Screening CKD Mathew & Corso Nephrology 09

nep_1113 367..373

Review Article

Review article: Early detection of chronic kidney disease inAustralia: Which way to go?TIMOTHY MATHEW1 and OLIVIA CORSO2

1Kidney Health Australia, Medical Section, Kent Town, and 2Kidney Health Australia, Health Services,Adelaide, South Australia, Australia

SUMMARY: Early detection of chronic kidney disease (CKD) followed by appropriate clinical managementappears the only means by which the increasing burden on the health-care system and affected individuals willbe reduced. The asymptomatic nature of CKD means that early detection can only occur through testing ofindividuals. The World Health Organization principles of screening for chronic disease can now be largely fulfilledfor CKD. The risk groups to be targeted, the expected yield and the tests to be performed are reviewed. For ascreening programme to be sustainable it must carry a greater benefit than risk of harm for the participant andbe shown to be cost-effective from the community point of view. Whole population screening for CKD isimpractical and is not cost-effective. Screening of those at increased risk of CKD could occur either throughspecial events run in the community, workplace or in selected locations such as pharmacies or throughopportunistic screening of high-risk people in general practice. Community screening programmes targeted atknown diabetics, hypertensives and those over 55 years have been described to detect 93% of all CKD in thecommunity. The yield of CKD stages 3–5 from community screening has been found to vary from 10% to 20%.The limitations of screening programmes including the cost and recruitment bias are discussed. The mostsustainable and likely the most cost-efficient model appears to be opportunistic general practice screening. Thechanging structure of general practice in Australia lends itself well to the requirements for early detection of CKD.

KEY WORDS: albuminuria, chronic kidney disease (CKD), glomerular filtration rate (GFR), proteinuria.

The burden of chronic disease attributable to kidney diseasein Australia is increasing. This is best-documented in thosewith kidney failure accepted on to Australian dialysis andtransplant treatment programmes where the prevalence ofpatients on dialysis has more than doubled in the last12 years.1 The prevalence of earlier stages of chronic kidneydisease (CKD) in Australia is not well-documented overtime and is confounded by changes in the measurement andreporting of serum creatinine concentrations and the rela-tively recent definition of stages of CKD. There seems littledoubt however that the Australian prevalence of early CKDhas risen in recent years driven by the increased numbers ofpeople with diabetes and the increasing age of the popula-tion. The situation is likely similar to the USA where theprevalence of stages 1–4 CKD was shown to increase from10% in 1988–1994 to 13.1% in 1999–2004.2

The early recognition of CKD is made difficult by itslargely asymptomatic nature. One consequence of this isthat about a quarter of all patients in Australia present totheir nephrologist in kidney failure less than 90 days beforestarting dialysis and this number is showing no sign ofimproving with time.3 An early diagnosis of CKD allowspreventive measures to be put in place that may favourablyaffect clinical outcomes and in those with progressivekidney failure facilitate a smooth, orderly and less morbidtransition on to dialysis and transplant programmes.

The detection of CKD early in its course relies on theperformance of tests on urine (albumin or protein) andblood (serum creatinine), and these together with a bloodpressure measurement have been popularly called a ‘kidneyhealth check’. There is no other simple clinical means toestablish the presence of kidney damage and to classify itinto stages by severity.4

It is important to recognize at the outset that screeningcan occur in two ways – population-based screening where atest is offered to all individuals in a targeted group andopportunistic screening when a test is offered to an indi-vidual without symptoms of the disease when they presentto the health-care system for other reasons. Screening for

Correspondence: Professor Timothy Mathew, Kidney HealthAustralia, Medical Section, 45 Wakefield Street, Kent Town, SA 5067,Australia. Email: [email protected]

Accepted for publication 17 February 2009.

