine
protein excretion, are obtained before labeling indivi-
duals as having CKD. When it is not accompanied by
a comprehensive education program, automatic report-
ing of eGFR by laboratories has undoubtedly led to con-
fusion among and between practitioners, patients and
policy makers, given the inconsistency in approaches to
management of individuals with mild CKD. Such confu-
sion has tended to polarize attitudes towards automatic
eGFR reporting (Box 2). The use of additional markers
of kidney function, such as cystatin C, may improve the
discrimination of the currently used formulae, particu-
larly with respect to identifying individuals at risk of
adverse outcomes.18,19
Current educational efforts have focused on identi-
fying reduced kidney function within specific high-
risk groups, such as individuals with comorbidities
strongly associated with CKD. In this way, early detec-
tion of renal impairment in these groups has been
facilitated, and health-care providers and/or patients
and carers can be educated to apply evidence-based
interventional strategies.
Prognostic information
Outcomes for patients with low eGFRs or CKD are uni-
formly poor, irrespective of the cohort studied or the
availability of health-care resources, and are worsened
by increasing albuminuria.20–24 The prognostic impor-
tance of albuminuria is underlined by studies demon-
strating that outcomes in patients with a GFR >60 ml/
min/1.73 m2 and moderately elevated proteinuria (an
albumin:creatinine ratio of 30–300 mg/g or proteinuria of
trace to 1+ on dipstick urinalysis) are significantly worse
than those of patients with a GFR below this threshold
who do not have proteinuria.21,22 Adverse outcomes (such
as progression of CKD, cardiovascular events and death)
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Table 2 | Guidelines on chronic kidney disease*
Guideline
Kidney Disease Outcomes Quality Initiative Clinical
Practice Guidelines for Chronic Kidney Disease2
Chronic Kidney Disease in Adults: UK Guidelines for
Identification, Management and Referral42
Management of Chronic Kidney Disease43
Prevention of Progression of Chronic Kidney Disease
Guidelines44
Diagnosis and Management of Chronic Kidney
Disease: A National Clinical Guideline45
Chronic Kidney Disease: National Clinical Guideline
for early Identification and Management in Adults in
Primary and Secondary Care3
Early Chronic Kidney Disease
Clinical Practice Guidelines for Chronic Kidney
Disease
*Many more guidelines exist worldwide that are not listed here owing to constraints of space and access. ‡Multinational.
are more than twice as frequent in patients with a GFR
>60 ml/min/1.73 m2 and severely elevated proteinuria
(albumin:creatinine ratio >300 mg/g or proteinuria of
2+ on dipstick urinalysis) than in patients with a GFR
of 45–59.9 ml/min/1.73 m2 but with a lesser degree of
protein uria. 23 Numerous publications describe an
increased risk of CVD (including heart failure and athero-
sclerotic events), infections, hospitalizations, and all-
cause mortality in patients with impaired kidney function
and/or proteinuria of any severity.20–24 These observations
have raised substantial interest among generalists and
specialists alike. A meta-analysis by the CKD Prognosis
Consortium, which examined over 1 million people from
a diverse set of studies and databases, together with 2
further analyses of these data, have described the relative
risks of a series of events, including AKI, infections, CVD,
ESRD and mortality in patients with CKD.24–26 These data
demonstrate that both GFR and albuminuria are inde-
pendent predictors of adverse outcomes (both kidney-
related and non-kidney-related) in patients with CKD.
The relative risk reductions for different combinations
of elevated urine protein excretion and levels of eGFR
have been reported by Astor et al.25 and Gansevoort and
colleagues.26 In addition to the high risk of these events
in CKD patients who are not on dialysis, those who are
dialysis-dependent have even worse outcomes, which
are often compared to those of patients with lung cancer.
