Early Chronic Kidney Disease

REVIEWS
Early chronic kidney disease: diagnosis,

management and models of care
Olivier J. Wouters, Donal J. ODonoghue, James Ritchie, Panos G. Kanavos and Andrew S. Narva
Abstract | Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care
of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and
economic rationale for the design of timely and appropriate health system responses to limit the progression
of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is
differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used
for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk
factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models
on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide
approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical
improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review
discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the
most suitable model of care to adopt.
Wouters, O. J. etal. Nat. Rev. Nephrol. 11, 491502 (2015); published online 9 June 2015; doi:10.1038/nrneph.2015.85
Introduction
LSE Health, Cowdray

House, London School
of Economics and
Political Science,
Houghton Street,
London WC2A 2AE,
UK(O.J.W., P.G.K.).
Department of Renal
Medicine, Salford
RoyalNHS Foundation
Trust, Stott Lane,
SalfordM68HD, UK
(D.J.O., J.R.). National
Institute of Diabetes
and Digestive and
Kidney Diseases,
National Institutes
ofHealth, Bethesda,
31Center Drive,
Bethesda,
MD208922560,
USA(A.S.N.).
Correspondence to:
D.J.O.
donal.odonoghue@
srft.nhs.uk
Chronic kidney disease (CKD) is a condition characterized by kidney damage and/or dysfunction, as well as an
increased risk of cardiovascular disease.1,2 Type2 diabetes
mellitus (T2DM) and hypertension cause up to twothirds of CKD;3 less frequent causative factors include
glomerulonephritis, nephrolithiasis and polycystic kidney
disease.4,5 CKD is currently classified by measuring the
estimated glomerular filtration rate (eGFR) and urinary
albumin excretion rate (Table1). Patients with an eGFR
60ml/min/1.73m2 are assessed for typical markers of
renal damage, such as abnormalities in urinary sediment
or organ structure, to help confirm a diagnosis of CKD.6
In a small proportion of cases, progressive CKD leads to
end-stage renal disease (ESRD), where dialysis and/or
kidney transplantation is essential for survival. The rate
of CKD progression varies between patients, depending
on the aetiology and pathology of the disease.7,8
CKD is prevalent in most high-income countries.1,7
The prevalence rate of CKD among non-institutionalized
adults in the USA increased from 12.0% (95% CI,
10.413.5%) to 14.0% (95% CI, 12.415.7%) between
the periods 19881994 and 19992004.9 Data obtained
from 20072012 suggest that this increase in prevalence
has reached a plateau of 13.7% (95% CI, 12.115.2%).9
Between 19992004 and 20072012, the prevalence of
CKD stages 35 in the USA increased from 6.2% to 6.5%
(Figure 1). By contrast, the prevalence of stages 35 CKD
in the UK decreased from 5.7% to 5.2% between 2003
and 20092010.10
Competing interests
The authors declare no competing interests.
Patients with ESRD represent <0.1% of the total population in many high-income countries, but account for
12% of all health-care spending.11 Estimates suggest that
>US$1trillion is spent on ESRD care worldwide.12 The
clinical and economic rationale for designing timely and
appropriate health-system responses to limit progression
of CKD to ESRD, therefore, is clear.1316 This Review outlines the gaps in our knowledge as to which health-care
interventions are most effective for early-stage (stages 13)
CKD. We highlight the ongoing debate as to whether earlystage CKD is a normal indicator of the ageing process or
is a genuine disease state. Finally, we discuss the optimum
time to intervene, and what model of care to adopt.
Diagnosis of CKD
The first step in outlining an intervention strategy for

CKD is to accurately define and identify those patients
who have early-stage disease. The first guidelines for
the diagnosis and treatment of CKD were published in
2002by the National Kidney Foundation, a US voluntary
health organization.17 These guidelines were an important advancement in bringing CKD to the attention of
policy makers. The National Kidney Foundation recommendations, referred to as the KDOQI guidelines, were
adopted by countries and institutions worldwide and
form the basis of the CKD classification system (Table1).
The most recent prevalence estimates (20072012) indicate that over 40 million people in the USA have CKD;
approximately one-third of the US population aged >60
years is affected.9 Interestingly, >95% of affected individuals in the USA have early-stage CKD, and a similar distribution across stages has been observed in a wide range of
NATURE REVIEWS | NEPHROLOGY
VOLUME 11 | AUGUST 2015 | 491

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REVIEWS
Key points
Chronic kidney disease (CKD) is associated with early-onset cardiovascular
disease, end-stage renal disease and premature death
Patients with mild-to-moderate reductions in estimated glomerular filtration
rates often have comorbidities that are more relevant to their current and future
well-being than a CKD diagnosis
An integrated care pathway is required for patients with CKD
A growing number of experiences from different countries have shown that
primary care models can lead to improvements in cardiovascular and renal
health outcomes among CKD patients
More research into early identification, screening, monitoring and management
strategies for CKD is required; this research should include the establishment
of CKD registries to permit healtheconomic analyses
Table 1 | Definition and classification of CKD

Category
Measure
Description
GFR (ml/min/1.73m2)
G1
90
Normal or high
G2
6089
Mildly decreased
G3a
4559
Mildly to moderately decreased
G3b
3044
Moderately to severely decreased
G4
1529
Severely decreased
G5
<15
Kidney failure
Albuminuria (mg/g per 24h)

A1
<30
Normal to mildly increased
A2
30300
Moderately increased
A3
>300
Severely increased
CKD is defined as either kidney damage or GFR <60ml/min/1.73m2 for

3months. Kidney damage is defined as pathologic abnormalities or markers
of damage, including abnormalities in blood or urine tests or imaging studies.
Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.
Data obtained from Kidney Int. Suppl. 3, 514 (2013).
countries (Figure 2).9,1823 One study suggests that the lifetime risk of developing CKD stages G3a+ (eGFR <60ml/
min/1.73m), G3b+ (eGFR <45ml/min/1.73m), G4+
(eGFR <30ml/min/1.73m), and ESRD for an individual
born in the USA in this generation is 59.1%, 33.6%, 11.5%,
and 3.6%, respectively.24 These estimates vary markedly by
gender and ethnicity.
Prevalence rates for CKD are based on eGFRa proxy
measure of renal functionwhich is usually calculated
using the CKD Epidemiology Collaboration (CKD
EPI) or Modification of Diet in Renal Disease (MDRD)
study formulae (Figure 3). Urinary levels of albuminuria
provide supplemental information on the severity of
CKD (Table1). In addition to these two measures, other
diagnostic procedures (for example, renal tract imaging)
are performed in the majority of patients with newly
diagnosed CKD,25 although some guidelines advocate a
more rationed approach.26 A retrospective cohort study
of 1,487 patients with CKD managed at Massachusetts
General Hospital in Boston, USA, found that clinicians
frequently ordered renal ultrasonography and other
biochemical tests (for example, serum protein electro
phore ses and parathyroid hormone measurements)
during the initial evaluation of CKD. These test results,
however, only affected the original diagnosis (based on
492 | AUGUST 2015 | VOLUME 11
eGFR and urinary albumin excretion rate) and/or the

clinical care in <5% of cases.25 This finding implies that
many of the diagnostic tests conducted during the initial
evaluation of patients with CKD are redundant, and supports the economic argument for distinguishing between
the diagnosis of early-stage CKD and the assessment of
complications in patients with CKD stages4 and 5.
Age-associated decline in renal function

The estimated high lifetime risk of CKD calls into question a distinction between early-stage CKD and normal
age-associated decline in renal function. A reduction in
renal blood flow and renal mass, as well as progressive
glomerulosclerosis, are part of the normal ageing process,
with eGFR typically falling by ~0.75ml/min/1.73m2 per
year from the age of 40years.27 This rate of progression
seems nonlinear, with eGFR loss slowing below 45ml/
min/1.73m2 among elderly patients.28 Population studies
have found that the majority of patients with CKD are
aged >60years, and that most of these patients do not
exhibit marked albuminuria.29,30 Difficulties are, therefore, apparent in differentiating between age-associated
loss of kidney function and renal disease. 31 Elderly
patients with a given reduction in eGFR are less likely to
progress to ESRD than are non-elderly patients with an
equivalent reduction in eGFR.28,32 The role of the ageing
process has long been recognized in other organ systems;
for example, the natural decline in forced expiratory
volume with age indicates premature or accelerated loss
of respiratory function.33
Meta-analyses of >1.5million patients have identified that the risk of ESRD is almost equivalent between
patients aged above or below 65years of age with an
eGFR 4559ml/min/1.73m 2 and an albumin-to-
creatinine ratio <1.13mg/mmol.34,35 Although the interaction between renal function and proteinuria does seem
to differ with agepotentially due to the competing risk
of deaththese data have been interpreted as evidence
against the introduction of differing thresholds for defining CKD based on age. Furthermore, it has been argued
that senescent changes in eGFR are caused by other
disease processes, such as hypertension and diabetes mellitus, rather than a natural decline in renal function.36,37
The differing interpretations of these data on eGFR loss
in the elderly underscore the need to consider eGFR
trends as a part of the clinical assessment. Whether these
changes in eGFR reflect intrinsic renal disease or normal
ageing is unclear, but CKD and senility are associated
with an elevated risk of morbidity and mortality in an
additive fashion.34
Many patients with CKD exhibit comorbidities. In the
UK, ~64% of patients aged >65years with CKD exhibit
at least four additional morbidities, including prostate,
respiratory, and cardiac diseases in men, and bone, joint,
and mental health problems in women.38 Although it is
acknowledged that multi-morbidity imposes an increased
need for health care, the risk factors for multi-morbidity
are poorly defined. 39,40 Further work is required to determine whether renal impairment in elderly patients is
either associated with or causative of otherconditions.
www.nature.com/nrneph
REVIEWS
7.00
19881994
19992004
20072012
Percentage of the population
6.00
of CKD should instead be made only after multiple estimates have been taken over several months. Moreover,
not all studies consider the albumin excretion rate when
estimating prevalence rates.
5.00
4.00
3.00
2.00
1.00
0
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
CKD stage
Figure 1 | Prevalence of CKD by stage in the USA between