© 2009 The AuthorsJournal compilation © 2009 Asian Pacific Society of Nephrology

NEPHROLOGY 2009; 14, 367–373 doi:10.1111/j.1440-1797.2009.01113.x

mailto:[email protected]

CKD is not currently practiced in Australia. This articlereviews the principles underlying and justifying the estab-lishment of a screening programme for CKD. The followingquestions will be addressed:

1 The principles of screening for chronic diseaseapplied to CKD.

2 Who should be screened and what is the likely yieldfrom screening programmes?

3 How should CKD be screened?4 Is there advantage for the participant in the screening

programme?5 Are CKD screening programmes cost-effective?6 Where to for Australia with CKD screening?

1 PRINCIPLES OF SCREENING AS APPLIED TOCKD EARLY DETECTION

The World Health Organization (WHO) principles ofscreening for disease were published 40 years ago (Table 1)5

and continue to underpin current screening recommenda-tions in Australia.6 It is instructive to consider the situationwith CKD screening against these criteria.

The condition (CKD)

The condition should be an important health problem

The scope of the health problem in Australia posed by CKDhas recently been reviewed by the Australian Institute ofHealth and Welfare7 and on a global level.8 Although notrecognized as a health priority in Australia by the Common-

wealth Government, the current and growing spend onrenal replacement and the contribution of CKD to prema-ture cardiovascular morbidity and mortality have been costin the UK at 2% of the National Health Service budget.9

There should be a recognizable latent or earlysymptomatic stage

Chronic kidney disease characteristically is a silent condi-tion yet kidney damage can be readily demonstrated bysimple tests (see following)

The natural history of the condition, includingdevelopment from latent to declared disease should beadequately understood

The natural history of CKD has been intensively studiedover the last 50 years and although complex, risk factors forprogression based on clinical tests have been established.The incidence, prevalence and trends of progressive declinein kidney function, the association with increased morbidityand mortality and the burden of disease by age and sex areknown.7 The importance of proteinuria as a risk markerfor progressive decline in kidney function has beenemphasized.10

Tests for CKD

There should be a suitable test or examination

The tests for establishing the presence of CKD are simple,cheap and widely available. The sensitivity and specificity oftests used for detection of CKD has been reviewed by Jaaret al.11 Urine testing for albumin demonstrates acceptablesensitivity and high specificity. The use of serum creatinineconcentration and estimated glomerular filtration rate(GFR) has limitations, and efforts are underway to improvethe performance of these measures. It should be stressed thatthe definition of CKD calls for the abnormalities to persistfor more than 3 months – a severe restriction on screeningfor CKD as a one-off test. Any screening results can only beregarded as suggestive, and confirmation of any abnor-malities requires serial tests over time.7 The advantages intargeting CKD testing to high-risk groups have beendemonstrated.12

The test should be acceptable to the population

The simple tests for CKD should prove readily acceptable tothe target population including Aboriginal and Torres StraitIslander people who have a high prevalence of CKD. Afinger prick-based serum creatinine test is currently underdevelopment and is being validated and standardized. Itsavailability for use in the field will assist in the acceptabilityof CKD testing.

Table 1 World Health Organization principles of early diseasedetection5

ConditionThe condition should be an important health problem.There should be a recognizable latent or early symptomatic

stage.The natural history of the condition, including

development from latent to declared disease should beadequately understood.

TestThere should be a suitable test or examination.The test should be acceptable to the population.

TreatmentThere should be an accepted treatment for patients with

recognized disease.Screening programme

There should be an agreed policy on whom to treat aspatients.

Facilities for diagnosis and treatment should be available.The cost of case findings (including diagnosis and

treatment of patients diagnosed) should be economicallybalanced in relation to possible expenditure on medicalcare as a whole.

Case findings should be a continuing process and not a‘once and for all’ project.

T Mathew and O Corso368


Systems should be in place for evidence-based follow upof all people with a positive screening test

The management of screen-detected cases of CKD wouldessentially be in the primary health-care system. This iswidely available to all Australians irrespective of location orsocioeconomic status.

