early chronic kidney disease

7/23/2019 Early Chronic Kidney Disease

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LSE Health, CowdrayHouse, London Schoolof Economics andPolitical Science,Houghton Street,London WC2A 2AE,UK (O.J.W., P.G.K.).Department of RenalMedicine, Salford

Royal NHS FoundationTrust, Stott Lane,Salford M6 8HD, UK(D.J.O., J.R.). NationalInstitute of Diabetesand Digestive andKidney Diseases,National Institutesof Health, Bethesda,31 Center Drive,Bethesda,MD 20892-2560,USA (A.S.N.).

Correspondence to:D.J.O.donal.o’[email protected]

Early chronic kidney disease: diagnosis,

management and models of careOlivier J. Wouters, Donal J. O’Donoghue, 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 clinicalimprovements 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. et al. Nat. Rev. Nephrol. 11, 491–502 (2015); published online 9 June 2015; doi:10.1038/nrneph.2015.85

Introduction

Chronic kidney disease (CKD) is a condition character-ized by kidney damage and/or dysfunction, as well as anincreased risk of cardiovascular disease.1,2 Type 2 diabetesmellitus (T2DM) and hypertension cause up to two-thirds of CKD;3 less frequent causative factors includeglomerulonephritis, nephrolithiasis and polycystic kidney

disease.4,5 CKD is currently classified by measuring theestimated glomerular filtration rate (eGFR) and urinaryalbumin excretion rate (Table 1). Patients with an eGFR≥60 ml/min/1.73 m2 are assessed for typical markers ofrenal damage, such as abnormalities in urinary sedimentor organ structure, to help confirm a diagnosis of CKD.6 In a small proportion of cases, progressive CKD leads toend-stage renal disease (ESRD), where dialysis and/orkidney transplantation is essential for survival. The rateof CKD progression varies between patients, dependingon 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,10.4–13.5%) to 14.0% (95% CI, 12.4–15.7%) betweenthe periods 1988–1994 and 1999–2004.9 Data obtainedfrom 2007–2012 suggest that this increase in prevalencehas reached a plateau of 13.7% (95% CI, 12.1–15.2%).9 Between 1999–2004 and 2007–2012, the prevalence ofCKD stages 3–5 in the USA increased from 6.2% to 6.5%(Figure 1). By contrast, the prevalence of stages 3–5 CKDin the UK decreased from 5.7% to 5.2% between 2003and 2009–2010.10

Patients with ESRD represent <0.1% of the total popu-lation in many high-income countries, but account for1–2% of all health-care spending.11 Estimates suggest that>US$1 trillion is spent on ESRD care worldwide.12 Theclinical and economic rationale for designing timely andappropriate health-system responses to limit progression

of CKD to ESRD, therefore, is clear.13–16 This Review out-lines the gaps in our knowledge as to which health-careinterventions are most effective for early-stage (stages 1–3)CKD. We highlight the ongoing debate as to whether early-stage CKD is a normal indicator of the ageing process oris a genuine disease state. Finally, we discuss the optimumtime to intervene, and what model of care to adopt.

Diagnosis of CKD

The first step in outlining an intervention strategy forCKD is to accurately define and identify those patientswho have early-stage disease. The first guidelines forthe diagnosis and treatment of CKD were published in

2002 by the National Kidney Foundation, a US voluntaryhealth organization.17 These guidelines were an impor-tant advancement in bringing CKD to the attention ofpolicy makers. The National Kidney Foundation recom-mendations, referred to as the ‘KDOQI’ guidelines, wereadopted by countries and institutions worldwide andform the basis of the CKD classification system (Table 1).

The most recent prevalence estimates (2007–2012) indi-cate that over 40 million people in the USA have CKD;approximately one-third of the US population aged >60years is affected.9 Interestingly, >95% of affected individu-als in the USA have early-stage CKD, and a similar distri-bution across stages has been observed in a wide range of

Competing interests

The authors declare no competing interests.

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countries (Figure 2).9,18–23 One study suggests that the life-time risk of developing CKD stages G3a+ (eGFR <60 ml/min/1.73 m²), G3b+ (eGFR <45 ml/min/1.73 m²), G4+(eGFR <30 ml/min/1.73 m²), and ESRD for an individualborn in the USA in this generation is 59.1%, 33.6%, 11.5%,and 3.6%, respectively.24 These estimates vary markedly bygender and ethnicity.

Prevalence rates for CKD are based on eGFR—a proxymeasure of renal function—which is usually calculatedusing 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 ofCKD (Table 1). In addition to these two measures, otherdiagnostic procedures (for example, renal tract imaging)are performed in the majority of patients with newlydiagnosed CKD,25 although some guidelines advocate amore rationed approach.26 A retrospective cohort studyof 1,487 patients with CKD managed at MassachusettsGeneral Hospital in Boston, USA, found that cliniciansfrequently ordered renal ultrasonography and otherbiochemical tests (for example, serum protein electro-phoreses and parathyroid hormone measurements)during the initial evaluation of CKD. These test results,however, only affected the original diagnosis (based on

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 renalhealth 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 health–economic analyses

eGFR and urinary albumin excretion rate) and/or theclinical care in <5% of cases.25 This finding implies thatmany of the diagnostic tests conducted during the initialevaluation of patients with CKD are redundant, and sup-ports the economic argument for distinguishing betweenthe diagnosis of early-stage CKD and the assessment ofcomplications in patients with CKD stages 4 and 5.

Age-associated decline in renal function

The estimated high lifetime risk of CKD calls into ques-tion a distinction between early-stage CKD and normalage-associated decline in renal function. A reduction inrenal blood flow and renal mass, as well as progressiveglomerulosclerosis, are part of the normal ageing process,with eGFR typically falling by ~0.75 ml/min/1.73 m2 peryear from the age of 40 years.27 This rate of progressionseems nonlinear, with eGFR loss slowing below 45 ml/min/1.73 m2 among elderly patients.28 Population studieshave found that the majority of patients with CKD areaged >60 years, and that most of these patients do notexhibit marked albuminuria.29,30 Difficulties are, there-

fore, apparent in differentiating between age-associatedloss of kidney function and renal disease.31 Elderlypatients with a given reduction in eGFR are less likely toprogress to ESRD than are non-elderly patients with anequivalent reduction in eGFR.28,32 The role of the ageingprocess has long been recognized in other organ systems;for example, the natural decline in forced expiratory volume with age indicates premature or accelerated lossof respiratory function.33

Meta-analyses of >1.5 million patients have identi-fied that the risk of ESRD is almost equivalent betweenpatients aged above or below 65 years of age with aneGFR 45–59 ml/min/1.73 m2 and an albumin-to-

creatinine ratio <1.13 mg/mmol.34,35 Although the inter-action between renal function and proteinuria does seemto differ with age—potentially due to the competing riskof death—these data have been interpreted as evidenceagainst the introduction of differing thresholds for defin-ing CKD based on age. Furthermore, it has been arguedthat senescent changes in eGFR are caused by otherdisease processes, such as hypertension and diabetes mel-litus, rather than a natural decline in renal function.36,37 The differing interpretations of these data on eGFR lossin the elderly underscore the need to consider eGFRtrends as a part of the clinical assessment. Whether thesechanges in eGFR reflect intrinsic renal disease or normal

ageing is unclear, but CKD and senility are associatedwith an elevated risk of morbidity and mortality in anadditive fashion.34

Many patients with CKD exhibit comorbidities. In theUK, ~64% of patients aged >65 years with CKD exhibitat least four additional morbidities, including prostate,respiratory, and cardiac diseases in men, and bone, joint,and mental health problems in women.38 Although it isacknowledged that multi-morbidity imposes an increasedneed for health care, the risk factors for multi-morbidityare poorly defined. 39,40 Further work is required to deter-mine whether renal impairment in elderly patients iseither associated with or causative of other conditions.

Table 1 | Definition and classification of CKD

Category Measure Description

GFR (ml/min/1.73 m2 )

G1 ≥90 Normal or high

G2 60–89 Mildly decreased

G3a 45–59 Mildly to moderately decreased

G3b 30–44 Moderately to severely decreased

G4 15–29 Severely decreased

G5 <15 Kidney failure

Albuminuria (mg/g per 24 h)

A1 <30 Normal to mildly increased

A2 30–300 Moderately increased

A3 >300 Severely increased

CKD is defined as either kidney damage or GFR <60 ml/min/1.73 m2 for≥3 months. Kidney damage is defined as pathologic abnormalities or markersof 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, 5–14 (2013).