1988
and 2012.
The
Nature
Reviews
| Nephrology
prevalence estimates are based on samples of non-institutionalized adults (aged
20years) who participated in the National Health and Nutrition Examination
Survey (NHANES) during the study years indicated. The sample sizes varied across
19881994 (n=15,488), 19992004 (n=13,233), and 20072012 (n=15,502).
The proteinuria measures were based on albumin:creatinine ratios from spot
morning urine samples. The estimated glomerular filtration rates were calculated
using the CKDEPI creatinine formula. Stage 3 CKD corresponds to a glomerular
filtration rate of 3059ml/min/1.73m2. The error bars show the 95% confidence
intervals. Data were obtained from the USRDS 2014 Annual Data Report.9 The
data reported here were supplied by the USRDS. 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 US government. Abbreviations: CKD,
chronic kidney disease; USRDS, United States Renal Data System.
Equations to estimate glomerular filtration rate

The creatinine-based formulae used to estimate glomerular filtration rate (GFR) have other known limitations, in addition to the confounds of age-associated
declinein renal function described above.41,42 These formulae were originally developed to identify patients with
an eGFR 60ml/min/1.73m2 at risk of renal failure, and
are not sensitive for identification of CKD stages 1 or 2
(Figure3).43 In isolation, eGFR is of little value for earlystage CKD intervention efforts. Some clinicians have
called for the removal of the first two stages of CKD from
the KDOQI guidelines,44 whereas others have proposed
alternative methods to classify the early stages of CKD.45
The MDRD study equation tends to underestimate
the true GFR among individuals with normal kidney
function,4649 whereas the CKDEPI equation tends to
overestimate GFR in individuals with or at high risk
of CKD.50 These two equations only estimate the GFR
within 30% of the actual value; the estimated values are
even less accurate in 15.9% of cases using the CKDEPI
equation51 and in 19.4% of cases using the MDRD equation.52 Differences in sex and ethnicity should also be
considered when evaluating GFR.32,44
Epidemiologic studies have used different eGFR
formulae, which limits direct comparison of different
studies owing to the varying level of accuracy of the different formulae among patients with a high eGFR.9,10,29
Such studies have often relied upon point estimates of
eGFR that might overstate prevalence rates.9 A diagnosis
Cystatin C-derived eGFR equations

The limitations of creatinine-based GFR estimates have
resulted in the investigation of other molecules, including trace protein53 and cystatin C, as markers of renal
function.54 The latter protein provides a more accurate
estimate of renal function than does trace protein, even
among elderly patients,5557 especially when it is used in
combination with measurements of serum creatinine.58
Moreover, cystatin C-derived formulae function well at
discriminating between high GFRs as compared with
creatinine-based formulae.26
The use of cystatin C-derived formulae is now recommended to confirm or exclude CKD in patients with mild
reductions in eGFR (as assessed using creatinine-based
estimates) and an albumin-to-creatinine ratio of <3mg/
mmol.6,26 This strategy might lead to future cost savings
by reducing health-care use among patients who are
wrongly diagnosed with CKD. An international standard reference for cystatin C measurement has now been
agreed upon (ERM-DA47/IFCC),59 but the assay is not
yet widely available. Diagnostic accuracy might improve
if uptake of the assay increases.
Albuminuria
Although urinary albumin excretion rates provide valuable diagnostic data, tests for albuminuria have limitations, such as poor testretest reliability,60,61 further
supporting the need to use more than one prognostic
factor to define CKD. Measurements of albuminuria can
vary depending on the type of assay (for example, monoclonal versus polyclonal antibody methods),62 the sample
collection method (for example, 24h collection versus
first morning void versus random spot sample),63 and
the sample storage procedure.64 Furthermore, although
standard thresholds for pathologic albumin excretion are
used across sex and age, both factors might affect urinary
albumin measurements.6567
Key points for clinical practice
Estimates of GFR that do not incorporate cystatin C
data are imprecise, and clinicians need to be aware of the
strengths and limitations of such diagnostic tools. Primary
care physicians (PCPs) should rely on their clinical judgement when evaluating individual patients with respect to
eGFR trends and albuminuria. Although these two parameters jointly provide accurate predictive information about
the risk of ESRD,68,69 clinicians should also consider the
severity of comorbidities, family histories and vascular risk
profiles.70,71 More work is needed to improve the sensitivity
and specificity of eGFR formulae and other risk equations
for identifying progressive CKD (Table2).
Management of early CKD
The majority of patients with CKD do not progress

to ESRD. Treatment of the entire CKD population is,

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Stage
Stage
Stage
Stage
Stage
20.00
n = 5,588
18.00
16.00
14.00
n = 13,925
n = 574,024
n = 2,356
1
2
3
4
5
n = 15,502
n = 462,293
12.00
10.00
n = 2,745
8.00
6.00
4.00
2.00
0.00
China
2005
2006
India
2005
2007
Japan
2000
2004
Korea
2006
Spain
2011
Taiwan
1994
2006
USA
2007
2012
Country and study period
Figure 2 | Breakdown of chronic kidney disease (CKD) by stage (15) in selected

Nature
Reviews | Nephrology
countries with data available from the 2000s.9,1823 Stage3
corresponds
to a
glomerular filtration rate of 3059ml/min/1.73m2. The Chinese study used
asample of individuals from Beijing,18 the Indian study used a sample from 13
academic and private medical centres located throughout the country,19 and the
Korean study used a sample from seven urban cities.21 The other studies used
nationally representative samples. For Japan, the prevalence estimate for stage4
includes both stages4 and5 CKD.20 All studies either sampled adults aged18
years or 20years, except for the Korean study which included adults aged
35years. All studies used a version of the four-variable MDRD study equation to
determine estimated glomerular filtration rate, except for the US study data, which
used the CKDEPI creatinine formula. The Chinese,18 Korean,21 Spanish,22 and US9
studies measured proteinuria using the spot morning urinary albumin:creatinine
ratio. The remaining studies used a urine dipstick analysis for proteinuria. The
Chinese study18 also measured haematuria by dipstick test.
therefore, neither clinically appropriate nor, given

the global scale of the disease, economically feasible.
Clinical care might improve if early-stage CKD with
risk of progression to ESRD is differentiated from
early-stage CKD that is unlikely to advance (Box1).
Interventional studies might also benefit from a selective definition of early-stage CKD. For example, the benefits of dietary salt restriction have not been conclusively
established.72 Apost hoc analysis of the ONTARGET
and TRANSCEND studies identified no renal benefit of
dietary salt restriction among patients with early CKD.73
Given the reported benefits of a low salt diet for patients
with advanced renal failure,74 it is possible that certain
patients might be better suited than others to dietary
saltrestrictions.
The screening debate

A systematic review of screening, monitoring and treating patients with CKD stages 13, commissioned by the
US Preventive Services Task Force (USPSTF), questioned
the clinical and economic value of screening both the
general population and those at high risk of developing
CKD.75 This stance is supported by the American College
of Physicians (ACP).76 The USPSTF systematic review
found no randomized controlled trials (RCTs) of CKD
screening in adults who were asymptomatic with or
without recognized risk factors for CKD incidence, progression, or complications, and no RCTs of monitoring adults with CKD stages1 to 3 for worsening kidney
function or damage.75
The position of the USPSTF and the ACP is not universally supported. In the UK, the National Institute for
Health and Care Excellence (NICE) advocates targeted
assessment for CKD in patients prescribed medications
known to be nephrotoxic (for example, calcineurin
inhibitors, NSAIDs and lithium), and in patients with
diseases linked to CKD, such as T2DM.26 The American
Society of Nephrology (ASN) contends that universal
screening for CKD is appropriate given the asymptomatic
nature of mild-to-moderate CKD and the difficulties in
performing an accurate clinical investigation. Although
the ASN acknowledges the lack of support from RCTs
for this position, the society proposes that early and
improved blood pressure control might slow progressive loss of renal function and that improved awareness
of CKD might be relevant during periods of hospitalization.77 A systematic review concluded that screening for proteinuria might be cost-effectivedefined as
<US$50,000 per quality-adjusted life year gainedfor
patients with T2DM and/or hypertension.78 The review
also found that eGFR screening might be cost-effective in
patients with T2DM. No studies of the cost-effectiveness
of eGFR screening in patients with hypertension have
been performed.78
Treatment of early-stage CKD