The most frequent cause of death in dialysis-dependent
patients with CKD is CVD, which is attributed to both
conventional and kidney-specific risk factors.27,28
Equations for predicting progression and the absence
of progression to ESRD in patients with CKD have identi-
fied similar variables as being important, irrespective of
the population in which the equation is derived: protein-
uria, hypertension, diabetes, male sex, young age, low
GFR and high serum phosphate level.29–36 Multiple efforts
at improving the sensitivity and specificity of prediction
equations across different age groups and geographical
locations have been undertaken, and numerous groups
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Author and country Publication year(s)
National Kidney Foundation, USA 2002
Royal College of Physicians, UK 2006
Canadian Society of Nephrology, Canada 2006, 2008
Caring for Australasians with Renal Impairment, 2006, 2007
Australia
Scottish Intercollegiate Guideline Network, Scotland 2008
National Institute for Health & Clinical Excellence, 2008
England and Wales
Caring for Australasians with Renal Impairment, Under development
Australia
Kidney Disease Improving Global Outcomes‡ Under development
are working on refinements to these equations, given the
need to improve our ability to plan for RRT in an ever-
increasing group of patients. None of these refinements
to our knowledge are currently in clinical use, although
one such equation has recently been made available for
a prospective study.37
Referral to the nephrology clinic
The clinical implications of stages 4 and 5 CKD are well
described and understood, but nevertheless until the
advent of mandatory eGFR reporting, few people with
even stage 4 CKD were recognized in primary care, and
most were not referred to a nephrologist.38 Studies to
support the referral and treatment of patients identified
as having CKD in an incidental manner, such as occurs
with laboratory reporting of eGFRs, have yet to appear
in the literature. Inconsistency in referrals to nephrolo-
gists in different areas of the world, and even within
health jurisdictions, remains evident. Although CKD is
recognized as an important problem, and many guidance
documents on this disorder have been developed to help
educate primary care physicians, within the nephrology
community there is no consensus of opinion on the
definition of ‘timely referral’. As the early identification
of patients can contribute to the avoidance of nephro-
toxins and episodes of AKI, and can lead to collabora-
tive interaction between physicians and medical teams,
referring all patients to a nephrology clinic at the time
of CKD identification would seem to be appropriate. In
practice the sheer numbers of patients involved are over-
whelming, as has been discussed in numerous publica-
tions and supported by concrete data.39,40 Most guidelines
suggest referral to a nephrology clinic for patients with
an eGFR <30 ml/min, those with evidence of an increase
in the rate of decline in renal function, or patients with
worsening proteinuria. Others assert that referral to a
nephrologist at least 12 months before initiation of dialy-
sis is sufficient to assess and prepare patients for RRT.
These messages may be construed as inconsistent and
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Box 2 | Arguments for and against routine eGFR reporting
Arguments in favor of eGFR reporting
■ Early identification of renal impairment and avoidance
of late referral
■ Prevention of renal disease progression
■ Reduction of complications of CKD
■ Avoidance of treatment with potentially nephrotoxic
agents
■ Improved medical management
■ Potential cost savings, through prevention of
progression and complications of renal disease
Arguments against eGFR reporting
■ Increased numbers of referrals, leading to unnecessary
swamping of specialist services
■ Individuals are labeled as having a disease where
previously they had none
■ Psychological factors: ‘sick’ role, worried well,
depression
■ Lack of insurability
■ Loss of income
■ Potential for increased costs through over-investigation
following a diagnosis of CKD in an otherwise
asymptomatic individual
Abbreviations: CKD, chronic kidney disease; eGFR, estimated
glomerular filtration rate.
difficult to implement. The latter presumes that physi-
cians are able to predict the outcomes of individual
patients with sufficient accuracy to determine when the
need for dialysis is 1 year away, which is not easily done.
Referral to a nephrology clinic might, however, enable
the etiology of the patient’s CKD to be determined,
which could influence both treatment choices and prog-
nosis. In some patients, knowledge of the underlying eti-
ology might also facilitate the introduction of strategies
to delay progression of CKD. After the advent of eGFR
reporting in British Columbia, Canada, patients’ median
eGFR at referral to the nephrology clinic rose from 22 ml/
min to 33 ml/min. This difference translates to an esti-
mated 2–3 years of additional exposure to expert care
teams.41 The long-term consequences of this change in
referral behavior have not been rigorously quantified to
date, although a reduction in the proportion of persons
with rapid progression was evident and dialysis rates
were reduced consistently by 2% per year for a period of
5 years after the introduction of the strategy. The rates
of new dialysis patients have now plateaued at 3–4%
per year.41
Multiple publications and guidelines for nephrolo-
gists and primary care physicians have been developed
and adapted for use around the world (Table 2).2,3,42–45
These documents have influenced public health policy
in some countries, and altered the health-care focus in
several jurisdictions. However, mandating or even rec-
ommending the optimal time for referral remains diffi-
cult, owing to variation in local health environments and
other issues, as discussed. To sum up, although specific
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guidance as to when to refer a patient with impaired
renal function to specialist services seems to be based on
information and resources available to nephrology teams,
variation persists as a result of differences in the resources
and education of both nephrologists and referring
doctors around the world.