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Equations to estimate glomerular filtration rate

The creatinine-based formulae used to estimate glo-merular filtration rate (GFR) have other known limi-

tations, in addition to the confounds of age-associateddecline in renal function described above.41,42 These for-mulae were originally developed to identify patients withan eGFR ≤60 ml/min/1.73 m2 at risk of renal failure, andare not sensitive for identification of CKD stages 1 or 2(Figure 3).43 In isolation, eGFR is of little value for early-stage CKD intervention efforts. Some clinicians havecalled for the removal of the first two stages of CKD fromthe KDOQI guidelines,44 whereas others have proposedalternative methods to classify the early stages of CKD.45 The MDRD study equation tends to underestimatethe true GFR among individuals with normal kidneyfunction,46–49 whereas the CKD–EPI equation tends to

overestimate GFR in individuals with or at high riskof CKD.50 These two equations only estimate the GFRwithin 30% of the actual value; the estimated values areeven less accurate in 15.9% of cases using the CKD–EPIequation51 and in 19.4% of cases using the MDRD equa-tion.52 Differences in sex and ethnicity should also beconsidered when evaluating GFR.32,44

Epidemiologic studies have used different eGFRformulae, which limits direct comparison of differentstudies owing to the varying level of accuracy of the dif-ferent formulae among patients with a high eGFR.9,10,29 Such studies have often relied upon point estimates ofeGFR that might overstate prevalence rates.9 A diagnosis

of CKD should instead be made only after multiple esti-mates have been taken over several months. Moreover,not all studies consider the albumin excretion rate whenestimating prevalence rates.

Cystatin C-derived eGFR equations

The limitations of creatinine-based GFR estimates haveresulted in the investigation of other molecules, includ-ing β-trace protein53 and cystatin C, as markers of renalfunction.54 The latter protein provides a more accurateestimate of renal function than does β-trace protein, evenamong elderly patients,55–57 especially when it is used incombination with measurements of serum creatinine.58 Moreover, cystatin C-derived formulae function well atdiscriminating between high GFRs as compared withcreatinine-based formulae.26

The use of cystatin C-derived formulae is now recom-mended to confirm or exclude CKD in patients with mildreductions in eGFR (as assessed using creatinine-basedestimates) 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 arewrongly diagnosed with CKD. An international stand-ard reference for cystatin C measurement has now beenagreed upon (ERM-DA47/IFCC),59 but the assay is notyet widely available. Diagnostic accuracy might improveif uptake of the assay increases.

Albuminuria

Although urinary albumin excretion rates provide valu-able diagnostic data, tests for albuminuria have limi-tations, such as poor test–retest reliability,60,61 furthersupporting the need to use more than one prognosticfactor to define CKD. Measurements of albuminuria can

vary depending on the type of assay (for example, mono-clonal versus polyclonal antibody methods),62 the samplecollection method (for example, 24 h collection versusfirst morning void versus random spot sample),63 andthe sample storage procedure.64 Furthermore, althoughstandard thresholds for pathologic albumin excretion areused across sex and age, both factors might affect urinaryalbumin measurements.65–67

Key points for clinical practice

Estimates of GFR that do not incorporate cystatin Cdata are imprecise, and clinicians need to be aware of thestrengths and limitations of such diagnostic tools. Primary

care physicians (PCPs) should rely on their clinical judge-ment when evaluating individual patients with respect toeGFR trends and albuminuria. Although these two param-eters jointly provide accurate predictive information aboutthe risk of ESRD,68,69 clinicians should also consider theseverity of comorbidities, family histories and vascular riskprofiles.70,71 More work is needed to improve the sensitivityand specificity of eGFR formulae and other risk equationsfor identifying progressive CKD (Table 2).

Management of early CKD

The majority of patients with CKD do not progressto ESRD. Treatment of the entire CKD population is,

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

CKD stage

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0

6.00

5.00

4.00

3.00

2.00

1.00

7.00

1988–1994

1999–2004

2007–2012

Figure 1 | Prevalence of CKD by stage in the USA between 1988 and 2012. Theprevalence estimates are based on samples of non-institutionalized adults (aged≥20 years) who par ticipated in the National Health and Nutrition ExaminationSurvey (NHANES) during the study years indicated. The sample sizes varied across

1988–1994 (n = 15,488), 1999–2004 (n= 13,233), and 2007–2012 (n= 15,502).The proteinuria measures were based on albumin:creatinine ratios from spotmorning urine samples. The estimated glomerular filtration rates were calculatedusing the CKD–EPI creatinine formula. Stage 3 CKD corresponds to a glomerularfiltration rate of 30–59 ml/min/1.73 m2. The error bars show the 95% confidenceintervals. Data were obtained from the USRDS 2014 Annual Data Report.9 Thedata reported here were supplied by the USRDS. The interpretation and reportingof these data are the responsibility of the authors and in no way should be seen asan official policy or interpretation of the US government. Abbreviations: CKD,chronic kidney disease; USRDS, United States Renal Data System.

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therefore, neither clinically appropriate nor, giventhe global scale of the disease, economically feasible.Clinical care might improve if early-stage CKD withrisk of progression to ESRD is differentiated fromearly-stage CKD that is unlikely to advance (B ox 1).Interventional studies might also benefit from a selec-tive definition of early-stage CKD. For example, the ben-efits of dietary salt restriction have not been conclusivelyestablished. 72 A post hoc analysis of the ONTARGETand TRANSCEND studies identified no renal benefit ofdietary salt restriction among patients with early CKD.73 Given the reported benefits of a low salt diet for patientswith advanced renal failure,74 it is possible that certain

patients might be better suited than others to dietarysalt restrictions.

The screening debate

A systematic review of screening, monitoring and treat-ing patients with CKD stages 1–3, commissioned by theUS Preventive Services Task Force (USPSTF), questionedthe clinical and economic value of screening both thegeneral population and those at high risk of developingCKD.75 This stance is supported by the American Collegeof Physicians (ACP).76 The USPSTF systematic reviewfound no randomized controlled trials (RCTs) of “CKDscreening in adults who were asymptomatic with or

without recognized risk factors for CKD incidence, pro-gression, or complications,” and no RCTs of “monitor-ing adults with CKD stages 1 to 3 for worsening kidneyfunction or damage.”75

The position of the USPSTF and the ACP is not uni- versally supported. In the UK, the National Institute forHealth and Care Excellence (NICE) advocates targetedassessment for CKD in patients prescribed medicationsknown to be nephrotoxic (for example, calcineurininhibitors, NSAIDs and lithium), and in patients withdiseases linked to CKD, such as T2DM.26 The AmericanSociety of Nephrology (ASN) contends that universalscreening for CKD is appropriate given the asymptomaticnature of mild-to-moderate CKD and the difficulties inperforming an accurate clinical investigation. Althoughthe ASN acknowledges the lack of support from RCTsfor this position, the society proposes that early andimproved blood pressure control might slow progres-sive loss of renal function and that improved awarenessof CKD might be relevant during periods of hospitali-zation.77 A systematic review concluded that screen-

ing for proteinuria might be cost-effective—defined as<US$50,000 per quality-adjusted life year gained—forpatients with T2DM and/or hypertension.78 The reviewalso found that eGFR screening might be cost-effective inpatients with T2DM. No studies of the cost-effectivenessof eGFR screening in patients with hypertension havebeen performed.78

Treatment of early-stage CKD

Some evidence suggests that lifestyle changes and the useof preventive medicines can reduce the risk of cardiovas-cular disease and possibly slow, halt, or even reverse CKDprogression during the early stages of disease.1,79 The evi-

dence collected thus far is generally of low quality, butprovides some support for calorie-controlled diets,80–83 physical exercise,84–86 and smoking cessation87–89 pre-dominantly in patients with T2DM that is comorbid withCKD. Most patients with CKD have comorbidities that areamenable to a systematic approach to prevention and earlymanagement, and many patients die from cardiovascularevents or other causes before developing ESRD.70,90,91

The pathophysiology of increased vascular risk evolvesover the natural history of CKD,92 and traditional riskfactors for atherosclerosis have a proportionately greaterimpact 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 alow association between LDL cholesterol and outcomesin patients with CKD stages 3–5.95 Improved awarenessof CKD as a risk factor for vascular disease could facilitatetimely use of these agents alongside other interventions,such as blood pressure control.96 RCTs of angiotensin-converting enzyme (ACE) inhibitors97 and angio-tensin II-receptor blockers (ARBs)98,99 have provided thestrongest evidence of a treatment benefit among patientswith early-stage CKD. These studies, however, focusedon patients with diabetic renal disease in the presenceof proteinuria, and the data to support the use of theseagents for other causes of CKD are weak.100

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Stage 5Stage 4Stage 3Stage 2Stage 1

India2005–2007

China2005–2006

Japan2000–2004

Korea2006

Spain2011

Taiwan1994–2006

USA2007–2012

n = 5,588

n = 13,925n = 574,024

n = 2,356

n = 2,745

n = 462,293

n = 15,502

Country and study period

Figure 2 | Breakdown of chronic kidney disease (CKD) by stage (1–5) in selectedcountries with data available from the 2000s.9,18–23 Stage 3 corresponds to aglomerular filtration rate of 30–59 ml/min/1.73 m2. The Chinese study useda sample of individuals from Beijing,18 the Indian study used a sample from 13academic and private medical centres located throughout the country,19 and theKorean study used a sample from seven urban cities.21 The other studies usednationally representative samples. For Japan, the prevalence estimate for stage 4includes both stages 4 and 5 CKD.20 All studies either sampled adults aged ≥18years or ≥20 years, except for the Korean study which included adults aged≥35 years. All studies used a version of the four-variable MDRD study equation todetermine estimated glomerular filtration rate, except for the US study data, whichused the CKD–EPI creatinine formula. The Chinese,18 Korean,21 Spanish,22 and US9 studies measured proteinuria using the spot morning urinary albumin:creatinineratio. The remaining studies used a urine dipstick analysis for proteinuria. TheChinese study 18 also measured haematuria by dipstick test.