Treatment of CKD

There should be an accepted treatment for patients withrecognized disease

The evidence-based clinical action pathways for CKD in itsvarious stages have been determined13,14 and published inAustralia (see Table 2).15

Screening programme for CKD

There should be an agreed policy on whom to treatas patients

While there is consensus in some areas of CKD management(e.g. proteinuria >1 g/day in a young person) there remainsuncertainty about how to approach a 75-year-old with a mild

reduction in eGFR (e.g. 55 mL/min per 1.73 m2) and noother abnormalities. Further studies are needed to establishthe best care pathway in the elderly with mild CKD.

Facilities for diagnosis and treatmentshould be available

The management of CKD in its early phases requires noexpensive diagnostic tests or treatment. The essential care isconsistent with cardiovascular risk reduction at the primarycare level.

The cost of case findings (including diagnosis andtreatment of patients diagnosed) should be economicallybalanced in relation to possible expenditure on medicalcare as a whole

The cost-effectiveness of early detection (opportunisticscreening of 50–69-year-olds in general practice) and inter-vention to prevent progression of CKD in Australia hasbeen established.16 Savings incurred through reduction inthe numbers progressing with CKD into the high-cost endof treating end-stage kidney failure provides a balance tothe costs of screening and may potentially represent agenuine saving. Further studies are needed to assess the

Table 2 eGFR clinical action plan15

eGFR (mL/minper 1.73 m2) Description Clinical action plan

390 Stage 1 CKD – kidneydamage† with normalkidney function

Further investigation for CKD may be indicated in those atincreased risk‡:• blood pressure• assessment of proteinuria• urinalysis

60–89 Stage 2 CKD – kidneydamage† with mild ↓kidney function

Cardiovascular risk reduction:• blood pressure• lipids• blood glucose• lifestyle modification (smoking, weight, physical activity, nutrition

and alcohol)30–59 Stage 3 CKD – moderate ↓

kidney functionAs above, plus:

• monitor eGFR 3 monthly• avoid nephrotoxic drugs• prescribe anti-proteinuric drugs (ACE inhibitors and/or ARB) if

appropriate• address common complications• ensure drug dosages appropriate for level of kidney function

Consider indications for referral to a nephrologist15–29 Stage 4 CKD – severe ↓

kidney functionAs above, plus, referral to nephrologist is usually indicated for physical

and psychosocial preparation for renal replacement therapy (dialysis,pre-emptive transplantation and transplantation) or conservativemedical management

<15 Stage 5 CKD – end-stagekidney disease

As above, plus referral to a nephrologist

†Imaging or biopsy abnormalities, or proteinuria/haematuria. ‡Hypertension, diabetes, smoker, age > 50 years, obesity, family history of kidneydisease, Aboriginal and Torres Strait Islander people. CKD, chronic kidney disease; GFR, glomerular filtration rate; ACE, angiotensin convertingenzyme; ARB, angiotensin receptor blocker.

Early detection of chronic kidney disease 369


cost-effectiveness of community- or work-based screeningprogrammes. There is a paucity of information on clinicaloutcomes recorded in screen-detected cases although thereseems little reason to doubt that the benefit of treatmentwould be similar to that demonstrated in cases foundthrough conventional channels.

Case findings should be a continuing process and not a‘once and for all’ project

This recommendation would well apply to CKD wherethere is a continuing risk of acquiring the condition withincreasing age and the development of diabetes, hyperten-sion and obesity.

Jaar et al. have recently published the ‘Principles ofScreening for Kidney Disease’ and concluded that ‘themajority of the Wilson and Junger (WHO) criteria could besatisfied for CKD screening and evidence is mounting that apopulation based screening programme should be imple-mented in certain high risk groups’. They further concludethat ‘further studies of the benefits, risks and costs of screen-ing for CKD including randomized controlled trials arestill needed’.11

Jaar et al. identified the lack of published randomizedtrials of clinical outcomes in screen-detected cases of CKDand acknowledged concerns about the validity of and biasin screening methods, and the need for further cost-effectiveness studies based on hard clinical outcomes.