Some evidence suggests that lifestyle changes and the use
of preventive medicines can reduce the risk of cardiovascular disease and possibly slow, halt, or even reverse CKD
progression during the early stages of disease.1,79 The evidence collected thus far is generally of low quality, but
provides some support for calorie-controlled diets,8083
physical exercise,8486 and smoking cessation8789 predominantly in patients with T2DM that is comorbid with
CKD. Most patients with CKD have comorbidities that are
amenable to a systematic approach to prevention and early
management, and many patients die from cardiovascular
events or other causes before developing ESRD.70,90,91
The pathophysiology of increased vascular risk evolves
over the natural history of CKD,92 and traditional risk
factors for atherosclerosis have a proportionately greater
impact on disease progression during early-stage CKD.
In early-stage CKD,93,94 treatment with lipid-lowering
agents reduces the risk of cardiovascular events despite a
low association between LDL cholesterol and outcomes
in patients with CKD stages 35.95 Improved awareness
of CKD as a risk factor for vascular disease could facilitate
timely use of these agents alongside other interventions,
such as blood pressure control.96 RCTs of angiotensinconverting enzyme (ACE) inhibitors 97 and angio
tensinIIreceptor blockers (ARBs)98,99 have provided the
strongest evidence of a treatment benefit among patients
with early-stage CKD. These studies, however, focused
on patients with diabetic renal disease in the presence
of proteinuria, and the data to support the use of these
agents for other causes of CKD are weak.100
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9.00
CKDEPI creatinine
MDRD study
8.00
7.00
6.00
5.00
4.00
3.00
2.00
1.00
0
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
CKD stage
Nephrology
Figure 3 | Comparison of CKD prevalence as determinedNature
using Reviews
different| formulae
toestimate glomerular filtration rate (CKDEPI creatinine versus the four-variable
MDRD study) in the USA between 1999 and 2004. The prevalence estimates are
based on samples of non-institutionalized adults (aged 20years) who participated
in the National Health and Nutrition Examination Survey (NHANES) during these
years (n=13,233). The CKDEPI data reported here were supplied by the USRDS.9
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 US
government. The four-variable MDRD study data were reported by Coresh etal.29
Both studies used measures of albumin:creatinine ratios from spot morning urine
samples. Stage3 CKD corresponds to a glomerular filtration rate of 3059ml/
min/1.73m2. The error bars show the 95% confidence intervals. The prevalence of
stage5 CKD was not estimated with the MDRD equation in this study29 as it was
deemed that estimates of this stage are likely to be unreliable due to the small
number of individuals and the likelihood that many of these individuals are ill or
receiving dialysis and would have a low response rate.29 Abbreviations: CKD,
chronic kidney disease; USRDS, United States Renal Data System.
The rate of increase in the incidence of ESRD is

slowing in some countries, including Australia, Canada,
northern European countries, New Zealand and the
USA, although these trends vary by subgroups, such as
age and race.101 The stabilization of these incidence rates
might reflect improvements in cardiovascular risk management in the general population and among individuals with T2DM and/or hypertension, although this effect
has yet to be shown conclusively.
Evidence gaps
The conflicting views of the ACP, ASN, NICE and
USPSTF highlight the need for more RCTs to evaluate
identification, screening, monitoring and treatment of
early CKD. In the meantime, population health management could focus on the control of vascular risk factors
and on the patients with CKD who are likely to progress
to ESRD, and will subsequently place a burden on healthcare costs.102,103 Given the asymptomatic and insidious
onset of CKD, research into new biomarkers and prognostic techniques is essential.104105 Development of such
assays is an active area of research, and new prediction
models are regularly published.105111 Nevertheless, more
work is needed to validate and refine these models. The
findings across patient groups should be examined to

determine how the data could be generalized: one model
could be appropriate for one patient population in a particular geographic region, but it might be less accurate,
or even lead to erroneous conclusions, when applied to
other patient groups or populations.
Expanding the definition of early CKD must be considered in connection with the adverse outcomes associated with a reduced eGFR.91 Two meta-analyses found
that patients with hypertension and/or T2DM and with
reductions in eGFR have an increased risk of ESRD and
death compared with those with reduced eGFR but no
hypertension or T2DM.112,113 In both studies, the risk of
ESRD was markedly elevated when eGFRs dropped to
<50ml/min/1.73m2, but the risk of death was increased
at eGFRs <90ml/min/1.73m2. Although these data could
be interpreted to support defining a mild reduction in
renal function as part of a disease state, it is important
to consider the difference in the threshold for the risk
of death and ESRD. These findings also raise the question ofpopulation risk versus individual risk. Patients
with early CKD but at low risk of ESRD still carry an
elevated risk of other complications compared to the
general population.114 Screening patients for reductions
in eGFR might not contribute meaningful prognostic
information at an individual level with regard to ESRD
risk. Small reductions in eGFR, however, can improve
discrimination in models of cardiovascular risk, and
the rate of change in eGFR might be a more effective
predictor ofrisk, as compared to absolute values.115,116
Stage 12 CKD should possibly be assessed in associ
ation with cardiovascular risk rather than renal risk. This
assessment might be particularly relevant when considering elderly patients with reduced measures of eGFR but
no appreciable albuminuria. The risk of ESRD and death
was associated with increased albuminuria in a linear
manner in the two meta-analyses described above,112,113
further emphasizing the importance of albuminuria in
defining the risk of CKD progression.
Models of CKD care

The Wagner chronic care model
Some evidence suggests that the prevailing care strategy for CKD should comprise three phases (Figure4).
Primary care management of vascular disease risk
during early-stage CKD forms the first phase of the care
strategy, which could involve exercise, dietary changes,
smoking cessation, blood pressure control, glycaemic
and lipid control and periodic monitoring of kidney
health. The second phase could provide structured care
to target comorbidities, such as anaemia, bone disease
and secondary hyperparathyroidism, which develop in
patients with CKD that progresses to stage 45. The final,
third phase involves multidisciplinary, intensive care
for patients transitioning to renal replacement therapy
(CKD stage 5 and ESRD).117,118
Given the current distribution of CKD cases across
stages 15 (Figures1 and 2),9 the majority of patients
with CKD would fall into the first phase of care described
above. Consequently, the management of CKD could be

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Table 2 | Selected observational studies of the quality of primary care for patients with CKD
Study
Design
Population
Period
Key results
Allen
etal.
2011135
Retrospective
cohort
166PCPs in 15health centres in

eastern Massachusetts, USA, caring
for 11,774 patients with CKD (eGFR
1560ml/min/1.73m2)
2004
2008
70% patients were not tested yearly for urine protein,

46% had blood pressure 130/80mmHg, 25% were
not receiving appropriate treatment with ACE
inhibitors or ARBs and 26% were receiving potentially
harmful medicines
Boulware
etal.
2006132
Cross-sectional
(questionnaire)
National, random, stratified sample

of 400nephrologists and 800PCPs
in the USA. Responses obtained from
126nephrologists and 178PCPs
2004
2005
Family practitioners (56.2%) and general internists

(70.7%) were less likely to recognize CKD than were
nephrologists (96.0%) (P<0.01)
Charles
etal.
2009133
Cross-sectional
(questionnaire)
Same population as in the study

byBoulware etal. (2006)
2004
2005
Only 48% of nephrologists, 19% of family practitioners,

and 33% of general internists followed the KDOQI
guidelines on the laboratory and radiological evaluation
of patients with CKD (P<0.001)
Fox etal.
2006134
Qualitative
interviews
10 PCPs from 10 health-care

facilities affiliated with the Upstate
New York Practice-based Research
Network
Not
stated
Awareness of KDOQI guidelines was low, and PCPs

often favoured less-accurate diagnostic tests for
CKD (serum creatinine). Uncertainty existed about
the appropriate timing of referral to a nephrologist
Israni
etal.
2009141
Cross-sectional
(questionnaire)
Random sample of 1,550US PCPs;

1,453eligible respondents.
Responses obtained from 470PCPs
2007
Only 35% of PCPs had adequate knowledge of CKD

based on responses to 27questions; for each
10year increase in age of the PCP, the odds of
having adequate knowledge decreased by 26%
Lea etal.
2006131
Cross-sectional
(survey)
PCPs in six predominantly

African-American communities
intheUSA. Responses obtained
from 464PCPs
2003
~34% and 22% of PCPs did not identify family history

and African-American ethnicity as risk factors for
CKD, respectively. PCPs had high awareness that
hypertension and T2DM are predictors of CKD
Minutolo
etal.
2005138
Cross-sectional
Nephrologists (tertiary care) and

39PCPs caring for hypertensive
patients with CKD (eGFR 1560ml/
min/1.73m2) in Italy
2003
Patients with CKD cared for by PCPs had higher

blood pressure levels than those cared for by a
nephrologist (P<0.0001). The risk of not attaining
blood pressure target values was 2.6-times greater
in primary care than in tertiary care settings,
controlling for age, sex, T2DM and eGFR
Ravera
etal.
2009140
Cross-sectional
PCPs caring for 7,582 hypertensive

patients with T2DM in Italy
2005
Only 10.4% of patients with T2DM in this population

achieved blood pressure<130/80mmHg. Of
patients with eGFR<60ml/min/1.73m2, only 17%
had been coded as having CKD
Ravera
etal.
2011139
Cross-sectional
PCPs caring for 39,525

hypertensive patients in Italy
(nationally representative sample
ofpatients)
2005
Only 13.8% of patients with eGFR <60ml/

min/1.73m2 and 72.6% of patients with
eGFR<30ml/min/1.73m2 were coded as having
CKD. Of patients with eGFR<60ml/min/1.73m2,
only 45.4% and 13.2% achieved blood pressure
<140/90mmHg and <130/80mmHg, respectively
Razavian
etal.
2012136
Cross-sectional
(survey)
Nationally-representative, clusterstratified sample of 534PCPs in

Australia; responses obtained from
322 PCPs caring for 4,966 patients
(age 55 years) with available data
on kidney function
2008
<18% patients were correctly diagnosed with CKD.