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The rate of increase in the incidence of ESRD isslowing in some countries, including Australia, Canada,northern European countries, New Zealand and theUSA, although these trends vary by subgroups, such asage and race.101 The stabilization of these incidence ratesmight reflect improvements in cardiovascular risk man-agement in the general population and among individu-als with T2DM and/or hypertension, although this effecthas yet to be shown conclusively.

Evidence gaps

The conflicting views of the ACP, ASN, NICE andUSPSTF highlight the need for more RCTs to evaluateidentification, screening, monitoring and treatment ofearly CKD. In the meantime, population health manage-ment could focus on the control of vascular risk factorsand on the patients with CKD who are likely to progressto ESRD, and will subsequently place a burden on health-care costs.102,103 Given the asymptomatic and insidiousonset of CKD, research into new biomarkers and prog-nostic techniques is essential.104–105 Development of suchassays is an active area of research, and new predictionmodels are regularly published.105–111 Nevertheless, morework is needed to validate and refine these models. The

findings across patient groups should be examined todetermine how the data could be generalized: one modelcould be appropriate for one patient population in a par-ticular geographic region, but it might be less accurate,or even lead to erroneous conclusions, when applied toother patient groups or populations.

Expanding the definition of early CKD must be con-sidered in connection with the adverse outcomes associ-ated with a reduced eGFR.91 Two meta-analyses foundthat patients with hypertension and/or T2DM and withreductions in eGFR have an increased risk of ESRD anddeath compared with those with reduced eGFR but nohypertension or T2DM.112,113 In both studies, the risk ofESRD was markedly elevated when eGFRs dropped to<50 ml/min/1.73 m2, but the risk of death was increasedat eGFRs <90 ml/min/1.73 m2. Although these data couldbe interpreted to support defining a mild reduction inrenal function as part of a disease state, it is importantto consider the difference in the threshold for the riskof death and ESRD. These findings also raise the ques-tion of population risk versus individual risk. Patients

with early CKD but at low risk of ESRD still carry anelevated risk of other complications compared to thegeneral population.114 Screening patients for reductionsin eGFR might not contribute meaningful prognosticinformation at an individual level with regard to ESRDrisk. Small reductions in eGFR, however, can improvediscrimination in models of cardiovascular risk, andthe rate of change in eGFR might be a more effectivepredictor of risk, as compared to absolute values.115,116

Stage 1–2 CKD should possibly be assessed in associ-ation with cardiovascular risk rather than renal risk. Thisassessment might be particularly relevant when consid-ering elderly patients with reduced measures of eGFR but

no appreciable albuminuria. The risk of ESRD and deathwas associated with increased albuminuria in a linearmanner in the two meta-analyses described above,112,113 further emphasizing the importance of albuminuria indefining the risk of CKD progression.

Models of CKD care

The Wagner chronic care model

Some evidence suggests that the prevailing care strat-egy for CKD should comprise three phases (Figure 4).Primary care management of vascular disease riskduring early-stage CKD forms the first phase of the carestrategy, which could involve exercise, dietary changes,

smoking cessation, blood pressure control, glycaemicand lipid control and periodic monitoring of kidneyhealth. The second phase could provide structured careto target comorbidities, such as anaemia, bone diseaseand secondary hyperparathyroidism, which develop inpatients with CKD that progresses to stage 4–5. The final,third phase involves multidisciplinary, intensive carefor patients transitioning to renal replacement therapy(CKD stage 5 and ESRD).117,118

Given the current distribution of CKD cases acrossstages 1–5 (Figures 1 and 2),9 the majority of patientswith CKD would fall into the first phase of care describedabove. Consequently, the management of CKD could be

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0

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Figure 3 | Comparison of CKD prevalence as determined using different formulaeto estimate glomerular filtration rate (CKD–EPI creatinine versus the four-variableMDRD study) in the USA between 1999 and 2004. The prevalence estimates arebased on samples of non-institutionalized adults (aged ≥20 years) who participatedin the National Health and Nutrition Examination Survey (NHANES) during theseyears (n = 13,233). The CKD–EPI data reported here were supplied by the USRDS.9 The interpretation and reporting of these data are the responsibility of the authorsand in no way should be seen as an official policy or interpretation of the USgovernment. The four-variable MDRD study data were reported by Coresh et al.29 Both studies used measures of albumin:creatinine ratios from spot morning urinesamples. Stage 3 CKD corresponds to a glomerular filtration rate of 30–59 ml/min/1.73 m2. The error bars show the 95% confidence intervals. The prevalence ofstage 5 CKD was not estimated with the MDRD equation in this study 29 as it wasdeemed that “estimates of this stage are likely to be unreliable due to the smallnumber of individuals and the likelihood that many of these individuals are ill orreceiving dialysis and would have a low response rate.” 29 Abbreviations: CKD,

chronic kidney disease; USRDS, United States Renal Data System.

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reconceptualized as a part of primary care.119 The adop-tion 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 caremodel developed by Edward H. Wagner, which consistsof six core parts: community resources and policies;health-care organization; self-management support;delivery system design; decision support; and clinicalinformation systems.121–124 The implementation of suchchanges in clinical practice is needed as the prevalencerates of T2DM and hypertension are expected to increaseand will add to the global burden of CKD. 125–127 A shiftto a primary care model might enable nephrologists and

other specialists to focus on patients with primary kidneydisease, progressive CKD and ESRD.

For all patients with CKD, PCPs should check for druginteractions, environmental toxins, and contrast dyesthat might cause acute kidney injury. These factors couldbe monitored with the help of information technologysystems, which could, for example, alert physicians topotentially harmful drug combinations. Some prescrip-tion and over-the-counter medicines, such as NSAIDs,can precipitate acute kidney injury in patients with CKD,and can accelerate progression of CKD.128–130

Numerous studies have highlighted the shortcomingsof primary care for patients with CKD (Table 2). Notably,

Table 2 | Selected observational studies of the quality of primary care for patients with CKD

Study Design Population Period Key results

Allenet al.

2011135

Retrospectivecohort

166 PCPs in 15 health centres ineastern Massachusetts, USA, caringfor 11,774 patients with CKD (eGFR15–60 ml/min/1.73 m2)

2004–2008

70% patients were not tested yearly for urine protein,46% had blood pressure ≥130/80 mmHg, 25% werenot receiving appropriate treatment with ACEinhibitors or ARBs and 26% were receiving potentiallyharmful medicines

Boulwareet al.

2006132

Cross-sectional(questionnaire)

National, random, stratified sampleof 400 nephrologists and 800 PCPsin the USA. Responses obtained from126 nephrologists and 178 PCPs

2004–2005

Family practitioners (56.2%) and general internists(70.7%) were less likely to recognize CKD than werenephrologists (96.0%) (P<0.01)

Charleset al.

2009133


Same population as in the studyby Boulware et al. (2006)

2004–2005

Only 48% of nephrologists, 19% of family practitioners,and 33% of general internists followed the KDOQIguidelines on the laboratory and radiological evaluationof patients with CKD (P<0.001)

Fox et al.

2006134

Qualitativeinterviews

10 PCPs from 10 health-carefacilities affiliated with the UpstateNew York Practice-based ResearchNetwork

Notstated

Awareness of KDOQI guidelines was low, and PCPsoften favoured less-accurate diagnostic tests forCKD (serum creatinine). Uncertainty existed aboutthe appropriate timing of referral to a nephrologist

Israniet al. 2009141


Random sample of 1,550 US PCPs;1,453 eligible respondents.Responses obtained from 470 PCPs

2007 Only 35% of PCPs had “adequate knowledge” of CKDbased on responses to 27 questions; for each10-year increase in age of the PCP, the odds ofhaving adequate knowledge decreased by 26%

Lea et al.

2006131

Cross-sectional(survey)

PCPs in six predominantlyAfrican-American communitiesin the USA. Responses obtainedfrom 464 PCPs

2003 ~34% and 22% of PCPs did not identify family historyand African-American ethnicity as risk factors forCKD, respectively. PCPs had high awareness thathypertension and T2DM are predictors of CKD

Minutoloet al.