2 WHO SHOULD BE SCREENED FOR CKD ANDWHAT IS THE LIKELY YIELD OF MODERATE TOSEVERE CKD?

The prevalence of CKD in Australian adults is about 16%with 2.4% having proteinuria and 7.8% CKD stages 3–5(from AusDiab relying on a one-off testing of the sampledpopulation).7 There is agreement that population-widescreening for CKD by early detection of urine protein is notcost-effective17 or is ‘at best a promising primary preventionstrategy’.18

The case for testing individuals at high risk for CKD hasbeen made in position statements published by the NationalKidney Foundation of USA19 and a position statement pub-lished from the not-for-profit organization KDIGO (KidneyDisease – Improving Global Outcomes) recommending ‘Allcountries should have a targeted screening programme forCKD’ – focusing on those people known to have diabetes,hypertension and cardiovascular disease.20

A large-scale general health survey from Norway in65 000 people from a single community (with a 71%response rate) begun in 1995 throws considerable light onwho to screen. The study concluded that screening peoplewith hypertension, diabetes or age > 55 years was the mosteffective strategy to detect people with CKD. This approachto targeting would have screened 37% of the population,detected 93% of all CKD present in the community andrequired 8.7 people to be screened per detected case of CKDstages 3–5. Other strategies of targeting detected a lower

percentage of CKD and were considered less effective.12

Given the high prevalence of CKD in some indigenouscommunities it would seem appropriate in Australia to addAboriginal and Torres Strait Islander people to the targetedcohort.

The US KEEP (Kidney Early Evaluation Program)targets people with self-reported diabetes or hypertension orthose with a first-order relative with hypertension, diabetesor kidney disease and found 19% of participants to haveCKD stages 3–5. The KEEP participants are characterizedby overrepresentation of Afro-Americans and women thatmight explain the high yield.21 The Australian KEY (KidneyEvaluation for You) pilot programme chose to target thosewith known diabetes, hypertension and those over 50 yearsand yielded 9.7% of participants to have CKD stages 3–5(Mathew T, Corso O, 2009). The KDIGO recommendstargeting patients with hypertension, diabetes and cardio-vascular disease.4 Clearly the higher the number of riskgroups included in the target cohort the higher the yield ofCKD but the less efficient the programme because of thegreater numbers screened. A reasonable conclusion mightbe to follow the Norwegian experience of targeting peoplewith diabetes and hypertension and to arguably elevate theage cut point to >60 years – this would likely furtherimprove the efficiency with little loss in the number of casesof serious kidney disease cases detected.

3 HOW SHOULD CKD BE SCREENED?

The progressive reduction of GFR in those people who aredestined to progress into kidney failure is the hallmarkof progressive kidney damage. The improved recognition ofearly reduction in GFR through the automatic reporting ofeGFR (based on serum creatinine measurement) has con-siderably advanced our ability to find early cases of people atspecial risk of developing kidney failure. The estimation ofGFR from a creatinine-based measurement will always haveits limitations, but improvement in the standardization ofmeasurement of creatinine has already occurred and a newformula for estimating GFR has been developed that is moreaccurate especially at a higher eGFR and is likely to replacethe current MDRD eGFR formula.22

However the risk of progression to kidney failure even inthose with a moderate reduction of GFR (stage 3) has beenshown to be small. The Norwegian study tracked 2389people with an eGFR of 45–59 mL/min per 1.73 m2 for8 years and showed only 0.4% progressed to end-stage renalfailure. Of those with an eGFR of 30–45 mL/min per1.73 m2 only 1.3% progressed to end-stage renal failure.12

Thus although measurement of GFR is integral to any CKDscreening programme additional tests to separate those atspecial risk of progression are needed.