Opportunities for intervention
The most important benefit of early CKD detection
is to prolong exposure of the patient to therapeutic
interventions that delay or attenuate adverse outcomes.
Behavioral and pharmacological interventions can be
offered to patients by both primary care physicians and
specialty teams. Many strategies, such as optimal blood
pressure control with angiotensin-converting-enzyme
inhibitors and angiotensin-receptor blockers, glycemic
control, and management of iron-deficiency anemia, can
be implemented by the primary care physician without
the need for referral to a nephrologist. The reader should
also note that, with appropriate education, community
physicians can identify nephrotoxic agents and alter
patients’ therapy with good outcomes.46 Some evidence
suggests that targeting people with stage 4 CKD for
appropriate disease management adds value in terms
of delayed progression of disease, and improved blood
pressure control and CVD risk management.47 Thus, the
ability of primary care physicians to identify CKD at
an early stage may enhance the longer term outcomes
of these patients. In addition, the presence of reduced
kidney function and/or proteinuria, irrespective of pro-
gression, is linked to an increased susceptibility to AKI.48
Even in patients with initially nonprogressive disease,
the evidence increasingly shows that AKI resulting from
drug treatment or intercurrent illness can change the
trajectory of progression of CKD.49,50 Early identifica-
tion of AKI also improves drug safety through appropri-
ate dose modification and monitoring of toxic effects.
Identifying individuals at increased risk of AKI by virtue
of decreased eGFR and/or albuminuria is, therefore,
highly valuable.
Limitations of early detection
The limitations of early detection lie not so much in
implementation, but rather in the accuracy of predicting
prognosis for any given individual (versus populations),
and the lack of data to guide appropriate intervention at
different levels of eGFR and proteinuria. The concern
raised by some that early detection of nonprogressive
CKD may create a group of ‘worried well’ individuals
may not be well founded.51 Given the poor outcomes
of this group, irrespective of the etiology of their renal
impairment or its treatment (as described in a meta-
analysis24 and in a Kidney Disease: Improving Global
Outcomes [KDIGO] conference report 52), we need to
identify these individuals and to understand how best
to manage them. As yet, however, no studies have exam-
ined the effect of blood pressure lowering and other risk-
reduction strategies in patients with nonprogressive renal
impairment, in those identified as having CKD solely
by laboratory screening, or in targeted high-risk groups
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Table 3 | Cohort studies comparing mortality, cardiovascular events and progression of renal disease
Study Population Median Mortality (% or as reported) CVD Renal outcome
follow-up events
(years) (%)
Community studies
Drey et al.53 Stage 3–5 CKD 5.5* 69 (SCr >150.28 μmol/l) 31.7 RRT: 4%
(2003) (n = 1,076) 59 (SCr >503.88 μmol/l)
John et al.38 Stage 3–5 CKD 2.6 38.6 15.3 Annual GFR decline ≥4 ml/
(2004) (n = 3,822) min/1.73 m2: 12%
Keith et al.54 CKD and no CKD 5.5 24.3 (stage 3) 24.9 RRT: 1.3% (stage 3), 19.9%
(2004) (n = 27,998) 45.7 (stage 4) (stage 4)
Hemmelgarn CKD and no CKD 2 2.3 (overall) NR RRT: 0.9%
et al.55 (2006) (n = 10,184) 6 (GFR <30 ml/min/1.73 m2)
Orlando et al.56 CKD‡ (n = 1,097) 3.5* 55 NR Progression to next CKD stage:
(2007) 57%
Hemmelgarn CKD and no CKD 2.9 3 (overall) 0.6§ Doubling of SCr: 0.4%
et al.23 (2010) (n = 920,985) RRT: 0.08%||
Nephrology clinic studies
Levin et al.57 CrCl 10–75 ml/min 1.9 2.6 20 RRT: 26%