2005138

Cross-sectional Nephrologists (tertiary care) and39 PCPs caring for hypertensivepatients with CKD (eGFR 15–60 ml/min/1.73 m2) in Italy

2003 Patients with CKD cared for by PCPs had higherblood pressure levels than those cared for by anephrologist (P<0.0001). The risk of not attainingblood pressure target values was 2.6-times greaterin primary care than in tertiary care settings,controlling for age, sex, T2DM and eGFR

Raveraet al.

2009140

Cross-sectional PCPs caring for 7,582 hypertensivepatients with T2DM in Italy

2005 Only 10.4% of patients with T2DM in this populationachieved blood pressure <130/80 mmHg. Ofpatients with eGFR <60 ml/min/1.73 m2, only 17%had been coded as having CKD

Raveraet al.

2011139

Cross-sectional PCPs caring for 39,525hypertensive patients in Italy(nationally representative sampleof patients)

2005 Only 13.8% of patients with eGFR <60 ml/min/1.73 m2 and 72.6% of patients witheGFR <30 ml/min/1.73 m2 were coded as havingCKD. Of patients with eGFR <60 ml/min/1.73 m2,only 45.4% and 13.2% achieved blood pressure<140/90 mmHg and <130/80 mmHg, respectively

Razavianet al.

2012136

Cross-sectional(survey)

Nationally-representative, cluster-stratified sample of 534 PCPs inAustralia; responses obtained from322 PCPs caring for 4,966 patients(age ≥55 years) with available dataon kidney function

2008 <18% patients were correctly diagnosed with CKD.The decisions by PCPs not to prescribe bloodpressure or lipid-lowering agents for patients withCKD only adhered to guideline recommendations in51% and 46% of cases, respectively

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II-receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtrationrate; KDOQI, Kidney Disease Outcomes Quality Initiative; PCP, primary care physician; T2DM, type 2 diabetes mellitus.

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there is low awareness of the KDOQI guidelines and diag-

nostic techniques,131–136 suboptimal prescribing andmanagement for patients with T2DM and/or hyper-tension,9,136–140 and poor recognition of the known riskfactors for CKD.131 A survey of 470 US-based PCPs foundthat only 35% had “adequate knowledge” of CKD basedon responses to 27 questions.141 For each 10-year increasein the age of the PCP, the odds of having adequate know-ledge decreased by 26%.141 Another study found that only19% of family practitioners and 33% of general intern-ists in the USA followed the KDOQI guidelines for thelaboratory and radiological evaluation of patients withCKD.133 In a study commissioned by the US NationalKidney Disease Education Program, approximately one-

third and one-quarter of US-based PCPs did not rec-ognize family history and African-American ethnicity

as risk factors for CKD, respectively.131 High awarenessthat 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 berepresentative of the general PCP population, and it ispossible that these findings—which already point to sub-stantial room for improvement—overstate the quality ofCKD care (Table 2).

The secondary care model

Timely involvement of renal specialists is required toimprove health outcomes for patients with progressiveCKD. Payers, however, which are any groups, other thanpatients, that are responsible for funding or reimbursingthe cost of health care, want to avoid unnecessary referralpatterns that could deplete resources. Depending on thecountry, the term ‘payer’ might refer to private or publicinsurers, 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 associatedwith better health outcomes and might be more cost-effective than late referral.142 RCTs that provide data onthe clinical effectiveness of early referral strategies werenot identified. Only two studies included patients whowere in the predialysis stage, and insufficient data wereavailable on the natural history of CKD and the costs andeffects of early referral. These data highlight the require-ment for long-term observational studies of patients withearly-stage CKD to enhance delineation of disease pro-gression and the incidence of cardiovascular events inpatients with and without associated health conditions,such as T2DM, pre-existing cardiovascular disease,

albuminuria or proteinuria. Finally, the authors of thesystematic review suggested that the substantial costsof early referral might be unaffordable for health-caresystems, even if early referral is cost-effective in the longterm. Further research is needed to evaluate the cost-effectiveness of improved primary care for patients withearly-stage CKD.

Early identification of CKD in the UK is financiallyincentivized in primary care, but some PCPs expressconcern as to whether early CKD is a genuine diseasestate across all ages.143 In geographical areas wherepatients are not correctly identified on CKD registers,cardiovascular management is suboptimal, with worse

control of blood pressure and cholesterol levels, comparedto those patients included on CKD registers.144 A transi-tion to a primary care model should be a universal deci-sion, unlike the development of current guidelines thathave 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(Box 2). Models of CKD care should be evaluated interms of value for money, and there must be an under-standing as to what approaches achieve a reliable servicedelivery to high-risk populations. CKD can provide

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 control led trial.

Primary care for cardiovascular disease

Exercise Healthy eating

Smoking cessation Blood pressure, glycaemic, and lipid control

Secondary care for CKD complications

Treatment and management of anaemiaand mineral and bone disorder

Nutrition management

Multidisciplinary care for RRT

Shared decision making between physicians and patients Dialysis and/or kidney

transplantation Surgical creation

of AVF Psychological

support

Phase 3(CKD

stage 5/ESRD)

Phase 2(CKD

stages4/5)

Phase 1(CKD

stages1–3)

Figure 4 | An integrated care continuum for CKD that is consistent with the chroniccare model. Abbreviations: AVF, arteriovenous fistula; CKD, chronic kidney disease;ESRD, end-stage renal disease; RRT, renal replacement therapy.

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a useful case study of how to enact a primary caremodel that is oriented towards public health and thatis patient-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 HealthService146–148 and Veterans Health Administration149)and private health-care organizations (for example,Kaiser Permanente150,151). In the 1990s, the Indian HealthService employed various primary care strategies tocombat the growing burden of T2DM and hypertensionamong American Indians and Alaskan Natives. Thesestrategies included the promotion of T2DM awarenessand lifestyle changes for patients (for example, healthyeating), the routine screening for CKD as part of primarycare, 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 ofdiabetes registries.146–148

By 2006–2007, >80% of patients in the Indian HealthService with comorbid hypertension and diabetes mel-litus were receiving an ACE inhibitor or ARB.147 Between1997 and 2007, the mean haemoglobin A1c and LDL chol-esterol levels decreased from 8.65% to 7.85% and from3.1 mmol/l (120 mg/dl) to 2.5 mmol/l (96 mg/dl), respec-tively.148 The age-adjusted incidence of ESRD amongAmerican Indians with diabetes mellitus decreasedby 31% (80.4 per 10,000 diabetic patients to 55.8 per10,000 diabetic patients) between 1990 and 2001.146 Thecare strategies used by the Indian Health Service have

demonstrated that a system-wide approach, even in anunderfunded system, can produce notable benefits interms of cardiovascular and renal health outcomes.

Kaiser Permanente of Southern California is a vertically-integrated health maintenance organizationthat has deviated from the KDOQI guidelines.151 Thisorganization instead applies a composite risk assess-ment to target patients whose conditions are expectedto worsen, and it uses automated information technologysystems that suggest treatment options based on input-ted patient information. The Hawaiian network of KaiserPermanente has also started to provide care to patientswith CKD based on risk stratification, and has found thatthis approach is associated with a statistically significantreduction in disease progression.150

CKD care pathways in the UK

Growing integration between primary and secondarycare is evident in the UK. A study performed in 2003—which preceded automated eGFR reporting—reviewedthe electronic primary care records of >130,000 patients

and found a high rate of undiagnosed CKD, with <20%of patients with an eGFR <30 ml/min/1.73 m2 beingcoded as having renal disease.152 Although automatedeGFR reporting has improved the detection of CKD inprimary care and has increased referral rates, this studysuggests that it is possible to alert PCPs about missedopportunities for preventive prescribing.

A model of CKD management similar to that intro-duced by Kaiser Permanente150 was initiated between 2003and 2006 in the West Midlands, UK. The initial resultsshow that patient outcomes have improved as a resultof this care strategy, with a reduction in the population-adjusted incidence of renal replacement therapy.153

Another study in West Lincolnshire, UK, evaluated thehealth outcomes of patients with CKD stages 4–5 treatedin primary care with a disease management programme,which was similar to a secondary care multidisciplinaryclinic. The programme improved health outcomes andslowed the reduction in eGFR over a 9-month period.154 Intensive, target-driven disease management programmeshave produced positive outcomes in the managementof T2DM,155 and scope exists for such approaches to beapplied to the care of patients with CKD.

Other international experiences

Other countries, including Australia and Canada, are

transitioning towards primary care models for the man-agement of CKD in the general population. Similarto the Indian Health Service, Australia has relied oncommunity-based CKD care for the population of theTiwi Islands, an aboriginal community.156 The model ofthe Tiwi Islands focuses on controlling blood pressureand lipid levels, and health education, with the aim toimprove cardiovascular health and preserve renal func-tion. The published data indicate that this strategy hasmarkedly improved cardiovascular and renal health out-comes in this population.156 These international experi-ences suggest that a holistic care model can be successfullyapplied across different types of health systems.