Proteinuria has emerged as the most important determi-nant of likely progression to kidney failure10,23 and has beenshown to be a strong independent predictor of kidneyfailure in a mass screening setting.24 The combination ofGFR reduction and proteinuria or albuminuria is especiallyimportant as a risk factor for end-stage renal failure as shown



in the MRFIT study where a GFR < 60 mL/min togetherwith proteinuria dipstick 2+ or more had a relative risk of 33for progression to end-stage renal failure compared withthose with a normal GFR and no proteinuria.25 Albumin/creatinine ratio has also been reported as being associatedwith a higher rate of GFR decline in men,26 and given thehigh number of people with diabetes targeted in CKDscreening albuminuria assessment appears essential.

Other biomarkers for the presence of CKD that are ableto improve on the accuracy of present tests in indicating anincreased propensity for progression are being sought. Cys-tatin C is being assessed as an alternative to creatinine forGFR estimation but appears to offer no advantage when theGFR is <60 mL/min. Urine biomarkers such as KIM-1 andNAG are promising for early diagnosis of acute kidneyinjury, but little help is on the horizon for CKD.27

Thus for the immediate future serum creatinine mea-surement, urine dipstick for protein and urine albumin/creatinine ratio (along with blood pressure measurement)are the mainstay of any CKD screening programme. Themeasurement at point of care of urine albumin andcreatinine is well-established, and recent advances haveoccurred in the technical aspects of measuring serum crea-tinine at the point of care. We have recently validatedvenous sampling of blood for an IDMS-aligned serum crea-tinine measurement and are in the process of validatingfinger prick sampling (Shephard M, Corso O, 2009). Pointof care assessment of these tests allows the feedback ofresults to participants within minutes of sampling andenhances the efficiency of communication within thescreening process.

4 IS THERE ADVANTAGE FOR THEPARTICIPANT IN CKD SCREENING?

The early detection of CKD allows preventive measures tobe put in place that may favourably affect clinical outcomesand facilitates a smooth and orderly transition on to dialysisand transplant programmes in those who progress undercontinuing care. The fact, as described above, that the riskof progressing to kidney failure is small needs to be modifiedby the increasingly appreciated reality that one reason forthis is the competing risk of death from cardiovasculardisease. For those with CKD stage 3 and followed for 5 yearsthis risk of cardiovascular mortality exceeds the risk of end-stage renal failure by a factor of almost 20 times.28 Thus anypreventive measure that follows the screen-detected diag-nosis of CKD must include cardiovascular risk reduction.While controlled trials have shown significant advantage toparticipants through reduction in the number progressing tokidney failure with the use of angiotensin-active agents,little attention has been paid to improved cardiovascularoutcomes in those with CKD.

A positive result obtained at a screening programme cancreate harm through anxiety in the participant, and this isparticularly so when there is an incidence of false positives.Mis-categorization of a significant number of people to CKDstage 3 may occur given the precise cut point of GFR at

60 mL/min and the lack of precision of the creatinine mea-surement. Improvement in creatinine standardization, thenew eGFR formula and the possible introduction of age-based reference intervals will help reduce the frequency ofmis-categorization. The diagnosis of CKD requires establish-ing the persistence of the abnormalities over a 3 monthperiod. Any screening programme thus relies on anyonewith an abnormality detected suggestive of CKD beingreferred to their general practitioner for further tests, adviceand follow up.

The answer to the question – ‘Is there advantage to theparticipant in CKD screening?’ – awaits careful assessmentin randomized trials of cardiovascular risk reduction andlong-term follow up in screen-detected cases.

5 ARE CKD SCREENING PROGRAMMESCOST-EFFECTIVE?

The demonstration of cost-effectiveness of a community-based targeted screening programme requires the demon-stration and proof of clinical benefit in the long term to thescreen-detected person with CKD. Potentially this benefitmay include the avoidance of dialysis or transplant depen-dence or delay in commencing dialysis treatment and areduction in the frequency of cardiovascular morbidity andmortality. These trials of cost-effectiveness have not yetbeen performed. The US KEEP has attempted follow up ofits participants, but the data to date are unclear because oflimited follow up, a low response rate and no costing analy-sis.29 It is clear that the community screening programmessuch as KEEP or KEY have high infrastructure costs andarguably attract only those motivated to better health care.