(2001) (n = 313)
Evans et al.58 Stage 4–5 CKD 5 42 (5 years) 15.9 RRT: 80%
(2005) (n = 920) 10 (pre-RRT)
Eriksen et al.59 Stage 3–4 CKD 5 46 (stage 3) NR ESRD: 4% (stage 3), 43%
(2006) (n = 1,363) 44 (stage 4) (stage 4)
Levin et al.34 Stage 4 CKD 3.1 45 per 1,000 patient-years NR RRT: 149 per 1,000 patient-
(2008) (n = 4,231) years
Orlando et al.56 CKD‡ (n = 456) 3.6* 40 NR Progression to next CKD stage:
(2007) 74%
Landray et al.29 Stage 3–5 CKD 4.1–6.0* 39 NR ESRD: 50%
(2010) (n = 382)
Hoefield et al.60 Stage 3–5 CKD 2.2 20 NR RRT: 13%
(2010) (n = 1,325)
Mixed
Rossing et al.61 T2DM ACR >300 mg 6.5 35 MI 17 Doubling of SCr or ESRD: 28%
(2004) daily (n = 227) Stroke 15
Tseng et al.62 CKD stage 3–4 1.6 15 (stage 3a) NR RRT: 1% (stage 3a), 3%
(2008) (n = 39,031) 22 (stage 3b) (stage 3b), 13% (stage 4)
33 (stage 4)
CKD CKD and no CKD 4.42* HR (95% CI) compared with GFR 95 ml/min/1.73 m2: NR HRs for eGFRs averaging 60, 45,
Consortium24,26 (n = 1,234,812) 1.18 (1.05–1.31) at GFR 60 ml/min/1.73 m2 and 15 were 4, 29, and 454,
(2011) 1.57 (1.39–1.78) at GFR 45 ml/min/1.73 m2 respectively, compared with an
3.14 (2.39–4.13) at GFR 15 ml/min/1.73 m2 eGFR of 95 ml/min/1.73 m2
*Mean. ‡Defined as SCr ≥123.76 μmol/l. §Admission with MI. ||Age-adjusted rates increased as GFR and/or proteinuria worsened. Abbreviations: ACR, albumin:creatinine ratio; CKD, chronic
kidney disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NR, not reported; RRT, renal
replacement therapy; SCr, serum creatinine; T2DM, type 2 diabetes mellitus.

with undetected CKD or who have yet to develop CKD.
Hence, current guidance for practitioners with respect
to the best available care for these patients is limited to
addressing their cardiovascular risk factors and associ-
ated comorbidities. Nonetheless, these groups of
individuals are indisputably at a higher risk of adverse
outcomes than are the general population, and perhaps
that knowledge will influence treatment choices, use of
medications and avoidance of imaging studies requiring
use of contrast media.
Prognosis and outcomes
Renal and nonrenal outcomes are both relevant
for patients with CKD. This section focuses on the
differences and similarities of these outcomes, and how
early detection may improve them.
Much of the current knowledge with respect to the out-
comes of patients who are identified as having CKD early
in the course of the disease is derived from observational
cohort studies. However, these studies were not designed
to answer questions related to the early identification of
impaired renal function. The findings of these studies
show notable variation in outcomes, particularly between
referred and nonreferred cohorts of patients, and even
within such cohorts.23,29,38,53–62 Furthermore, patient
outcomes differ depending on the characteristics of the
cohort (Table 3). For example, studies of individuals in
the general population describe an increased likelihood

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© 2011 Macmillan Publishers Limited. All rights reserved
 REVIEWS
450 – Australia
Bangladesh
400 – Belgium (Dutch)
Belgium (French)
350 –
Incidence of RRT (per million people)
Finland
300 – Greece
Japan
250 – Malaysia
Netherlands
200 –
Norway
150 – New Zealand
Poland
100 – Republic of Korea
Sweden
50 –
Taiwan
0– UK
2003 2004 2005 2006 2007 Uruguay
Year USA
Figure 2 | Comparison of end-stage renal disease incidence rates, 2003–2007.
This figure, from the 12th Annual Report of the UK Renal Registry illustrates an
international comparison of the incidence of RRT between 2003 and 2007. The
figure shows that although some countries still have a rising incidence of RRT, in
other countries it has stabilized, and in some countries has started to fall.