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 early-stage (1–3) 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 kidneydisease; eGFR, estimated glomerular filtration rate; GFR,glomerular filtration rate; PCP, primary care physician.

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Health-economic modelling of CKD care

As previously described, physicians should consider thelimitations of population-based equations to estimateGFR and instead evaluate individual patient charac-teristics when predicting disease risk and developingtreatment plans. Structured, early CKD intervention pro-

grammes 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 asto the appropriate scope and impact of such programmesis needed. Health-care providers, payers and the generalpublic should be made aware of the cost-effectiveness ofinvesting in CKD intervention programmes (Box 3).

Systems modelling is an inexpensive method to studythe effects of different interventions on chronic disease out-comes and costs.157–159 Software can be used to design com-prehensive care models in patient populations and observethe burdens of T2DM, hypertension, CKD and ESRD overtime.160 This method of modelling allows for sensitivity

analyses to test the degree of uncertainty around the modelassumptions. These analyses can provide an indication ofthe reliability and strength of the results, and highlightareas where further research is needed.

Alongside systems modelling, long-term prospectivecohort studies are required to interpret the clinical andeconomic value of different intervention strategies froma payer or societal perspective. Ideally, these studiesshould incorporate RCTs of CKD treatments into theirdesign. Furthermore, economic analyses should be con-ducted in parallel with outcome evaluations. Notably,the Nord–Trøndelag Health Study (HUNT) performedin Norway,161 the Kaiser Permanente151 and WestMidlands studies,153 and the majority of CKD qualityimprovement studies do not consider health-care costs.Incorporating health-economic evaluations into thesepopulation-based studies would generate useful evidenceto guide approaches to CKD care. Relevant stakeholdersshould also establish registries to monitor the long-termhealth and cost effects of different care pathways and thetiming of care initiation.

Conclusions

Insufficient evidence has been generated regarding theclinical and economic benefits of early CKD interven-

tion, especially in comparison to other diseases, such asT2DM and stroke. To date, no RCTs have assessed theclinical and economic outcomes of early interventionstrategies, and comprehensive patient-level data are notreadily accessible. Early diagnosis, treatment and man-agement of CKD could alter the natural history of thisdisease and generate substantial cost savings. Improvedunderstanding of the merits and disadvantages of dif-ferent care approaches for CKD and knowledge as towhere evidence is lacking are essential to improve healthoutcomes and minimize expenditure.

CKD, like many chronic conditions, can be consid-ered a broad indicator of overall health. Patients with

mild-to-moderate reductions in eGFR often havecomorbidities that are more relevant to their current andfuture well-being than is their CKD diagnosis.162 Thesecomorbidities should remain the focus of treatment andmanagement, as a low proportion of patients who arediagnosed with CKD will develop ESRD.

The difficulty for PCPs and nephrologists to identifypatients with progressive CKD has weakened the effec-tiveness of early interventions. New biomarkers thatmight improve the detection and prognosis of CKD arebecoming increasingly available,163 but it is unlikely thatany ‘magic bullet’ will fully address the disease burdenof CKD. A unified care strategy across health-care pro-

viders and payers should be promoted. This assertionholds true for CKD, a particularly complex disease thatinvolves many health-care providers over the lifetime ofa patient, but also applies to other chronic illnesses.

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

PCP–specialist 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 health–economic 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,primary care physician.

1. James, M. T., Haemmelgarn, B. R. & Tonelli, M.Early recognition and prevention of chronickidney disease. Lancet 376, 162–162 (2010).

2. Sarnak, M. J. et al. Kidney disease as a riskfactor for development of cardiovasculardisease–a statement from the American HeartAssociation councils on kidney in cardiovasculardisease, high blood pressure research, clinicalcardiology, and epidemiology and prevention.Circulation 108, 2154–2169 (2003).

3. Chen, R. A., Scott, S., Mattern, W. D., Mohini, R.& Nissenson, A. R. The case for diseasemanagement in chronic kidney disease.Dis. Manag. 9, 86–92 (2006).

4. Jha, V. et al. Chronic kidney disease: globaldimension and perspectives. Lancet 382,260–272 (2013).

5. Atkins, R. C. The epidemiology of chronickidney disease. Kidney Int. Suppl. 94, S14–S18(2005).

6. Kidney Disease: Improving Global Outcomes(KDIGO) CKD Work Group. KDIGO 2012 clinicalpractice guideline for the evaluation andmanagement of chronic kidney disease. Kidney

Int. Suppl. 3, 1–150 (2013).7. Levey, A. S. & Coresh, J. Chronic kidney disease.

Lancet 379, 165–180 (2012).8. Haynes, R. et al. Evaluating the contribution of

the cause of kidney disease to prognosis inCKD: results from the Study of Heart and Renal

REVIEWS




Protection (SHARP). Am. J. Kidney Dis. 64, 40–48(2014).

9. United States Renal Data System. USRDS 2014

annual data report [online], http://www.usrds.org/adr.aspx (2015).

10. Aitken, G. R. et al. Change in prevalence ofchronic kidney disease in England over time:comparison of nationally representative cross-sectional surveys from 2003 to 2010. BMJ Open 4, e005480 (2014).

11. De Vecchi, A. F., Dratwa, M. & Wioedemann, M. E.Healthcare systems and end-stage renal disease(ESRD) therapies—an international review: costsand reimbursement/funding of ESRD therapies.Nephrol. Dial. Transplant. 14 (Suppl. 6), 31–41(1999).

12. Stenvinkel, P. Chronic kidney disease: a publichealth priority and harbinger of prematurecardiovascular disease. J. Int. Med.268,456–467 (2010).

13. Feehally, J. et al. Early detection of chronickidney disease. BMJ 337, a1618 (2008).

14. Levin, A. & Stevens, P. E. Early detection of CKD:the benefits, limitations and effects on prognosis.Nat. Rev. Nephrol. 7, 446–457 (2011).

15. Locatelli, F., Del Vecchio, L. & Pozzoni, P. Theimportance of early detection of chronic kidney

disease. Nephrol. Dial. Transplant. 17, 2–7(2002).16. El Nahas, A. M. & Bello, A. K. Chronic kidney

disease: the global challenge. Lancet 365,331–340 (2005).

17. National Kidney Foundation. KIDOQI ClinicalPractice Guidelines for Chronic Kidney Disease:Evaluation, Classification and Stratification.

Am. J. Kidney Dis. 39, S1–S266 (2002).18. Zhang, L. et al. Prevalence and factors

associated with CKD: a population study fromBeijing. Am. J. Kidney Dis. 51, 373–384 (2008).

19. Singh, A. K. et al. Epidemiology and risk factors ofchronic kidney disease in India–results from theSEEK (Screening and Early Evaluation of KidneyDisease) study. BMC Nephrol. 14, 114 (2013).

20. Imai, E. et al. Prevalence of chronic kidney

disease in the Japanese general population.Clin. Exp. Nephrol. 16, 621–630 (2009).21. Kim, S. et al. The prevalence of chronic kidney

disease (CKD) and the associated factors toCKD in urban Korea: a population-based cross-sectional epidemiology study. J. Korean Med. Sci. 24 (Suppl. 1), S11–S21 (2009).

22. Otero, A. et al. Prevalence of chronic renaldisease in Spain: results of the EPIRCE study.Nefrologia 30, 78–86 (2010).

23. Wen, C. P. et al. All-cause mortality attributable tochronic kidney disease: a prospective cohortstudy based on 462,293 adults in Taiwan.Lancet 371, 2173–2182 (2008).

24. Grams, M. E., Chow, E. K. H., Segev, D. L. &Coresh, J. Lifetime Incidence of CKD Stages 3–5in the United States. Am. J. Kidney Dis. 62,

245–252 (2013).25. Mendu, M. L. et al. The usefulness of diagnostictesting in the initial evaluation of chronic kidneydisease. JAMA Intern. Med. 175, 853–856(2015).

26. National Institute for Health and Clinical CareExcellence. 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).

27. Lindeman, R. D., Tobin, J. & Shock, N. W.Longitudinal-studies on the rate of decline inrenal function with age. J. Am. Geriatr. Soc. 33,278–285 (1985).

28. O’Hare, A. M. et al. Age affects outcomes inchronic kidney disease. J. Am. Soc. Nephrol. 18,2758–2765 (2007).

29. Coresh, J. et al. Prevalence of chronic kidneydisease in the United States. JAMA 298,2038–2047 (2007).

30. Glassock, R. J. & Winearls, C. Ageing andthe glomerular filtration rate: truths andconsequences. Trans. Am. Clin. Climatol. Assoc. 120, 419–428 (2009).