The decisions by PCPs not to prescribe blood
pressure or lipid-lowering agents for patients with
CKD only adhered to guideline recommendations in
51% and 46% of cases, respectively
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II-receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration
rate; KDOQI, Kidney Disease Outcomes Quality Initiative; PCP, primary care physician; T2DM, type 2 diabetes mellitus.
reconceptualized as a part of primary care.119 The adoption of an integrated care approach might help to coordi
nate the continuum of care for patients with CKD.120
This care strategy would be aligned with the chronic care
model developed by Edward H. Wagner, which consists
of six core parts: community resources and policies;
health-care organization; self-management support;
delivery system design; decision support; and clinical
information systems.121124 The implementation of such
changes in clinical practice is needed as the prevalence
rates of T2DM and hypertension are expected to increase
and will add to the global burden of CKD.125127 Ashift
to a primary care model might enable nephrologists and
other specialists to focus on patients with primary kidney

disease, progressive CKD and ESRD.
For all patients with CKD, PCPs should check for drug
interactions, environmental toxins, and contrast dyes
that might cause acute kidney injury. These factors could
be monitored with the help of information technology
systems, which could, for example, alert physicians to
potentially harmful drug combinations. Some prescription and over-the-counter medicines, such as NSAIDs,
can precipitate acute kidney injury in patients with CKD,
and can accelerate progression of CKD.128130
Numerous studies have highlighted the shortcomings
of primary care for patients with CKD (Table2). Notably,
REVIEWS
Box 1 | Prevention strategies for early-stage CKD
Primary and secondary
Clarification of CKD staging and prognostication to
improve PCP engagement
Patient and clinician education to link public health
programmes to kidney health
Target population
Development of high quality evidence via RCTs to guide
screening programmes for CKD
Patients at risk of AKI or with previous AKI
Continued assessment of high-risk populations
Assessment of impact of interventions
Assessment of patient awareness of disease and
personal clinical data
Proportion of patients experiencing cardiovascular
events, a preventable loss of renal function, or
requiring referral to secondary care centres
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease;
PCP, primary care physician; RCT, randomized controlled trial.
there is low awareness of the KDOQI guidelines anddiagnostic techniques, 131136 suboptimal prescribingand
management for patients with T2DM and/or hypertension,9,136140 and poor recognition of the known risk
factors for CKD.131 A survey of 470US-based PCPs found
that only 35% had adequate knowledge of CKD based
on responses to 27 questions.141 For each 10-year increase
in the age of the PCP, the odds of having adequate know
ledge decreased by 26%.141 Another study found that only
19% of family practitioners and 33% of general internists in the USA followed the KDOQI guidelines for the
laboratory and radiological evaluation of patients with
CKD.133 In a study commissioned by the US National
Kidney Disease Education Program, approximately onethird and one-quarter of USbased PCPs did not recognize family history and African-American ethnicity
Phase 1
(CKD
stages
13)
Primary care for cardiovascular disease

Exercise
Healthy eating
Smoking cessation
Blood pressure, glycaemic, and lipid control
Phase 2
(CKD
stages
4/5)
Secondary care for CKD complications

Treatment and management of anaemia
and mineral and bone disorder
Nutrition management
Phase 3
(CKD
stage 5/
ESRD)
Multidisciplinary care for RRT

Shared decision making between
physicians and patients
Dialysis and/or kidney
transplantation
Surgical creation
of AVF
Psychological
support
Figure 4 | An integrated care continuum for CKD that isNature

consistent
with| the
chronic
Reviews
Nephrology
care model. Abbreviations: AVF, arteriovenous fistula; CKD, chronic kidney disease;
ESRD, end-stage renal disease; RRT, renal replacement therapy.
as risk factors for CKD, respectively.131 High awareness

that T2DM and hypertension are predictors of CKD was,
however, identified.127 These three surveys131,133,141 were
voluntary and had low response rates, ranging from 7.6%
to 32.4%. The participants of these studies might not be
representative of the general PCP population, and it is
possible that these findingswhich already point to substantial room for improvementoverstate the quality of
CKD care (Table2).
The secondary care model

Timely involvement of renal specialists is required to
improve health outcomes for patients with progressive
CKD. Payers, however, which are any groups, other than
patients, that are responsible for funding or reimbursing
the cost of health care, want to avoid unnecessary referral
patterns that could deplete resources. Depending on the
country, the term payer might refer to private or public
insurers, employers, or other third-party payers.
A systematic review of the clinical and cost-
effectiveness of early versus late (or no) referral to a
nephrologist found that an early referral is associated
with better health outcomes and might be more costeffective than late referral.142 RCTs that provide data on
the clinical effectiveness of early referral strategies were
not identified. Only two studies included patients who
were in the predialysis stage, and insufficient data were
available on the natural history of CKD and the costs and
effects of early referral. These data highlight the requirement for long-term observational studies of patients with
early-stage CKD to enhance delineation of disease progression and the incidence of cardiovascular events in
patients with and without associated health conditions,
such as T2DM, pre-existing cardiovascular disease,
albuminuria or proteinuria. Finally, the authors of the
systematic review suggested that the substantial costs
of early referral might be unaffordable for health-care
systems, even if early referral is cost-effective in the long
term. Further research is needed to evaluate thecosteffectiveness of improved primary care for patients with
early-stage CKD.
Early identification of CKD in the UK is financially
incentivized in primary care, but some PCPs express
concern as to whether early CKD is a genuine disease
state across all ages. 143 In geographical areas where
patients are not correctly identified on CKD registers,
cardiovascular management is suboptimal, with worse
control of blood pressure and cholesterol levels, compared
to those patients included on CKD registers.144 Atransition to a primary care model should be a universal decision, unlike the development of current guidelines that
have been driven by secondary care providers.145
Integrated care pathways for CKD
A unified strategy for patients across health-care providers and payers might improve overall outcomes
(Box2). Models of CKD care should be evaluated in
terms of value for money, and there must be an understanding as to what approaches achieve a reliable service
delivery to high-risk populations. CKD can provide

REVIEWS
Box 2 | Service delivery for CKD
Primary care
Patient assessment by eGFR trend and/or trajectory
reporting
Classification of CKD based on risk of progression
Identification of CKD as an indicator of elevated
cardiovascular risk, with early modification of traditional
risk factors
Patient advocacy and self-management during earlystage (13) CKD
Referral to secondary care for specialist treatment of
CKD complications
Secondary care
Multidisciplinary management of disease complications
Ongoing support for patient self-management
programmes
Integration with other secondary care services to
manage the burden of comorbidities
Personalized treatment goals with consideration of
quality of life
Integration into primary care to support periodic
monitoring of stable patients by PCPs
Structured follow-up for patients having experienced AKI,
with data collection to describe the long-term effects on
GFR trajectory
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney
disease; eGFR, estimated glomerular filtration rate; GFR,
glomerular filtration rate; PCP, primary care physician.
a useful case study of how to enact a primary care

model that is oriented towards public health and that
ispatient-centred.
CKD care pathways in the USA

Despite the fragmentation of the US health system,
improvements in CKD care have been observed in public
health-care organizations (for example, the Indian Health
Service146148 and Veterans Health Administration149)
and private health-care organizations (for example,
Kaiser Permanente150,151). In the 1990s, the Indian Health
Service employed various primary care strategies to
combat the growing burden of T2DM and hypertension
among American Indians and Alaskan Natives. These
strategies included the promotion of T2DM awareness
and lifestyle changes for patients (for example, healthy
eating), the routine screening for CKD as part of primary
care, the continued education of providers (for example,
PCPs, advanced practice nurses, and pharmacists),
the improvement of pharmacologic care for patients
with T2DM and hypertension, and the greater use of
diabetesregistries.146148
By 20062007, >80% of patients in the Indian Health
Service with comorbid hypertension and diabetes mellitus were receiving an ACE inhibitor or ARB.147 Between
1997 and 2007, the mean haemoglobin A1c and LDL chol
esterol levels decreased from 8.65% to 7.85% and from
3.1mmol/l (120mg/dl) to 2.5mmol/l (96mg/dl), respectively.148 The age-adjusted incidence of ESRD among
American Indians with diabetes mellitus decreased
by 31% (80.4 per 10,000 diabetic patients to 55.8 per
10,000 diabetic patients) between 1990 and 2001.146 The
care strategies used by the Indian Health Service have
demonstrated that a system-wide approach, even in an

underfunded system, can produce notable benefits in
terms of c ardiovascular and renal healthoutcomes.
Kaiser Permanente of Southern California is a
vertically-integrated health maintenance organization
that has deviated from the KDOQI guidelines.151 This
organization instead applies a composite risk assessment to target patients whose conditions are expected
to worsen, and it uses automated information technology
systems that suggest treatment options based on inputted patient information. The Hawaiian network of Kaiser
Permanente has also started to provide care to patients
with CKD based on risk stratification, and has found that
this approach is associated with a statistically significant
reduction in disease progression.150
CKD care pathways in the UK

Growing integration between primary and secondary
care is evident in the UK. A study performed in 2003
which preceded automated eGFR reportingreviewed
the electronic primary care records of >130,000 patients
and found a high rate of undiagnosed CKD, with <20%
of patients with an eGFR <30ml/min/1.73m 2 being
coded as having renal disease.152 Although automated
eGFR reporting has improved the detection of CKD in
primary care and has increased referral rates, this study
suggests that it is possible to alert PCPs about missed
opportunities for preventive prescribing.
A model of CKD management similar to that introduced by Kaiser Permanente150 was initiated between 2003
and 2006 in the West Midlands, UK. The initial results
show that patient outcomes have improved as a result
of this care strategy, with a reduction in the population-
adjusted incidence of renal replacement therapy. 153
Another study in West Lincolnshire, UK, evaluated the
health outcomes of patients with CKD stages 45 treated
in primary care with a disease management programme,
which was similar to a secondary care multidisciplinary
clinic. The programme improved health outcomes and
slowed the reduction in eGFR over a 9month period.154
Intensive, target-driven disease management programmes
have produced positive outcomes in the management
of T2DM,155 and scope exists for such approaches to be
applied to the care of patients with CKD.
Other international experiences
Other countries, including Australia and Canada, are
transitioning towards primary care models for the management of CKD in the general population. Similar
to the Indian Health Service, Australia has relied on
community-based CKD care for the population of the
Tiwi Islands, an aboriginal community.156 The model of
the Tiwi Islands focuses on controlling blood pressure
and lipid levels, and health education, with the aim to
improve cardiovascular health and preserve renal function. The published data indicate that this strategy has
markedly improved cardiovascular and renal health outcomes in this population.156 These international experiences suggest that a holistic care model can be successfully
applied across different types of health systems.
REVIEWS
Box 3 | Workforce, ICT, and other strategies to improve care for early-stage CKD
Workforce
Motivated and educated workforce and patient population
Easy access to laboratory monitoring
Specialist nursing staff to support patient understanding of the disease
Financially viable secondary care renal services for a potentially smaller but very
ill patient population
PCPspecialist interface
Multi-specialty clinics in primary care to support PCP education and patient care
Defined referral and discharge criteria for secondary care
Role of ICT and decision-support systems
Integration of primary and secondary care records
Accessible results reported to patients in any location
Automated analysis of eGFR and/or trends in proteinuria
Incorporation of validated predictive models for ESRD into laboratory reports
Electronic prescribing linked to biochemical results
Health-economic impact and health-system financing
Economic analyses built into all studies of CKD screening and treatment
Financial incentives balanced towards prevention of progression to ESRD
Establishment of CKD registries to permit healtheconomic analyses
Leadership, governance, and role of national and international organizations
International, evidence-based accordance between national and international
bodies regarding CKD screening and treatment
Increased data sharing between health systems of epidemiologic trends in CKD
Strong patient representation in all organizations
Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate;
ESRD,end-stage renal disease; ICT, information and communications technology; PCP,
primarycare physician.
Health-economic modelling of CKD care
As previously described, physicians should consider the