Abbreviations: RRT, renal replacement therapy. Permission obtained from the UK
Renal Registry © Donovan, K. et al. Chapter 16 of the 12th Annual Report of the
UK Renal Registry: International Comparisons with the UK RRT Programme [online],
http://www.renalreg.com/Report-Area/Report%202009/Chap16_Renal09_web.
pdf (2009).72 The data reported here have been supplied by the UK Renal Registry
of the Renal Association. The interpretation and reporting of these data are the
responsibility of the authors and in no way should be seen as an official policy or
interpretation of the UK Renal Registry or the Renal Association.
of dying but not of progression to ESRD in individuals
who develop CKD, whereas those conducted in referred
populations describe the opposite pattern. Furthermore,
even within referred populations the rate of progression
is variable; differential progression for those with severely
reduced eGFR is also unpredictable, with some patients
progressing more rapidly than others.
Kidney outcomes: ESRD and transplantation
Several publications have described the effect of referral
to nephrology teams or the implementation of disease
management strategies for individuals identified as
having CKD.39,40,63–66 Most demonstrate improved patient
outcomes, such as longer time to dialysis, a slower rate
of decline in eGFR, and more timely preparation for
dialysis including choice of modality and creation of
gold standard vascular access, both of which have been
associated with better survival. Early referral might also
lead to an increase in the rate of pre-emptive transplanta-
tion.67 Delayed progression of CKD and reduced protein-
uria as a consequence of control of blood pressure and
glycemia, and renin–angiotensin–aldosterone system
blockade, have been demonstrated in numerous trials.
Nonetheless, most of these studies enrolled patients with
established CKD, who were not necessarily individuals
in whom this disorder was detected early. Whether early
intervention (that is, treatment of patients with stages 1
or 2 CKD) offers a clear benefit over treatment during
452 | AUGUST 2011 | VOLUME 7
© 2011 Macmillan Publishers Limited. All rights reserved
stages 3–5 remains to be proven, particularly with respect
to preventing or slowing progression to ESRD. The
rise in prevalence of CVD as CKD progresses, and the
increased risk of mortality from CVD in patients identi-
fied as having CKD argue strongly for early interven-
tion. However, we lack high-level evidence of the value
and cost-effectiveness of this strategy, above and beyond
those of current strategies to address CVD risk factors in
this population.
A summary of the evidence in support of delayed pro-
gression of CKD in patients who receive early treatment
is beyond the scope of this Review, but has been com-
prehensively discussed elsewhere,68 as well as in many
of the existing published guidelines for the manage-
ment of CKD.2,3,42–45 Of late, some regions or countries
have reported a ‘leveling off ‘ of ESRD incidence,69,70 as
demonstrated in the current US Renal Data Systems
report, 71 which includes a comparison of data from
various countries, and in the United Kingdom Renal
Registry Report (Figure 2).72 This plateau seems to be
temporally associated with the implementation of eGFR
reporting, strategies that increase awareness of CKD, and
educational efforts directed at primary care physicians
in those jurisdictions. Although observational in nature,
this plateau may provide some evidence that early detec-
tion is of value, in that early identification of CKD can
be presumed to have led to increased implementation of
treatments that delay progression and improve outcomes.
However, this assumption still needs to be supported with
data. Large-scale, population-based studies of the effects
of increased awareness on patient outcomes are difficult
to perform, as increased awareness (and, therefore, early
detection of a condition) is usually accompanied by a
multitude of changes within a society and health-care
system. Nonetheless, ongoing surveillance of this trend,
as a surrogate for the success of education and early
detection programs, should help to inform this issue.
Acute kidney injury and CKD
The risk of AKI and other adverse outcomes is certainly
higher in patients with CKD than in those without it,
irrespective of stage. AKI is both a consequence and a
predictor of CKD. That CKD is a risk factor for AKI
has been recognized for some time,73–79 but research-
ers increasingly accept that even transient changes in
kidney function can worsen outcomes for individuals
with CKD80 (Figure 3).
The risk of AKI rises with increasing severity of CKD.