31. Turin, T. C. et al. Proteinuria and rate of changein kidney function in a community-basedpopulation. J. Am. Soc. Nephrol. 24, 1661–1667

(2013).32. Eriksen, B. O. & Ingebretsen, O. C. Theprogression of chronic kidney disease: A 10-yearpopulation-based study of the effects of genderand age. Kidney Int. 69, 375–382 (2006).

33. Speizer, F. E. & Tager, I. B. Epidemiology ofchronic mucus hypersecretion and obstructiveairways disease. Epidemiol. Rev. 1, 124–142(1979).

34. Gansevoort, R. T. et al. Lower estimated GFR andhigher albuminuria are associated with adversekidney outcomes. A collaborative meta-analysisof general and high-risk population cohorts.Kidney Int. 80, 93–104 (2011).

35. Levey, A. S. et al. The definition, classification,and prognosis of chronic kidney disease:a KDIGO Controversies Conference report.

Kidney Int. 80, 17–28 (2011).36. Fliser, D., Zeier, M., Nowack, R. & Ritz, E. Renalfunctional reserve in healthy elderly subjects.

J. Am. Soc. Nephrol. 3, 1371–1377 (1993).37. Abdelhafiz, A. H., Brown, S. H., Bello, A. &

El Nahas, M. Chronic kidney disease in olderpeople: physiology, pathology or both? Nephron

Clin. Pract. 116, c19–c24 (2010).38. Jones, R. Trends in elderly diagnoses: links with

multi-morbidity. British J. Healthcare Manage. 19,553–558 (2013).

39. Orueta, J. F., Nuno-Solinis, R., Garcia-Alvarez, A.& Alonso-Moran, E. Prevalence of multimorbidityaccording to the deprivation level among theelderly in the Basque Country. BMC Public Health 13, 918 (2013).

40. Marengoni, A. et al. Aging with multimorbidity:

a systematic review of the literature. Ageing Res.Rev. 10, 430–439 (2011).41. Glassock, R. J. & Winearls, C. Diagnosing

chronic kidney disease. Curr. Opin. Nephrol.

Hypertens. 19, 123–128 (2010).42. Glassock, R. J. & Winearls, C. Screening for CKD

with eGFR: Doubts and dangers. Clin. J. Am. Soc.

Nephrol. 3, 1563–1568 (2008).43. Stevens, L. A., Coresh, J., Greene, T. &

Levey, A. S. Assessing kidney function—measured and estimated glomerular filtrationrate. N. Engl. J. Med. 354, 2473–2483 (2006).

44. Bauer, C., Melamed, M. L. & Hostetter, T. H.Staging of chronic kidney disease: time fora course correction. J. Am. Soc. Nephrol. 19,844–846 (2008).

45. Tonelli, M. et al. Using proteinuria and estimated

glomerular filtration rate to classify risk inpatients with chronic kidney disease: a cohortstudy. Ann. Intern. Med. 154, 12–21 (2011).

46. Lin, J., Knight, E. L., Hogan, M. L. & Singh, A. K.A comparison of prediction equations forestimating glomerular filtration rate in adultswithout kidney disease. J. Am. Soc. Nephrol. 14,2573–2580 (2003).

47. Rule, A. D. et al. Measured and estimated GFRin healthy potential kidney donors. Am. J. Kidney

Dis. 43, 112–119 (2004).48. Poggio, E. D., Wang, X., Greene, T., Van Lente, F.

& Hall, P. M. Performance of the modification ofdiet in renal disease and Cockcroft-Gaultequations in the estimation of GFR in health andin chronic kidney disease. J. Am. Soc. Nephrol. 16, 459–466 (2005).

49. Stevens, L. A. et al. Impact of creatininecalibration on performance of GFR estimatingequations in a pooled individual patientdatabase. Am. J. Kidney Dis. 50, 21–35 (2007).

50. Murata, K. et al. Relative performance of theMDRD and CKD-EPI equations for estimatingglomerular filtration rate among patients withvaried clinical presentations. Clin. J. Am. Soc.

Nephrol. 6, 1963–1972 (2011).51. Levey, A. S. et al. A new equation to estimate

glomerular filtration rate. Ann. Intern. Med. 150,604–612 (2009).52. Stevens, L. A. et al. Evaluation of the

modification of diet in renal disease studyequation in a large diverse population. J. Am.

Soc. Nephrol. 18, 2749–2757 (2007).53. Hoffmann, A., Nimtz, M. & Conradt, H. S.

Molecular characterization of beta-trace proteinin human serum and urine: a potentialdiagnostic marker for renal diseases.Glycobiology 7, 499–506 (1997).

54. Stevens, L. A. et al. Estimating GFR using serumcystatin C alone and in combination with serumcreatinine: A pooled analysis of 3,418individuals with CKD. Am. J. Kidney Dis. 51,395–406 (2008).

55. Kilbride, H. S. et al. Accuracy of the MDRD

(Modification of Diet in Renal Disease) studyand CKD-EPI (CKD Epidemiology Collaboration)equations for estimation of GFR in the elderly.

Am. J. Kidney Dis. 61, 57–66 (2013).56. Fan, L. et al. Comparing GFR estimating

equations using cystatin C and creatinine inelderly individuals. J. Am. Soc. Nephrol. (2014).

57. Schaeffner, E. S. et al. Two novel equations toestimate kidney function in persons aged 70years or older. Ann. Intern. Med. 157, 471–481(2012).

58. Inker, L. A. et al. Estimating glomerular filtrationrate from serum creatinine and cystatin C.N. Engl. J. Med. 367, 20–29 (2012).

59. Inker, L. A. et al. Expressing the CKD-EPI (ChronicKidney Disease Epidemiology Collaboration)cystatin C equations for estimating GFR with

standardized serum cystatin C values. Am. J.Kidney Dis. 58, 682–684 (2011).60. Saydah, S. H. et al. Albuminuria prevalence

in first morning void compared with previousrandom urine from adults in the National Healthand Nutrition Examination Survey, 2009–2010Clin. Chem. 59, 675–683 (2013).

61. Naresh, C. N., Hayen, A., Weening, A., Craig, J. C.& Chadban, S. J. Day-to-day variability in spoturine albumin-creatinine ratio. Am. J. Kidney Dis. 62, 1095–1101 (2013).

62. Bakker, S. J., Gansevoort, R. T. & de Zeeuw, D.Albuminuria: what can we expect from thedetermination of nonimmunoreactive albumin?Curr. Hypertens. Rep. 11, 111–117 (2009).

63. Witte, E. C. et al. First morning voids are morereliable than spot urine samples to assess

microalbuminuria. J. Am. Soc. Nephrol. 20,436–443 (2009).64. Brinkman, J. W. et al. Falsely low urinary albumin

concentrations after prolonged frozen storage ofurine samples. Clin. Chem. 51, 2181–2183(2005).

65. Warram, J. H., Gearin, G., Laffel, L. &Krolewski, A. S. Effect of duration of type Idiabetes on the prevalence of stages of diabeticnephropathy defined by urinary albumin/creatinine ratio J. Am. Soc. Nephrol. 7, 930–937(1996).

66. Long, D. A. et al. Albuminuria is associated withtoo few glomeruli and too much testosterone.Kidney Int. 83, 1118–1129 (2013).

67. Lambers Heerspink, H. J. et al. Albuminuriaassessed from first-morning-void urine samples

REVIEWS


http://www.usrds.org/adr.aspx


http://www.nice.org.uk/CG182

http://www.nice.org.uk/CG182





versus 24-hour urine collections as a predictorof cardiovascular morbidity and mortality. Am. J.

Epidemiol. 168, 897–905 (2008).68. Hallan, S. I. et al. Combining GFR and

albuminuria to classify CKD improves predictionof ESRD. J. Am. Soc. Nephrol. 20, 1069–1077(2009).

69. Tangri, N. et al. A predictive model forprogression of chronic kidney disease to kidneyfailure. JAMA 305, 1553–1559 (2011).

70. Tonelli, M. et al. Chronic kidney disease andmortality risk: A systematic review. J. Am. Soc.

Nephrol. 17, 2034–2047 (2006).71. Sehestedt, T. et al. Risk prediction is improved

by adding markers of subclinical organ damageto SCORE. Eur. Heart J. 31, 883–891 (2010).

72. Jones-Burton, C. et al. An in-depth review of theevidence linking dietary salt intake andprogression of chronic kidney disease.

Am. J. Nephrol. 26, 268–275 (2006).73. Smyth, A. et al. The relationship between

estimated sodium and potassium excretionand subsequent renal outcomes. Kidney Int. 86,1205–1212 (2014).

74. McMahon, E. J. et al. A randomized trial ofdietary sodium restriction in CKD. J. Am. Soc.

Nephrol. 24, 2096–2103 (2013).

75. Fink, H. A. et al. Screening for, monitoring, andtreatment of chronic kidney disease stages 1to 3: a systematic review for the US PreventiveServices Task Force and for an AmericanCollege of Physicians Clinical PracticeGuideline. Ann. Intern. Med. 156, 570–581(2012).