limitations of population-based equations to estimate
GFR and instead evaluate individual patient characteristics when predicting disease risk and developing
treatment plans. Structured, early CKD intervention programmes can form the basis for such personalized care.
Given the heterogeneity of patients with early-stage CKD,
and the variable risks in different populations, clarity as
to the appropriate scope and impact of such programmes
is needed. Health-care providers, payers and the general
public should be made aware of the cost-effectiveness of
investing in CKD intervention programmes (Box3).
Systems modelling is an inexpensive method to study
the effects of different interventions on chronic disease outcomes and costs.157159 Software can be used to design comprehensive care models in patient populations and observe
the burdens of T2DM, hypertension, CKD andESRD over
time.160 This method of modelling allows for sensitivity
analyses to test the degree of uncertainty around the model
assumptions. These analyses can provide an indication of
the reliability and strength of the results, and highlight
areas where further research is needed.
1.
2.
James, M.T., Haemmelgarn, B.R. & Tonelli, M.

Early recognition and prevention of chronic
kidney disease. Lancet 376, 162162 (2010).
Sarnak, M.J. etal. Kidney disease as a risk
factor for development of cardiovascular
diseasea statement from the American Heart
Association councils on kidney in cardiovascular
disease, high blood pressure research, clinical
cardiology, and epidemiology and prevention.
Circulation 108, 21542169 (2003).
3.
4.
5.
Alongside systems modelling, long-term prospective

cohort studies are required to interpret the clinical and
economic value of different intervention strategies from
a payer or societal perspective. Ideally, these studies
should incorporate RCTs of CKD treatments into their
design. Furthermore, economic analyses should be conducted in parallel with outcome evaluations. Notably,
the NordTrndelag Health Study (HUNT) performed
in Norway, 161 the Kaiser Permanente 151 and West
Midlands studies,153 and the majority of CKD quality
improvementstudies do not consider health-care costs.
Incorporating health-economic evaluations into these
population-based studies would generate useful evidence
to guide approaches to CKD care. Relevant stakeholders
should also establish registries to monitor the long-term
health and cost effects of different care pathways and the
timing of care initiation.
Conclusions
Insufficient evidence has been generated regarding the

clinical and economic benefits of early CKD intervention, especially in comparison to other diseases, such as
T2DM and stroke. To date, no RCTs have assessed the
clinical and economic outcomes of early intervention
strategies, and comprehensive patient-level data are not
readily accessible. Early diagnosis, treatment and management of CKD could alter the natural history of this
disease and generate substantial cost savings. Improved
understanding of the merits and disadvantages of different care approaches for CKD and knowledge as to
where evidence is lacking are essential to improve health
outcomes and minimize expenditure.
CKD, like many chronic conditions, can be considered a broad indicator of overall health. Patients with
mild-to-moderate reductions in eGFR often have
comorbidities that are more relevant to their current and
future well-being than is their CKD diagnosis.162 These
comorbidities should remain the focus of treatment and
management, as a low proportion of patients who are
diagnosed with CKD will develop ESRD.
The difficulty for PCPs and nephrologists to identify
patients with progressive CKD has weakened the effectiveness of early interventions. New biomarkers that
might improve the detection and prognosis of CKD are
becoming increasingly available,163 but it is unlikely that
any magic bullet will fully address the disease burden
of CKD. A unified care strategy across health-care providers and payers should be promoted. This assertion
holds true for CKD, a particularly complex disease that
involves many health-care providers over the lifetime of
a patient, but also applies to other chronic illnesses.
Chen, R.A., Scott, S., Mattern, W.D., Mohini, R.

& Nissenson, A.R. The case for disease
management in chronic kidney disease.
Dis.Manag. 9, 8692 (2006).
Jha, V. etal. Chronic kidney disease: global
dimension and perspectives. Lancet 382,
260272 (2013).
Atkins, R.C. The epidemiology of chronic
kidneydisease. Kidney Int. Suppl. 94, S14S18
(2005).
6.
7.
8.
Kidney Disease: Improving Global Outcomes

(KDIGO) CKD Work Group. KDIGO 2012 clinical
practice guideline for the evaluation and
management of chronic kidney disease. Kidney
Int. Suppl. 3, 1150 (2013).
Levey, A.S. & Coresh, J. Chronic kidney disease.
Lancet 379, 165180 (2012).
Haynes, R. etal. Evaluating the contribution of
the cause of kidney disease to prognosis in
CKD: results from the Study of Heart and Renal

REVIEWS
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Protection (SHARP). Am. J. Kidney Dis. 64, 4048

(2014).
United States Renal Data System. USRDS 2014
annual data report [online], http://www.usrds.
org/adr.aspx (2015).
Aitken, G.R. etal. Change in prevalence of
chronic kidney disease in England over time:
comparison of nationally representative crosssectional surveys from 2003 to 2010.BMJ Open
4, e005480 (2014).
De Vecchi, A.F., Dratwa, M. & Wioedemann,M.E.
Healthcare systems and end-stage renal disease
(ESRD) therapiesan international review: costs
and reimbursement/funding of ESRD therapies.
Nephrol. Dial. Transplant. 14 (Suppl. 6), 3141
(1999).
Stenvinkel, P. Chronic kidney disease: a public
health priority and harbinger of premature
cardiovascular disease. J. Int. Med.268,
456467 (2010).
Feehally, J. etal. Early detection of chronic
kidney disease. BMJ 337, a1618 (2008).
Levin, A. & Stevens, P.E. Early detection of CKD:
the benefits, limitations and effects on prognosis.
Nat. Rev. Nephrol. 7, 446457 (2011).
Locatelli, F., Del Vecchio, L. & Pozzoni, P. The
importance of early detection of chronic kidney
disease. Nephrol. Dial. Transplant. 17, 27
(2002).
El Nahas, A.M. & Bello, A.K. Chronic kidney
disease: the global challenge. Lancet 365,
331340 (2005).
National Kidney Foundation. KIDOQI Clinical
Practice Guidelines for Chronic Kidney Disease:
Evaluation, Classification and Stratification.
Am.J. Kidney Dis. 39, S1S266 (2002).
Zhang, L. etal. Prevalence and factors
associated with CKD: a population study from
Beijing. Am. J. Kidney Dis. 51, 373384 (2008).
Singh, A. K. etal. Epidemiology and risk factors of
chronic kidney disease in Indiaresults from the
SEEK (Screening and Early Evaluation of Kidney
Disease) study. BMC Nephrol. 14, 114 (2013).
Imai, E. etal. Prevalence of chronic kidney
disease in the Japanese general population.
Clin. Exp. Nephrol. 16, 621630 (2009).
Kim, S. etal. The prevalence of chronic kidney
disease (CKD) and the associated factors to
CKD in urban Korea: a population-based crosssectional epidemiology study. J. Korean Med. Sci.
24 (Suppl. 1), S11S21 (2009).
Otero, A. etal. Prevalence of chronic renal
disease in Spain: results of the EPIRCE study.
Nefrologia 30, 7886 (2010).
Wen, C. P. etal. All-cause mortality attributable to
chronic kidney disease: a prospective cohort
study based on 462,293 adults in Taiwan.
Lancet 371, 21732182 (2008).
Grams, M.E., Chow, E.K.H., Segev, D.L. &
Coresh, J. Lifetime Incidence of CKD Stages 35
in the United States. Am. J. Kidney Dis. 62,
245252 (2013).
Mendu, M.L. etal. The usefulness of diagnostic
testing in the initial evaluation of chronic kidney
disease. JAMA Intern. Med. 175, 853856
(2015).
National Institute for Health and Clinical Care
Excellence. Chronic kidney disease: early
identification and management of chronic kidney
disease in adults in primary and secondary care
[online],www.nice.org.uk/CG182 (2014).
Lindeman, R.D., Tobin, J. & Shock, N.W.
Longitudinal-studies on the rate of decline in
renal function with age. J. Am. Geriatr. Soc. 33,
278285 (1985).
OHare, A.M. etal. Age affects outcomes in
chronic kidney disease. J. Am. Soc. Nephrol. 18,
27582765 (2007).
29. Coresh, J. etal. Prevalence of chronic kidney