Hsu et al.78 reported that the adjusted odds ratio for
development of AKI requiring dialysis increased with
increasing stages of CKD, compared to patients with
eGFR >60 ml/min/1.73 m2: 1.95 for stage 3a; 3.54 for
stage 3b; 28.50 for stage 4; 40.07 for stage 5. Lafrance
et al. have also noted that even transient increases in
serum creatinine levels of >25 μmol/l are associated with
increases in the risk of both progression to dialysis and
death in a referred cohort of patients with CKD.81 Patients
with documented proteinuria are also more likely than
patients without this symptom to develop AKI, inde-
pendent of their GFR. Grams et al.82 reported adjusted
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hazard ratios for AKI of 1.9, 2.2 and 4.8 for patients
with urinary albumin:creatinine ratios of 11–29 mg/g,
30–299 mg/g and ≥300 mg/g, respectively, versus the ref-
erence group (those with a urinary albumin:creatinine
ratio <10 mg/g). These associations between AKI and
eGFR, and AKI and proteinuria, are not surprising given
that as CKD progresses so too does the patient’s burden
of comorbidity. Thus, progression results in patients
being far more likely to be exposed to nephrotoxic agents
and drugs that increase an individual’s susceptibility to
AKI (for example, angiotensin- converting-enzyme
inhibitors, angiotensin-receptor blockers and diuretics).
Huerta et al. evaluated 386,916 individuals in the general
population who were free of known renal disorders and
aged 50–84 years.83 In this study, NSAID users had a
threefold greater risk of receiving a first ever diagnosis
of clinical AKI compared with nonusers of these drugs.
Concomitant use of cardiovascular drugs was associated
with an even greater increase in the risk of AKI, as were
heart failure, hypertension, diabetes, and hospitalizations
in the previous year.
Possible outcomes of AKI include death, dialysis
dependence, and partial recovery (or full recovery) of
renal function. Development of de novo CKD or pro-
gression of pre-existing CKD might, therefore, follow
an episode of AKI. The outcomes of patients with AKI
are heavily influenced by pre-existing CKD. 49 Out of
89 patients followed up for 3 years after surviving an
episode of dialysis-dependent AKI in the intensive care
unit, CKD was present in 32 patients from the onset, and
developed de novo in 25 patients. ESRD developed in
nine patients (of whom eight had pre-existing CKD), and
29 patients died. At 3 years, survival was 67% overall;
mortality was 50% for those with pre-existing kidney
disease, 71% for those with new-onset CKD, and 82%
in patients without CKD. In a meta-analysis of over
47,000 patients with AKI from 48 studies, Coca et al.50
found an incidence rate of new-onset CKD of 7.8 events
per 100 patient-years and an incidence rate for ESRD of
4.9 events per 100 patient-years.
AKI occurring in individuals in the community is
an area of considerable research interest, yet one about
which we have little information. AKI in such individuals
might go unrecognized or undetected, but the individual
concerned will be subject to the same risk factors as a
patient who has AKI that is recognized and detected.
Renal functional recovery may be complete or incom-
plete, and these silent episodes of AKI may contribute to
the development and progression of CKD. AKI occurring
in individuals in the community might be of consider-
able importance in developing countries. Repeated epi-
sodes of AKI resulting from dehydration or infection
could contribute to CKD development in susceptible
individuals, such as those with low birth weight and
poor nutrition. This area is ripe for further investigation
and research.