76. Qaseem, A. et al. Screening, monitoring, andtreatment of stage 1 to 3 chronic kidneydisease: a clinical practice guideline from theAmerican College of Physicians. Ann. Intern.

Med. 159, 835–847 (2013).77. American Society of Nephrology. ASN

emphasizes need for early detection of kidney

disease, a silent killer [online], http://www.asn-online.org/news/2013/asn_comm_acp_screening_response_102213_r12.pdf (2013).

78. Komenda, P. et al. Cost-effectiveness of primaryscreening for CKD: a systematic review. Am. J.

Kidney Dis. 63, 789–797 (2014).79. Menzin, J. et al. A review of the costs and cost

effectiveness of interventions in chronic kidneydisease implications for policy.Pharmacoeconomics 29, 839–861 (2011).

80. Morales, E., Valero, M. A., Leon, M.,Hernandez, E. & Praga, M. Beneficial effects ofweight loss in overweight patients with chronicproteinuric nephropathies. Am. J. Kidney Dis. 41,319–327 (2003).

81. Saiki, A. et al. Effect of weight loss using formuladiet on renal function in obese patients withdiabetic nephropathy. Int. J. Obes. (Lond.) 29,1115–1120 (2005).

82. Solerte, S. B., Fioravanti, M., Schifino, N. &

Ferrari, E. Effects of diet-therapy on urinaryprotein excretion albuminuria and renalhaemodynamic function in obese diabeticpatients with overt nephropathy. Int. J. Obes. 13,203–211 (1989).

83. Navaneethan, S. D. et al. Weight lossinterventions in chronic kidney disease:a systematic review and meta-analysis. Clin. J.

Am. Soc. Nephrol. 4, 1565–1574 (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. et al. Physical activity andchange in estimated GFR among persons withCKD. J. Am. Soc. Nephrol. 25, 399–406 (2014).

86. Robinson-Cohen, C. et al. Physical activity andrapid decline in kidney function among olderadults. Arch. Intern. Med. 169, 2116–2123(2009).

87. Sawicki, P. T. et al. Smoking is associated withprogression of diabetic nephropathy. Diabetes

Care 17, 126–131 (1994).88. Chase, H. P. et al. Cigarette-smoking increases

the risk of albuminuria among subjects withtype-I diabetes. JAMA 265, 614–617 (1991).

89. Schiffl, H., Lang, S. M. & Fischer, R. Stoppingsmoking slows accelerated progression of renalfailure in primary renal disease. J. Nephrol. 15,270–274 (2002).

90. Dalrymple, L. S. et al. Chronic kidney diseaseand the risk of end-stage renal disease versusdeath. J. Gen. Intern. Med. 26, 379–385 (2011).

91. Go, A. S., Chertow, G. M., Fan, D. J.,McCulloch, C. E. & Hsu, C. Y. Chronic kidneydisease and the risks of death, cardiovascularevents, and hospitalization. N. Engl. J. Med. 351,1296–1305 (2004).

92. Taal, M. W. Arterial stiffness in chronic kidneydisease: an update. Curr. Opin. Nephrol.

Hypertens. 23, 169–173 (2014).93. Upadhyay, A. et al. Lipid-lowering therapy

in persons with chronic kidney disease:

a systematic review and meta-analysis. Ann. Intern. Med. 157, 251–262 (2012).94. Palmer, S. C. et al. HMG CoA reductase

inhibitors (statins) for people with chronickidney disease not requiring dialysis.Cochrane Database Syst. Rev. Issue 5.Art. No.:CD007784 http://dx.doi.org/10.1002/14651858.CD007784.pub2.

95. Tonelli, M. et al. Association between LDL-C andrisk of myocardial infarction in CKD. J. Am. Soc.

Nephrol. 24, 979–986 (2013).96. Upadhyay, A., Earley, A., Haynes, S. M. &

Uhlig, K. Systematic review: blood pressuretarget in chronic kidney disease and proteinuriaas an effect modifier. Ann. Intern. Med. 154,541–548 (2011).

97. Ruggenenti, P. et al. Renal function and

requirement for dialysis in chronic nephropathypatients on long-term ramipril: REIN follow-uptrial. Gruppo Italiano di Studi Epidemiologici inNefrologia (GISEN). Ramipril efficacy innephropathy. Lancet 352, 1252–1256 (1998).

98. Brenner, B. M. et al. Effects of losartan on renaland cardiovascular outcomes in patients withtype 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

99. Rodby, R. A. et al. The Irbesartan type II diabeticnephropathy trial: study design and baselinepatient characteristics. For the CollaborativeStudy Group. Nephrol. Dial. Transplant. 15,487–497 (2000).

100. Sharma, P. et al. Angiotensin-converting enzymeinhibitors and angiotensin receptor blockers foradults 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 r ise inthe incidence of renal replacement therapy indeveloped countries come to an end? Nephrol.

Dial. Transplant. 22, 678–680 (2007).102. Vassalotti, J. A., Gracz-Weinstein, L.,

Gannon, M. R. & Brown, W. W. Targeted screeningand treatment of chronic kidney disease: lessonslearned from the kidney early evaluation program.Dis. Manag. Health Out. 14, 341–352 (2006).

103. Katz, I. J., Gerntholtz, T. E., van Deventer, M.,Schneider, H. & Naicker, S. Is there a need forearly detection programmes for chronic kidneydisease? Clin. Nephrol. 74, S113–S118 (2010).

104. Lash, J. P. et al. Chronic Renal InsufficiencyCohort (CRIC) Study: baseline characteristicsand associations with kidney function. Clin. J.

Am. Soc. Nephrol. 4, 1302–1311 (2009).105. Feldman, H. I. et al. The Chronic Renal

Insufficiency Cohort (CRIC) study: design andmethods. J. Am. Soc. Nephrol. 14, S148–S153(2003).

106. Kronenberg, F. Emerging risk factors andmarkers of chronic kidney disease progression.

Nat. Rev. Nephrol. 5, 677–689 (2009).107. Johnson, E. S., Smith, D. H., Thorp, M. L.,Yang, X. H. & Juhaeri, J. Predicting the risk ofend-stage renal disease in the population-basedsetting: 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 dialysisand transplant among patients with CKD:a retrospective cohort study. Am. J. Kid. Dis. 52,653–660 (2008).

109. Levin, A., Djurdjev, O., Beaulieu, M. & Er, L.Variability and risk factors for kidney diseaseprogression and death following attainment ofstage 4 CKD in a referred cohort. Am. J. Kid. Dis. 52, 661–671 (2008).

110. McClellan, W. M. & Flanders, W. D. Risk factors

for progressive chronic kidney disease. J. Am.Soc. Nephrol. 14 (Suppl. 2), S65–S70 (2003).

111. Peralta, C. A. et al. Detection of chronic kidneydisease with creatinine, cystatin C, and urinealbumin-to-creatinine ratio and association withprogression to end-stage renal disease andmortality. JAMA 305, 1545–1552 (2011).

112. Mahmoodi, B. K. et al. Associations of kidneydisease measures with mortality and end-stagerenal disease in individuals with and withouthypertension: a meta-analysis. Lancet 380,1649–1661 (2012).

113. Fox, C. S. et al. Associations of kidney diseasemeasures with mortality and end-stage renaldisease in individuals with and without diabetes:a meta-analysis. Lancet 380, 1662–1673(2012).

114. Rose, G. Sick individuals and sick populations.Int. J. Epidemiol. 30, 427–432 (2001).115. Leoncini, G. et al. Global risk stratification in

primary hypertension: the role of the kidney. J. Hypertens. 26, 427–432 (2008).

116. Perkins, R. M. et al. GFR Decline and MortalityRisk among Patients with Chronic KidneyDisease. Clin. J. Am. Soc. Nephrol. 6, 1879–1886(2011).

117. Saweirs, W. W. M. & Goddard, J. What are thebest treatments for early chronic kidneydisease? A background paper prepared for theUK consensus conference on early chronickidney disease. Nephrol. Dial. Transplant. 22,31–38 (2007).

118. Loud, F. & Gallagher, H. Kidney health: deliveringexcellence. Kidney Health Report 1–52 (2013).

119. Shahinian, V. B. & Saran, R. The role of primarycare in the management of the chronic kidneydisease population. Adv. Chronic Kidney Dis. 17,246–253 (2010).

120. Levin, A. The need for optimal and coordinatedmanagement of CKD. Kidney Int. 68, 7–10(2005).

121. Bodenheimer, T., Wagner, E. H. & Grumbach, K.Improving primary care for patients with chronicillness. JAMA 288, 1775–1779 (2002).

122. Bodenheimer, T., Wagner, E. H. & Grumbach, K.Improving primary care for patients with chronicillness—the chronic care model, part 2. JAMA 288, 1909–1914 (2002).