disease in the United States. JAMA 298,
20382047 (2007).
30. Glassock, R.J. & Winearls, C. Ageing and
theglomerular filtration rate: truths and
consequences. Trans. Am. Clin. Climatol. Assoc.
120, 419428 (2009).
31. Turin, T.C. etal. Proteinuria and rate of change
inkidney function in a community-based
population. J. Am. Soc. Nephrol. 24, 16611667
(2013).
32. Eriksen, B.O. & Ingebretsen, O.C. The
progression of chronic kidney disease: A 10-year
population-based study of the effects of gender
and age. Kidney Int. 69, 375382 (2006).
33. Speizer, F.E. & Tager, I.B. Epidemiology of
chronic mucus hypersecretion and obstructive
airways disease. Epidemiol. Rev. 1, 124142
(1979).
34. Gansevoort, R.T. etal. Lower estimated GFR and
higher albuminuria are associated with adverse
kidney outcomes. A collaborative meta-analysis
of general and high-risk population cohorts.
Kidney Int. 80, 93104 (2011).
35. Levey, A.S. etal. The definition, classification,
and prognosis of chronic kidney disease:
aKDIGO Controversies Conference report.
Kidney Int. 80, 1728 (2011).
36. Fliser, D., Zeier, M., Nowack, R. & Ritz, E. Renal
functional reserve in healthy elderly subjects.
J.Am. Soc. Nephrol. 3, 13711377 (1993).
37. Abdelhafiz, A.H., Brown, S.H., Bello, A. &
ElNahas, M. Chronic kidney disease in older
people: physiology, pathology or both? Nephron
Clin. Pract. 116, c19c24 (2010).
38. Jones, R. Trends in elderly diagnoses: links with
multi-morbidity. British J. Healthcare Manage. 19,
553558 (2013).
39. Orueta, J.F., Nuno-Solinis, R., Garcia-Alvarez, A.
& Alonso-Moran, E. Prevalence of multimorbidity
according to the deprivation level among the
elderly in the Basque Country. BMC Public Health
13, 918 (2013).
40. Marengoni, A. etal. Aging with multimorbidity:
asystematic review of the literature. Ageing Res.
Rev. 10, 430439 (2011).
41. Glassock, R.J. & Winearls, C. Diagnosing
chronic kidney disease. Curr. Opin. Nephrol.
Hypertens. 19, 123128 (2010).
42. Glassock, R.J. & Winearls, C. Screening for CKD
with eGFR: Doubts and dangers. Clin. J. Am. Soc.
Nephrol. 3, 15631568 (2008).
43. Stevens, L.A., Coresh, J., Greene, T. &
Levey,A.S. Assessing kidney function
measured and estimated glomerular filtration
rate. N. Engl. J. Med. 354, 24732483 (2006).
44. Bauer, C., Melamed, M.L. & Hostetter, T.H.
Staging of chronic kidney disease: time for
acourse correction. J. Am. Soc. Nephrol. 19,
844846 (2008).
45. Tonelli, M. etal. Using proteinuria and estimated
glomerular filtration rate to classify risk in
patients with chronic kidney disease: a cohort
study. Ann. Intern. Med. 154, 1221 (2011).
46. Lin, J., Knight, E.L., Hogan, M.L. & Singh, A.K.
Acomparison of prediction equations for
estimating glomerular filtration rate in adults
without kidney disease. J. Am. Soc. Nephrol. 14,
25732580 (2003).
47. Rule, A.D. etal. Measured and estimated GFR
inhealthy potential kidney donors. Am. J. Kidney
Dis. 43, 112119 (2004).
48. Poggio, E.D., Wang, X., Greene, T., Van Lente, F.
& Hall, P.M. Performance of the modification of
diet in renal disease and Cockcroft-Gault
equations in the estimation of GFR in health and
in chronic kidney disease. J. Am. Soc. Nephrol.
16, 459466 (2005).
49. Stevens, L.A. etal. Impact of creatinine

calibration on performance of GFR estimating
equations in a pooled individual patient
database. Am. J. Kidney Dis. 50, 2135 (2007).
50. Murata, K. etal. Relative performance of the
MDRD and CKD-EPI equations for estimating
glomerular filtration rate among patients with
varied clinical presentations. Clin. J. Am. Soc.
Nephrol. 6, 19631972 (2011).
51. Levey, A.S. etal. A new equation to estimate
glomerular filtration rate. Ann. Intern. Med. 150,
604612 (2009).
52. Stevens, L.A. etal. Evaluation of the
modification of diet in renal disease study
equation in a large diverse population. J. Am.
Soc. Nephrol. 18, 27492757 (2007).
53. Hoffmann, A., Nimtz, M. & Conradt, H.S.
Molecular characterization of beta-trace protein
in human serum and urine: a potential
diagnostic marker for renal diseases.
Glycobiology 7, 499506 (1997).
54. Stevens, L.A. etal. Estimating GFR using serum
cystatin C alone and in combination with serum
creatinine: A pooled analysis of 3,418
individuals with CKD. Am. J. Kidney Dis. 51,
395406 (2008).
55. Kilbride, H.S. etal. Accuracy of the MDRD
(Modification of Diet in Renal Disease) study
andCKD-EPI (CKD Epidemiology Collaboration)
equations for estimation of GFR in the elderly.
Am. J. Kidney Dis. 61, 5766 (2013).
56. Fan, L. etal. Comparing GFR estimating
equations using cystatin C and creatinine in
elderly individuals. J. Am. Soc. Nephrol. (2014).
57. Schaeffner, E.S. etal. Two novel equations to
estimate kidney function in persons aged 70
years or older. Ann. Intern. Med. 157, 471481
(2012).
58. Inker, L.A. etal. Estimating glomerular filtration
rate from serum creatinine and cystatin C.
N.Engl. J. Med. 367, 2029 (2012).
59. Inker, L.A. etal. Expressing the CKD-EPI (Chronic
Kidney Disease Epidemiology Collaboration)
cystatin C equations for estimating GFR with
standardized serum cystatin C values. Am. J.
Kidney Dis. 58, 682684 (2011).
60. Saydah, S.H. etal. Albuminuria prevalence
infirst morning void compared with previous
random urine from adults in the National Health
and Nutrition Examination Survey, 20092010
Clin. Chem. 59, 675683 (2013).
61. Naresh, C.N., Hayen, A., Weening, A., Craig, J.C.
& Chadban, S.J. Daytoday variability in spot
urine albumin-creatinine ratio. Am. J. Kidney Dis.
62, 10951101 (2013).
62. Bakker, S.J., Gansevoort, R.T. & de Zeeuw, D.
Albuminuria: what can we expect from the
determination of nonimmunoreactive albumin?
Curr. Hypertens. Rep. 11, 111117 (2009).
63. Witte, E.C. etal. First morning voids are more
reliable than spot urine samples to assess
microalbuminuria. J. Am. Soc. Nephrol. 20,
436443 (2009).
64. Brinkman, J.W. etal. Falsely low urinary albumin
concentrations after prolonged frozen storage of
urine samples. Clin. Chem. 51, 21812183
(2005).
65. Warram, J.H., Gearin, G., Laffel, L. &
Krolewski,A.S. Effect of duration of typeI
diabetes on the prevalence of stages of diabetic
nephropathy defined by urinary albumin/
creatinine ratio J. Am. Soc. Nephrol. 7, 930937
(1996).
66. Long, D.A. etal. Albuminuria is associated with
too few glomeruli and too much testosterone.
Kidney Int. 83, 11181129 (2013).
67. Lambers Heerspink, H.J. etal. Albuminuria
assessed from firstmorningvoid urine samples
REVIEWS
versus 24-hour urine collections as a predictor
of cardiovascular morbidity and mortality. Am. J.
Epidemiol. 168, 897905 (2008).
68. Hallan, S.I. etal. Combining GFR and
albuminuria to classify CKD improves prediction
of ESRD. J.Am. Soc. Nephrol. 20, 10691077
(2009).
69. Tangri, N. etal. A predictive model for
progression of chronic kidney disease to kidney
failure. JAMA 305, 15531559 (2011).
70. Tonelli, M. etal. Chronic kidney disease and
mortality risk: A systematic review. J. Am. Soc.
Nephrol. 17, 20342047 (2006).
71. Sehestedt, T. etal. Risk prediction is improved
by adding markers of subclinical organ damage
to SCORE. Eur. Heart J. 31, 883891 (2010).
72. Jones-Burton, C. etal. An in-depth review of the
evidence linking dietary salt intake and
progression of chronic kidney disease.
Am. J. Nephrol. 26, 268275 (2006).
73. Smyth, A. etal. The relationship between
estimated sodium and potassium excretion
andsubsequent renal outcomes. Kidney Int. 86,
12051212 (2014).
74. McMahon, E.J. etal. A randomized trial of
dietary sodium restriction in CKD. J. Am. Soc.
Nephrol. 24, 20962103 (2013).
75. Fink, H.A. etal. Screening for, monitoring, and
treatment of chronic kidney disease stages 1
to3: a systematic review for the US Preventive
Services Task Force and for an American
College of Physicians Clinical Practice
Guideline. Ann. Intern. Med. 156, 570581
(2012).
76. Qaseem, A. etal. Screening, monitoring, and
treatment of stage 1 to 3 chronic kidney
disease: a clinical practice guideline from the
American College of Physicians. Ann. Intern.
Med. 159, 835847 (2013).
77. American Society of Nephrology. ASN
emphasizes need for early detection of kidney
disease, a silent killer [online], http://www.asnonline.org/news/2013/asn_comm_acp_
screening_response_102213_r12.pdf (2013).
78. Komenda, P. etal. Cost-effectiveness of primary
screening for CKD: a systematic review. Am. J.
Kidney Dis. 63, 789797 (2014).
79. Menzin, J. etal. A review of the costs and cost
effectiveness of interventions in chronic kidney
disease implications for policy.
Pharmacoeconomics 29, 839861 (2011).
80. Morales, E., Valero, M.A., Leon, M.,
Hernandez,E. & Praga, M. Beneficial effects of
weight loss in overweight patients with chronic
proteinuric nephropathies. Am. J. Kidney Dis. 41,
319327 (2003).
81. Saiki, A. etal. Effect of weight loss using formula
diet on renal function in obese patients with
diabetic nephropathy. Int. J. Obes. (Lond.) 29,
11151120 (2005).
82. Solerte, S.B., Fioravanti, M., Schifino, N. &
Ferrari, E. Effects of diet-therapy on urinary
protein excretion albuminuria and renal
haemodynamic function in obese diabetic
patients with overt nephropathy. Int. J. Obes. 13,
203211 (1989).
83. Navaneethan, S.D. etal. Weight loss
interventions in chronic kidney disease:
asystematic review and meta-analysis. Clin. J.
Am. Soc. Nephrol. 4, 15651574 (2009).
84. Heiwe, S. & Jacobson, S.H. Exercise training for
adults with chronic kidney disease. Cochrane
Database Syst. Rev. Issue 10. Art. No.:
CD003236. http://dx.doi.org/10.1002/
14651858.CD003236.pub2.
85. Robinson-Cohen, C. etal. Physical activity and
change in estimated GFR among persons with
CKD. J. Am. Soc. Nephrol. 25, 399406 (2014).
86. Robinson-Cohen, C. etal. Physical activity and