Cardiovascular outcomes
CVD in patients with CKD has been comprehensively
reviewed elsewhere,84 and at a recent KDIGO conference
NATURE REVIEWS | NEPHROLOGY
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Prerenal Initiation Extension Maintenance Repair CKD progression and/or ESRD
100 –
AKI: Complete recovery
90 –
AKI: CKD progression
80 – AKI on CKD: CKD progression
70 –
60 –
eGFR (%)
50 –
40 –
30 –
20 –
10 – RRT
0–
0 1 3 9
(days) (weeks) (years)
Time after AKI
Figure 3 | The natural history of AKI. This figure follows the phases of AKI and
the potential outcomes. Results from 15 studies with long-term follow-up data
suggest a CKD incidence rate of 7.8 events per 100 patient-years and an end-
stage renal disease rate of 4.9 events per 100 patient-years.50 Abbreviations: AKI,
acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular
filtration rate; RRT, renal replacement therapy. Permission obtained from the
American Society of Nephrology © Okusa, M. D. et al. Clin. J. Am. Soc. Nephrol. 4,
520–522 (2009).80
held in London, UK, in October 2010.85 The incidence
and prevalence of myocardial infarction, chronic heart
failure (CHF), peripheral vascular disease and stroke are
all higher in individuals with CKD than in the general
population. 86 Outcomes of patients with CKD who
develop these conditions are poorer than those who do
not. Many studies have lacked the capability to determine
whether the benefits gained from drugs and therapeutic
strategies tested in CKD populations are at least equal
to those already tried and tested in non-CKD popula-
tions. 87–100 Within the cardiology community, some
degree of pessimism about the efficacy of interven-
tions to reduce the incidence of cardiovascular events in
patients with CKD (versus those without CKD) exists,
leading to differences in therapeutic decision-making,
which subsequently confounds the observational lit-
erature. 90,93,101–108 Nonetheless, the exclusion of these
patients from randomized studies has made it difficult
to understand which therapies are most efficacious in
these populations.109
Some re-analysis of data from existing studies, strati-
fied by eGFR category, has improved our understanding
of the utility of renin–angiotensin–aldosterone system
blockade in patients with CKD, irrespective of stage.87–89
Of particular interest is the strong association between
heart failure and CKD. This association has received
much attention, such that the concept of ‘cardiorenal’
syndrome has been proposed.110 Although this construct
has some appeal, the details remain to be validated and
appropriately reviewed. Irrespective of the underlying
etiology, the treatment and outcomes of individuals
VOLUME 7 | AUGUST 2011 | 453
REVIEWS
with CHF and CKD are complicated by the coexistence
of these two conditions. An important report from the
Study of Heart and Renal Protection (SHARP) clearly
describes a benefit of lipid-lowering strategies in CKD
populations. In this study, the combination of a low-dose
statin and ezetimibe resulted in a 16.5% reduction in the
overall risk of major atherosclerotic events, and the treat-
ment had an excellent safety profile.111 This randomized
controlled trial, which involved almost 9,500 patients
around the world, has improved our understanding of
the pathological processes occurring within this diverse
population. The results showed that intervention did
reduce the risk of atherosclerotic events, but that the
risk of death from heart failure and other causes is not
sufficiently addressed with lipid-lowering strategies to
influence mortality. Research is ongoing into how best
to define and treat these different nonatherosclerotic,
nonischemic cardiovascular conditions, and to deter-
mine the prognosis of patients with the combination of
CKD and CVD.
The early detection of CKD in patients with CVD
might lead to an intensification of the management of
their CVD risk factors, given the additional adverse
prognosis that CKD confers. What is not known with
the currently available evidence is whether invasive
interventions, such as percutaneous coronary inter-
vention and coronary artery bypass graft surgery, are
beneficial. The SWEDEHEART study 112 described a
benefit of surgical versus medical approaches for CKD
populations in an observational cohort study that
combined information from several population-based
databases. However, given the inevitable confounding
by indication in registry-based studies (owing to thera-
pies not being assigned randomly), a void in our knowl-
edge remains as to the appropriate timing of intervent
ions, and the most suitable type of intervention at each
CKD stage.
Limitations of knowledge and practice
The limitations of early detection include the following:
issues related to the sensitivity of currently available tests;
the pre-test probability of disease in the population of
interest; a lack of ability to accurately predict progres-
sion in individuals; and, in some parts of the world, the
inability to offer therapy irrespective of diagnosis.
Detection of albuminuria remains a cost-effective
method by which to identify CKD in large populations,
and has been successfully implemented in several parts
of the world, both in clinical practice and in trial set-
tings.113–118 Although the presence of albuminuria is
clearly an adverse prognostic sign in all populations
studied to date, research is required to determine the
value of abnormalities (including hematuria, alone or in
combination with albuminuria) observed in one isolated
urinalysis and the utility of urine albumin:creatinine
ratios in establishing specific risk in different circum-
stances and patient populations. We must not confuse
what we can demonstrate in groups of patients enrolled
in observational studies with the implications for the
treatment and prognosis of individual patients.