123. Wagner, E. H. Chronic disease management:what will it take to improve care for chronicillness? Eff. Clin. Pract. 1, 2–4 (1998).

REVIEWS


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http://dx.doi.org/10.1002/14651858.CD003236.pub2














http://slidepdf.com/reader/full/early-chronic-kidney-disease 12/12

124. Wagner, E. H., Austin, B. T. & VonKorff, M.Organizing care for patients with chronic illness.Milbank Q. 74, 511–544 (1996).

125. Hajjar, I., Kotchen, J. M. & Kotchen, T. A.Hypertension: Trends in prevalence, incidence,and control. Annu. Rev. Public Health 27,465–490 (2006).

126. Danaei, G. et al. National, regional, and globaltrends in fasting plasma glucose and diabetesprevalence since 1980: systematic analysis of

health examination surveys and epidemiologicalstudies with 370 country-years and 2.7 millionparticipants. Lancet 378, 31–40 (2011).

127. Finucane, M. M. et al. National, regional, andglobal trends in body-mass index since 1980:systematic analysis of health examinationsurveys and epidemiological studies with 960country-years and 9.1 million participants.Lancet 377, 557–567 (2011).

128. Venkatachalam, M. A. et al. Acute kidney injury:a springboard for progression in chronic kidneydisease. Am. J. Physiol. Renal Physiol. 298, F1078–F1094 (2010).

129. Chawla, L. S. & Kimmel, P. L. Acute kidney injuryand chronic kidney disease: an integrated clinicalsyndrome. Kidney Int. 82, 516–524 (2012).

130. Rewa, O. & Bagshaw, S. M. Acute kidney injur y-

epidemiology, outcomes and economics. Nat.Rev. Nephrol. 10, 193–207 (2014).

131. Lea, J. P., McClellan, W. M., Melcher, C.,Gladstone, E. & Hostetter, T. CKD risk factorsreported by primary care physicians: doguidelines make a difference? Am. J. Kidney Dis. 47, 72–77 (2006).

132. Boulware, L. E., Troll, M. U., Jaar, B. G.,Myers, D. I. & Powe, N. R. Identification andreferral of patients with progressive CKD:a national study. Am. J. Kidney Dis. 48, 192–204(2006).

133. Charles, R. F. et al. Clinical testing patterns andcost implications of variation in the evaluation ofCKD among US physicians. Am. J. Kidney Dis. 54,227–237 (2009).

134. Fox, C. H., Brooks, A., Zayas, L. E., McClellan, W.

& Murray, B. Primary care physicians’ knowledgeand practice patterns in the treatment of chronickidney disease: an Upstate New York Practice-based Research Network (UNYNET) study. J. Am.

Board Fam. Med. 19, 54–61 (2006).135. Allen, A. S. et al. Primary Care Management of

Chronic Kidney Disease. J. Gen. Intern. Med. 26,386–392 (2011).

136. Razavian, M. et al. Cardiovascular riskmanagement in chronic kidney disease in generalpractice (the AusHEART study). Nephrol. Dial.

Transplant. 27, 1396–1402 (2012).137. Winkelmayer, W. C. et al. Underuse of ACE

inhibitors and angiotensin II receptor blockers inelderly patients with diabetes. Am. J. Kidney Dis. 46, 1080–1087 (2005).

138. Minutolo, R. et al. Management of hypertension

in patients with CKD: Differences between

primary and tertiary care settings. Am. J. Kidney

Dis. 46, 18–25 (2005).139. Ravera, M. et al. CKD awareness and blood

pressure control in the primary carehypertensive population. Am. J. Kidney Dis.57,71–77 (2011).

140. Ravera, M. et al. Chronic kidney disease andcardiovascular risk in hypertensive type 2diabetics: a primary care perspective. Nephrol.

Dial Transplant. 24, 1528–1533 (2009).

141. Israni, R. K., Shea, J. A., Joffe, M. M. &Feldman, H. I. Physician characteristics andknowledge of CKD management. Am. J. Kidney

Dis. 54, 238–247 (2009).142. Black, C. et al. Early referral strategies for

management of people with markers of renaldisease: a systematic review of the evidence ofclinical effectiveness, cost-effectiveness andeconomic analysis. Health Technol. Assess. 14,1–184 (2010).

143. Crinson, I., Gallagher, H., Thomas, N. &de Lusignan, S. How ready is general practiceto improve quality in chronic kidney disease?A diagnostic analysis. Br. J. Gen. Pract. 60,403–409 (2010).

144. Jain, P., Calver t, M., Cockwell, P. &McManus, R. J. The need for improved

identification and accurate classification ofstages 3–5 chronic kidney disease in primarycare: retrospective cohort study. PLoS ONE 9, e100831 (2014).

145. Stevens, P. E., Levin, A. & Global, K. D. I.Evaluation and management of chronic kidneydisease: synopsis of the Kidney Disease:Improving Global Outcomes 2012 ClinicalPractice Guideline. Ann. Intern. Med. 158,825–830 (2013).

146. Narva, A. S. Reducing the burden of chronickidney disease among American Indians.

Adv. Chronic Kidney Dis. 15, 168–173 (2008).147. Narva, A. S. & Sequist, T. D. Reducing health

disparities in American Indians with chronickidney disease. Semin. Nephrol. 30, 19–25(2010).

148. Sequist, T. D., Cullen, T. & Acton, K. J. Indianhealth service innovations have helped reducehealth disparities affecting american Indian andalaska native people. Health Aff. (Millwood) 30,1965–1973 (2011).

149. Patel, T. G., Pogach, L. M. & Barth, R. H. CKDscreening and management in the VeteransHealth Administration: the impact of systemorganization and an innovative electronic record.

Am. J. Kidney Dis. 53 (Suppl. 3), S78–S85 (2009).150. Lee, B. et al. Effects of proactive population-

based nephrologist oversight on progression ofchronic kidney disease: a retrospective controlanalysis. BMC Health Serv. Res. 12, 252 (2012).

151. Rutkowski, M. et al. Implementing KDOQI CKDDefinition and Staging Guidelines in SouthernCalifornia Kaiser Permanente. Am. J. Kidney Dis.

53 (Suppl. 3), S86–S99 (2009).

152. Stevens, P. E. et al. Chronic kidney diseasemanagement in the United Kingdom: NEOERICAproject results. Kidney Int. 72, 92–99 (2007).

153. Rayner, H. C. et al. Does community-wide chronickidney disease management improve patientoutcomes? Nephrol. Dial. Transplant. 29,644–649 (2014).

154. Richards, N. et al. Primary care-based diseasemanagement of chronic kidney disease (CKD),based on estimated glomerular filtration rate

(eGFR) reporting, improves patient outcomes.Nephrol. Dial. Transplant. 23, 549–555 (2008).155. Gaede, P., Lund-Andersen, H., Parving, H. H.

& Paedersen, O. Effect of a multifactorialintervention on mortality in type 2 diabetes.N. Engl. J. Med. 358, 580–591 (2008).

156. Hoy, W. E., Baker, P. R., Kelly, A. M. & Wang, Z.Reducing premature death and renal failurein Australian aboriginals. A community-basedcardiovascular and renal protective programme.Med. J. Aust. 172, 473–478 (2000).

157. Hirsch, G., Homer, J., Evans, E. & Zielinski, A.A system dynamics model for planningcardiovascular disease interventions.

Am. J. Public Health 100, 616–622 (2010).158. Homer, J. B. & Hirsch, G. B. System dynamics

modeling for public health: background and

opportunities. Am. J. Public Health 96, 452–458(2006).159. Ness, R. B., Koopman, J. S. & Roberts, M. S.

From the American College of EpidemiologyAnnual Meeting 2006—causal system modelingin chronic disease epidemiology: a proposal.

Ann. Epidemiol. 17, 564–568 (2007).160. Zhou, H. et al. A computer simulation model of

diabetes progression, quality of life, and cost.Diabetes Care 28, 2856–2863 (2005).

161. Hallan, S. I. et al. International comparison ofthe relationship of chronic kidney diseaseprevalence and ESRD risk. J. Am. Soc. Nephrol. 17, 2275–2284 (2006).

162. Jesky, M., Lambert, A., Burden, A. C. &Cockwell, P. The impact of chronic kidney diseaseand cardiovascular comorbidity on mortality in a

multiethnic population: a retrospective cohortstudy. BMJ Open 3, e003458 (2013).163. Fassett, R. G. et al. Biomarkers in chronic kidney

disease: a review. Kidney Int 80, 806–821(2011).

Acknowledgements

We would like to thank Dr Shari Ling and Dr KimberlySmith (Centers for Medicare and Medicaid Services,Baltimore, MD, USA) for their useful comments onearly versions of this manuscript.

Author contributions

O.J.W., D.J.O., and J.R. wrote the article. All authorsresearched the data for the article, providedsubstantial contributions to discussions of its content,and undertook review and/or editing of the manuscript

before submission.

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