rapid decline in kidney function among older
adults. Arch. Intern. Med. 169, 21162123
(2009).
87. Sawicki, P.T. etal. Smoking is associated with
progression of diabetic nephropathy. Diabetes
Care 17, 126131 (1994).
88. Chase, H.P. etal. Cigarette-smoking increases
the risk of albuminuria among subjects with
typeI diabetes. JAMA 265, 614617 (1991).
89. Schiffl, H., Lang, S.M. & Fischer, R. Stopping
smoking slows accelerated progression of renal
failure in primary renal disease. J. Nephrol. 15,
270274 (2002).
90. Dalrymple, L.S. etal. Chronic kidney disease
and the risk of end-stage renal disease versus
death. J. Gen. Intern. Med. 26, 379385 (2011).
91. Go, A.S., Chertow, G.M., Fan, D.J.,
McCulloch,C.E. & Hsu, C.Y. Chronic kidney
disease and the risks of death, cardiovascular
events, and hospitalization. N. Engl. J. Med. 351,
12961305 (2004).
92. Taal, M.W. Arterial stiffness in chronic kidney
disease: an update. Curr. Opin. Nephrol.
Hypertens. 23, 169173 (2014).
93. Upadhyay, A. etal. Lipid-lowering therapy
inpersons with chronic kidney disease:
asystematic review and meta-analysis.
Ann.Intern. Med. 157, 251262 (2012).
94. Palmer, S.C. etal. HMG CoA reductase
inhibitors (statins) for people with chronic
kidney disease not requiring dialysis.
CochraneDatabase Syst. Rev. Issue 5.
Art.No.:CD007784 http://dx.doi.org/
10.1002/14651858.CD007784.pub2.
95. Tonelli, M. etal. Association between LDLC and
risk of myocardial infarction in CKD. J. Am. Soc.
Nephrol. 24, 979986 (2013).
96. Upadhyay, A., Earley, A., Haynes, S.M. &
Uhlig,K. Systematic review: blood pressure
target in chronic kidney disease and proteinuria
as an effect modifier. Ann. Intern. Med. 154,
541548 (2011).
97. Ruggenenti, P. etal. Renal function and
requirement for dialysis in chronic nephropathy
patients on long-term ramipril: REIN follow-up
trial. Gruppo Italiano di Studi Epidemiologici in
Nefrologia (GISEN). Ramipril efficacy in
nephropathy. Lancet 352, 12521256 (1998).
98. Brenner, B.M. etal. Effects of losartan on renal
and cardiovascular outcomes in patients with
type2 diabetes and nephropathy. N. Engl. J. Med.
345, 861869 (2001).
99. Rodby, R.A. etal. The Irbesartan typeII diabetic
nephropathy trial: study design and baseline
patient characteristics. For the Collaborative
Study Group. Nephrol. Dial. Transplant. 15,
487497 (2000).
100. Sharma, P. etal. Angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers for
adults with early (stage 1 to 3) non-diabetic
chronic kidney disease. Cochrane Database Syst.
Rev. Issue 10. Art. No.: CD007751 http://
dx.doi.org/10.1002/14651858.CD007751.
pub2.
101. Jager, K.J. & van Dijk, P.C.W. Has the rise in
theincidence of renal replacement therapy in
developed countries come to an end? Nephrol.
Dial. Transplant. 22, 678680 (2007).
102. Vassalotti, J.A., Gracz-Weinstein, L.,
Gannon,M.R. & Brown, W.W. Targeted screening
and treatment of chronic kidney disease: lessons
learned from the kidney early evaluation program.
Dis. Manag. Health Out. 14, 341352 (2006).
103. Katz, I.J., Gerntholtz, T.E., van Deventer, M.,
Schneider, H. & Naicker, S. Is there a need for
early detection programmes for chronic kidney
disease? Clin. Nephrol. 74, S113S118 (2010).
104. Lash, J.P. etal. Chronic Renal Insufficiency

Cohort (CRIC) Study: baseline characteristics
and associations with kidney function. Clin. J.
Am. Soc. Nephrol. 4, 13021311 (2009).
105. Feldman, H.I. etal. The Chronic Renal
Insufficiency Cohort (CRIC) study: design and
methods. J. Am. Soc. Nephrol. 14, S148S153
(2003).
106. Kronenberg, F. Emerging risk factors and
markers of chronic kidney disease progression.
Nat. Rev. Nephrol. 5, 677689 (2009).
107. Johnson, E.S., Smith, D.H., Thorp, M.L.,
Yang,X.H. & Juhaeri, J. Predicting the risk of
end-stage renal disease in the population-based
setting: a retrospective case-control study. BMC
Nephrol. 12, 17 (2011).
108. Johnson, E.S., Thorp, M.L., Platt, R.W. &
Smith,D.H. Predicting the risk of dialysis
andtransplant among patients with CKD:
aretrospective cohort study. Am. J. Kid. Dis. 52,
653660 (2008).
109. Levin, A., Djurdjev, O., Beaulieu, M. & Er, L.
Variability and risk factors for kidney disease
progression and death following attainment of
stage 4 CKD in a referred cohort. Am. J. Kid. Dis.
52, 661671 (2008).
110. McClellan, W.M. & Flanders, W.D. Risk factors
for progressive chronic kidney disease. J. Am.
Soc. Nephrol. 14 (Suppl. 2), S65S70 (2003).
111. Peralta, C.A. etal. Detection of chronic kidney
disease with creatinine, cystatin C, and urine
albumintocreatinine ratio and association with
progression to end-stage renal disease and
mortality. JAMA 305, 15451552 (2011).
112. Mahmoodi, B.K. etal. Associations of kidney
disease measures with mortality and end-stage
renal disease in individuals with and without
hypertension: a meta-analysis. Lancet 380,
16491661 (2012).
113. Fox, C.S. etal. Associations of kidney disease
measures with mortality and end-stage renal
disease in individuals with and without diabetes:
a meta-analysis. Lancet 380, 16621673
(2012).
114. Rose, G. Sick individuals and sick populations.
Int. J. Epidemiol. 30, 427432 (2001).
115. Leoncini, G. etal. Global risk stratification in
primary hypertension: the role of the kidney.
J.Hypertens. 26, 427432 (2008).
116. Perkins, R.M. etal. GFR Decline and Mortality
Risk among Patients with Chronic Kidney
Disease. Clin. J. Am. Soc. Nephrol. 6, 18791886
(2011).
117. Saweirs, W.W.M. & Goddard, J. What are the
best treatments for early chronic kidney
disease? A background paper prepared for the
UK consensus conference on early chronic
kidney disease. Nephrol. Dial. Transplant. 22,
3138 (2007).
118. Loud, F. & Gallagher, H. Kidney health: delivering
excellence. Kidney Health Report 152 (2013).
119. Shahinian, V.B. & Saran, R. The role of primary
care in the management of the chronic kidney
disease population. Adv. Chronic Kidney Dis. 17,
246253 (2010).
120. Levin, A. The need for optimal and coordinated
management of CKD. Kidney Int. 68, 710
(2005).
121. Bodenheimer, T., Wagner, E.H. & Grumbach, K.
Improving primary care for patients with chronic
illness. JAMA 288, 17751779 (2002).
122. Bodenheimer, T., Wagner, E.H. & Grumbach, K.
Improving primary care for patients with chronic
illnessthe chronic care model, part 2. JAMA
288, 19091914 (2002).
123. Wagner, E.H. Chronic disease management:
what will it take to improve care for chronic
illness? Eff. Clin. Pract. 1, 24 (1998).