454 | AUGUST 2011 | VOLUME 7
© 2011 Macmillan Publishers Limited. All rights reserved
The best timing of interventions in individuals with
identified CKD, irrespective of how identified, is not yet
well established. As previously mentioned, the costs and
benefits of early implementation of therapies known to
reduce progression of CKD or CVD or both (in cases—
such as hypertension—when a common etiology is
shared), have not been fully determined in all popula-
tions of patients with renal impairment. For example, we
do not yet know whether the commencement of renin–
angiotensin–aldosterone system blockade and achieve-
ment of blood pressure targets in individuals with CKD
(as defined by the presence of albuminuria or reduced
eGFR) who are over the age of 80 years confers the
same risk:benefit ratio as it would in someone 20 years
younger. Nor do we know what the absolute versus rela-
tive risks are in those individuals. Given that the finding
of CKD in different populations (for example, the elderly,
the very young and those with cardiac disease) may carry
very different prognoses, both the timing and type of
interventions required in these various groups might
need to differ.
The results from large-scale, randomized, controlled
trials published in the past 5–6 years have underscored
the need to test hypotheses generated by observational
studies in CKD populations, using a robust study design
and clear inclusion and exclusion criteria.111,119–123 The
limitations in our current knowledge about which are
the optimal treatments after early detection of CKD and
about the timing of treatments should be addressed by
appropriate studies designed to answer these key ques-
tions. We believe that testing of interventions in different
populations—that is, in individuals at different stages of
CKD, and with differing levels of albuminuria—remains
the most important research agenda for the field of
nephrology at the current time. Without these studies,
nephrologists will continue to discuss the implications
of various stages of CKD, the ability or inability of neph-
rologists to manage patients with various stages of this
disease, and the importance of specific equations used
to estimate GFR in helping to identify these populations
accurately. Although all of these questions are important,
we do need to determine what we can offer patients with
CKD (irrespective of the precision of that diagnosis) who
have notably poor outcomes.
Conclusions
The early identification of CKD should increase the
amount of time that patients are exposed to therapeutic
strategies of proven benefit. Such increased exposure is
expected to have several beneficial effects: preventing or
delaying progression to ESRD; improving patient safety
through avoidance of nephrotoxic effects of drugs and/or
procedures (for example, contrast-based imaging); and,
possibly, preventing AKI episodes in patients identified as
having CKD. In turn, these improvements should lead to
a reduction in the need for RRT and improved health for
these individuals. Given the already large burden of CKD
on health-care resources, which is projected to increase
still further in both developed and developing countries,
improvements in CKD detection, an improved ability to
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 REVIEWS

predict individual patients’ prognosis and better treat-
ment strategies are necessary. As the incidence of dia-
betes increases in the developing world, and exposure to
infections and drug therapies remain a constant threat
to all, the impetus to ensure that identification of CKD
occurs as early as possible must continue.
The medical community has made great strides
over the past decade with respect to recognizing CKD
and improving the general understanding of the condi-
tion and its epidemiology. The challenge now is to
continue and build upon these efforts through the appro-
priate design and execution of large-scale clinical trials
to identify the best timing and choice of interventions to
reduce morbidity and mortality in this population. In the
last 5 years, we have noted an increased commitment to
recruit patients with kidney disease for large-scale clini-
cal trials; this may well be an indication that the com-
munity is prepared to address this void. In so doing, the
outlook for acquiring new knowledge about best practices
for patients with CKD is highly promising.
Review criteria
For this Review, we identified English-language original
research and review papers published after 2003 using
the PubMed and Google Scholar databases. Keywords
included the following MeSH terms: “CKD”, “referral”,
“outcomes” (including “mortality”, “progression of
CKD”, “doubling of serum creatinine”, and “end stage
renal disease”), “cardiovascular disease”, “acute kidney
injury”, “heart failure”, “prediction equations”, “dialysis”
and “guidelines”. Some pre-2003 references were also
included where relevant. In addition, the reference lists
of reviews published in 2010 were studied to identify
further relevant papers. Articles chosen for inclusion were
selected by the authors as representative of key issues
and landmark studies.

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33. Johnson, E. S., Thorp, M. L., Platt, R. W. &
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35. Hsu, C. Y., Iribarren, C., McCulloch, C. E.,
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Acknowledgments
A. Levin and P. E. Stevens are co-Chairs of the Working
Group for the Development of Chronic Kidney Disease
Guidelines, which is sponsored by Kidney Disease:
Improving Global Outcomes (KDIGO).
Author contributions
Both authors contributed equally to all aspects of this
manuscript.
VOLUME 7 | AUGUST 2011 | 457