Opportunistic screening in general practice on an annualbasis from age 50 to 69 years for diabetes, hypertension andproteinuria combined with intensive treatment for thosedetected to (or previously known to) have these conditionswas modelled for cost-effectiveness in Australia.16 The keyfindings were:

1 The early detection and appropriate management ofhigh blood pressure, diabetes and protein in the urineby general practice-based annual screening in 50–69-year-olds (during visits to general practitioners),along with intensification of management in thosealready known to have these conditions, would becost-effective and in some cases highly cost-effective.

2 The benefit from such a programme lies in reducingdeaths from heart attacks and kidney failure and inreducing the number of people needing dialysis ortransplantation.• End-stage kidney failure. For every 1000 people

screened (age from 50 to 69 years) and followed fortheir lifetime

High blood pressure screening prevents 11 casesof kidney failure (requiring dialysis)Diabetes screening prevents two cases of kidneyfailure (requiring dialysis)Proteinuria screening prevents two cases ofkidney failure (requiring dialysis)



• Cardiovascular deaths. For every 1000 peoplescreened (age from 50 to 69 years) and followedfor their lifetime

High blood pressure screening results in 65fewer deaths from heart attack and vascularcausesDiabetes screening results in 23 fewer deathsfrom heart attack and vascular causesProteinuria screening results in 14 fewer deathsfrom heart attack and vascular causes

3 In value for money terms (cost per life year saved orcost per quality-adjusted life year) the CKD-targetedscreening programme is as cost-effective (or in mostcases more cost-effective) than the estimated effi-ciency of screening programmes (e.g. breast, cervicaland bowel cancer) already available in Australia.

In a US setting a health economic analysis similarlyconcluded that screening for nephropathy followed byoptimal antihypertensive therapy with reno-protectiveagents in type 2 diabetes and hypertension led to a 44%reduction in the cumulative incidence of end-stage renalfailure and represented excellent value for money.30

Thus there is a lack of evidence for the cost-effectivenessof community-based CKD screening but opportunisticscreening in general practice for hypertension, diabetes andproteinuria appears cost-effective.

6 WHERE TO FOR AUSTRALIA WITHCKD SCREENING?

The current indications are that general practice-basedopportunistic screening for CKD is an achievable, sustain-able and effective means for Australia to pursue early detec-tion and appropriate management of CKD. Eighty-five percent of all adult Australians attend a general practitioner atleast once a year thus providing an opportunity for earlydetection of kidney disease. This could follow the protocolproposed by the modelling study16 or focus on just high-riskindividuals such as those known to have diabetes, hyper-tension and those over the age of 60 years.

Screening programmes mounted in the community(including the workplace, pharmacies and so on) are costly,attract clientele who are more likely to want to improvetheir health care and rely on a connection back to thegeneral practitioner to achieve any positive outcome.However community-based programmes have the advan-tage of increasing awareness of CKD in the wider populationthrough associated publicity and provide an opportunity forhealth professional education. The sustainability of suchprogrammes is also an issue with it being unlikely that acommunity CKD screening event would recycle to a par-ticular town or region more often than every few years.

The best and most sustainable model and likely the mostcost-efficient appears to be opportunistic general practicescreening. The structure of general practice in Australia ischanging with an increased emphasis on chronic diseasemanagement, preventive health care and a multidisciplinaryteam approach. The early detection and best care of CKD

readily fits into this mould, given the ease of identificationof the high-risk groups, the simple tests needed to establishthe presence of and the staging of CKD and the overlap ofthe action plans for CKD with those for best care of peoplewith diabetes and cardiovascular risk reduction. Howeverfor this approach to be successful in general practice sub-stantial effort at education is required and the application ofthe protocols will need to be made cost-effective for thepractitioner.

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Screening CKD Mathew & Corso Nephrology 09