REVIEWS
124. Wagner, E.H., Austin, B.T. & VonKorff, M.
Organizing care for patients with chronic illness.
Milbank Q. 74, 511544 (1996).
125. Hajjar, I., Kotchen, J.M. & Kotchen, T.A.
Hypertension: Trends in prevalence, incidence,
and control. Annu. Rev. Public Health 27,
465490 (2006).
126. Danaei, G. etal. National, regional, and global
trends in fasting plasma glucose and diabetes
prevalence since 1980: systematic analysis of
health examination surveys and epidemiological
studies with 370 country-years and 2.7 million
participants. Lancet 378, 3140 (2011).
127. Finucane, M.M. etal. National, regional, and
global trends in body-mass index since 1980:
systematic analysis of health examination
surveys and epidemiological studies with 960
country-years and 9.1 million participants.
Lancet 377, 557567 (2011).
128. Venkatachalam, M.A. etal. Acute kidney injury:
aspringboard for progression in chronic kidney
disease. Am. J. Physiol. Renal Physiol. 298,
F1078F1094 (2010).
129. Chawla, L.S. & Kimmel, P.L. Acute kidney injury
and chronic kidney disease: an integrated clinical
syndrome. Kidney Int. 82, 516524 (2012).
130. Rewa, O. & Bagshaw, S.M. Acute kidney injuryepidemiology, outcomes and economics. Nat.
Rev. Nephrol. 10, 193207 (2014).
131. Lea, J.P., McClellan, W.M., Melcher, C.,
Gladstone, E. & Hostetter, T. CKD risk factors
reported by primary care physicians: do
guidelines make a difference? Am. J. Kidney Dis.
47, 7277 (2006).
132. Boulware, L.E., Troll, M.U., Jaar, B.G.,
Myers,D.I. & Powe, N.R. Identification and
referral of patients with progressive CKD:
anational study. Am. J. Kidney Dis. 48, 192204
(2006).
133. Charles, R.F. etal. Clinical testing patterns and
cost implications of variation in the evaluation of
CKD among US physicians. Am. J. Kidney Dis. 54,
227237 (2009).
134. Fox, C.H., Brooks, A., Zayas, L.E., McClellan, W.
& Murray, B. Primary care physicians knowledge
and practice patterns in the treatment of chronic
kidney disease: an Upstate New York Practicebased Research Network (UNYNET) study. J. Am.
Board Fam. Med. 19, 5461 (2006).
135. Allen, A.S. etal. Primary Care Management of
Chronic Kidney Disease. J. Gen. Intern. Med. 26,
386392 (2011).
136. Razavian, M. etal. Cardiovascular risk
management in chronic kidney disease in general
practice (the AusHEART study). Nephrol. Dial.
Transplant. 27, 13961402 (2012).
137. Winkelmayer, W.C. etal. Underuse of ACE
inhibitors and angiotensin II receptor blockers in
elderly patients with diabetes. Am. J. Kidney Dis.
46, 10801087 (2005).
138. Minutolo, R. etal. Management of hypertension
in patients with CKD: Differences between
primary and tertiary care settings. Am. J. Kidney

Dis. 46, 1825 (2005).
139. Ravera, M. etal. CKD awareness and blood
pressure control in the primary care
hypertensive population. Am. J. Kidney Dis. 57,
7177 (2011).
140. Ravera, M. etal. Chronic kidney disease and
cardiovascular risk in hypertensive type2
diabetics: a primary care perspective. Nephrol.
Dial Transplant. 24, 15281533 (2009).
141. Israni, R.K., Shea, J.A., Joffe, M.M. &
Feldman,H.I. Physician characteristics and
knowledge of CKD management. Am. J. Kidney
Dis. 54, 238247 (2009).
142. Black, C. etal. Early referral strategies for
management of people with markers of renal
disease: a systematic review of the evidence of
clinical effectiveness, cost-effectiveness and
economic analysis. Health Technol. Assess. 14,
1184 (2010).
143. Crinson, I., Gallagher, H., Thomas, N. &
deLusignan, S. How ready is general practice
toimprove quality in chronic kidney disease?
Adiagnostic analysis. Br. J. Gen. Pract. 60,
403409 (2010).
144. Jain, P., Calvert, M., Cockwell, P. &
McManus,R.J. The need for improved
identification and accurate classification of
stages 35 chronic kidney disease in primary
care: retrospective cohort study. PLoS ONE 9,
e100831 (2014).
145. Stevens, P.E., Levin, A. & Global, K.D.I.
Evaluation and management of chronic kidney
disease: synopsis of the Kidney Disease:
Improving Global Outcomes 2012 Clinical
Practice Guideline. Ann. Intern. Med. 158,
825830 (2013).
146. Narva, A.S. Reducing the burden of chronic
kidney disease among American Indians.
Adv.Chronic Kidney Dis. 15, 168173 (2008).
147. Narva, A.S. & Sequist, T.D. Reducing health
disparities in American Indians with chronic
kidney disease. Semin. Nephrol. 30, 1925
(2010).
148. Sequist, T.D., Cullen, T. & Acton, K.J. Indian
health service innovations have helped reduce
health disparities affecting american Indian and
alaska native people. Health Aff. (Millwood) 30,
19651973 (2011).
149. Patel, T.G., Pogach, L.M. & Barth, R.H. CKD
screening and management in the Veterans
Health Administration: the impact of system
organization and an innovative electronic record.
Am. J. Kidney Dis. 53 (Suppl. 3), S78S85 (2009).
150. Lee, B. etal. Effects of proactive populationbased nephrologist oversight on progression of
chronic kidney disease: a retrospective control
analysis. BMC Health Serv. Res. 12, 252 (2012).
151. Rutkowski, M. etal. Implementing KDOQI CKD
Definition and Staging Guidelines in Southern
California Kaiser Permanente. Am. J. Kidney Dis.
53 (Suppl. 3), S86S99 (2009).
152. Stevens, P.E. etal. Chronic kidney disease

management in the United Kingdom: NEOERICA
project results. Kidney Int. 72, 9299 (2007).
153. Rayner, H.C. etal. Does community-wide chronic
kidney disease management improve patient
outcomes? Nephrol. Dial. Transplant. 29,
644649 (2014).
154. Richards, N. etal. Primary care-based disease
management of chronic kidney disease (CKD),
based on estimated glomerular filtration rate
(eGFR) reporting, improves patient outcomes.
Nephrol. Dial. Transplant. 23, 549555 (2008).
155. Gaede, P., Lund-Andersen, H., Parving, H.H.
&Paedersen, O. Effect of a multifactorial
intervention on mortality in type2 diabetes.
N.Engl. J. Med. 358, 580591 (2008).
156. Hoy, W.E., Baker, P.R., Kelly, A.M. & Wang, Z.
Reducing premature death and renal failure
inAustralian aboriginals. A community-based
cardiovascular and renal protective programme.
Med. J. Aust. 172, 473478 (2000).
157. Hirsch, G., Homer, J., Evans, E. & Zielinski, A.
Asystem dynamics model for planning
cardiovascular disease interventions.
Am. J. Public Health 100, 616622 (2010).
158. Homer, J.B. & Hirsch, G.B. System dynamics
modeling for public health: background and
opportunities. Am. J. Public Health 96, 452458
(2006).
159. Ness, R.B., Koopman, J.S. & Roberts, M.S.
From the American College of Epidemiology
Annual Meeting 2006causal system modeling
in chronic disease epidemiology: a proposal.
Ann. Epidemiol. 17, 564568 (2007).
160. Zhou, H. etal. A computer simulation model of
diabetes progression, quality of life, and cost.
Diabetes Care 28, 28562863 (2005).
161. Hallan, S.I. etal. International comparison of
therelationship of chronic kidney disease
prevalence and ESRD risk. J. Am. Soc. Nephrol.
17, 22752284 (2006).
162. Jesky, M., Lambert, A., Burden, A.C. &
Cockwell,P. The impact of chronic kidney disease
and cardiovascular comorbidity on mortality in a
multiethnic population: a retrospective cohort
study. BMJ Open 3, e003458 (2013).
163. Fassett, R.G. etal. Biomarkers in chronic kidney
disease: a review. Kidney Int 80, 806821
(2011).
Acknowledgements
We would like to thank Dr Shari Ling and Dr Kimberly
Smith (Centers for Medicare and Medicaid Services,
Baltimore, MD, USA) for their useful comments on
early versions of this manuscript.
Author contributions
O.J.W., D.J.O., and J.R. wrote the article. All authors
researched the data for the article, provided
substantial contributions to discussions of its content,
and undertook review and/or editing of the manuscript
before submission.

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REVIEWS

Early chronic kidney disease: diagnosis,

LSE Health, Cowdray

The first step in outlining an intervention strategy for

NATURE REVIEWS | NEPHROLOGY

VOLUME 11 | AUGUST 2015 | 491

Table 1 | Definition and classification of CKD

Mildly to moderately decreased

Moderately to severely decreased

Albuminuria (mg/g per 24h)

Normal to mildly increased

CKD is defined as either kidney damage or GFR <60ml/min/1.73m2 for

eGFR and urinary albumin excretion rate) and/or the

Age-associated decline in renal function

Percentage of the population

Figure 1 | Prevalence of CKD by stage in the USA between

Equations to estimate glomerular filtration rate

Cystatin C-derived eGFR equations

Management of early CKD

The majority of patients with CKD do not progress

NATURE REVIEWS | NEPHROLOGY

VOLUME 11 | AUGUST 2015 | 493

Country and study period

Figure 2 | Breakdown of chronic kidney disease (CKD) by stage (15) in selected

therefore, neither clinically appropriate nor, given

The screening debate

Treatment of early-stage CKD

Percentage of the population

The rate of increase in the incidence of ESRD is

findings across patient groups should be examined to

Models of CKD care

NATURE REVIEWS | NEPHROLOGY

VOLUME 11 | AUGUST 2015 | 495

166PCPs in 15health centres in

70% patients were not tested yearly for urine protein,

National, random, stratified sample

Family practitioners (56.2%) and general internists

Same population as in the study

Only 48% of nephrologists, 19% of family practitioners,

10 PCPs from 10 health-care

Awareness of KDOQI guidelines was low, and PCPs

Random sample of 1,550US PCPs;

Only 35% of PCPs had adequate knowledge of CKD

PCPs in six predominantly

~34% and 22% of PCPs did not identify family history

Nephrologists (tertiary care) and

Patients with CKD cared for by PCPs had higher

PCPs caring for 7,582 hypertensive

Only 10.4% of patients with T2DM in this population

PCPs caring for 39,525

Only 13.8% of patients with eGFR <60ml/

Nationally-representative, clusterstratified sample of 534PCPs in

<18% patients were correctly diagnosed with CKD.

other specialists to focus on patients with primary kidney

Primary care for cardiovascular disease

Secondary care for CKD complications

Multidisciplinary care for RRT

Figure 4 | An integrated care continuum for CKD that isNature

as risk factors for CKD, respectively.131 High awareness

The secondary care model

Integrated care pathways for CKD

NATURE REVIEWS | NEPHROLOGY

VOLUME 11 | AUGUST 2015 | 497

a useful case study of how to enact a primary care