Selected Summaries

Screening for proteinuria: Is it cost-effective? [PDF]

Boulware LE, Jaar BG, Tarver-Carr ME, Brancati FL, Powe NR. (Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD, USA.) Screening for proteinuria in US adults: A cost-effectiveness analysis. JAMA 2003;290:3101–14.

SUMMARY
Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) retard the progression of chronic kidney disease (CKD) towards end-stage renal disease (ESRD). They are also known to reduce cardiovascular disease (CVD)-related mortality. This study presents a cost-effectiveness analysis (Markov decision analysis) of population-based screening for proteinuria using dipstick testing and subsequent treatment with an ACEI or ARB in reducing ESRD or mortality. It compares a strategy of annual screening with no screening (usual care) for proteinuria in the US population starting at the age of 50 years in subjects without hypertension or diabetes. A cost-effectiveness ratio of <=US$ 50 000 per quality-adjusted life-year (QALY) was considered highly favourable towards screening. The results show that, in the screening strategy, a gain of 0.0022 QALY is mediated through the prevention of 1 new case of ESRD and 7 deaths per 1 million persons screened per year. The base-case cost-effectiveness ratio for screening v. no screening is highly unfavourable (US$ 82 818 per QALY saved). This decision analysis argues against populationwide screening for proteinuria as a cost-effective measure for reducing the burden of ESRD or mortality in the US population.

COMMENT
The incidence of ESRD is increasing worldwide. It is projected that in the US alone, more than 600 000 persons may progress to ESRD by 2010.1 These patients have a poor quality of life and society incurs a high cost in caring for these individuals. The cost-effectiveness of early detection and treatment of patients with kidney disease is a contentious issue as many such patients do not progress to ESRD; whereas those who do, go undetected until it is too late to intervene.
     Proteinuria is the most readily measured marker of kidney disease. Therapy with ACEI and ARB subsequent to the detection of proteinuria (and thus early kidney disease) could potentially reduce progression towards ESRD.2 Further, there may be a beneficial effect on mortality due to CVD, which accounts for up to two-thirds of deaths due to CKD.3
     In essence, this study is a statistical estimation to arrive at the optimal point where ACEI/ARB therapy should be initiated as a premium for insurance against the development of ESRD. The authors developed a state-transition Markov analytical model to simulate the clinical path of patients from normal kidney function to ESRD and analyse the cost-effectiveness of screening for proteinuria from a societal perspective. The best available evidence in the literature was used for the calculations. The cost of premium included the cost of screening and fall-outs from the detection of proteinuria such as further investigations, i.e. imaging, immunology work-up, biopsies, cost and adverse effects of drugs, etc. The major outcome variables were an increase in QALYs on account of preservation of the glomerular filtration rate (GFR), reduction in all-cause mortality, and the benefits to healthcare agencies and society in general, especially by reducing the loss of man-hours. The base-case model strata consisted of US adults 50 years of age with previously undetected proteinuria presenting to a primary physician for routine annual examination. In the screening strategy, these patients underwent a urine dipstick test to detect proteinuria, and positive results were followed up with a quantitative reassessment of the levels of urinary protein, serum creatinine and GFR. This resulted in either treatment with an ACEI/ARB, or referral to a nephrologist. Those with positive dipstick test results but negative quantitative results were considered to have non-persistent proteinuria and were not given any treatment. The no-screening or usual care strategy consisted of no dipstick testing and natural progression of CKD with an annual opportunity for incidental testing or symptom development and disease detection.
     The variables used in the model were age and cause-specific mortality rates for the US population with proteinuria, rates of progression from normal kidney function towards CKD and ESRD, incidence and prevalence of the disease, dipstick test characteristics, adherence to drugs, rates of spontaneous symptom development and incidental testing, cost of screening, effectiveness of therapy in slowing the progression of kidney disease, costs of physician visits and diagnostic components, lost wages and similar costs. These variables were abstracted from the published data. The determination of QALY required assigning the health state utility value (a numerical value reflecting the relative importance of different health states or clinical outcomes to patients) and this ranged from 0 (worst) to 1 (optimal health). Some representative utility values were: 0.99 for GFR >90 ml/minute without proteinuria representing almost normal health, 0.95 for GFR 15–89 ml/minute, and a value of 0.7 for GFR <15 ml/minute, which includes ESRD.
      For persons with neither hypertension nor diabetes, who comprised the base population for the decision analysis, a gain of 0.0022 QALY was mediated through the prevention of only 1 new case of ESRD and 7 deaths per 1 million persons per year in the screening strategy. The cost of achieving this was huge (US$ 282 818 per QALY saved) and thus highly unfavourable. The model was further applied to persons with hypertension and diabetes. For persons with hypertension, the cost-effectiveness ratio was highly favourable (US$ 18 621 per QALY saved). A gain of 0.03 QALYs was mediated through the prevention of approximately 14 new cases of ESRD and 104 deaths per 1 million persons per year. In contrast, for persons with diabetes, the screening strategy was dominant over the no-screening strategy (US$ 217 saved and a gain of 0.10 QALY per person) mediated through the prevention of 84 new cases of ESRD and 541 deaths per 1 million persons per year. The reduction in mortality due to therapy with ACEI/ARBs had a more profound cost-saving impact than prevention of ESRD. On further analysis, it was found that for persons with neither hypertension nor diabetes, the cost-effectiveness ratio was unfavourable until screening began at the age of 60 years whereas for hypertensives, annual screening beginning at 30 years was highly favourable. In terms of its harms, screening 1 million persons with neither hypertension nor diabetes resulted in the conduction of 135 biopsies, 7 complications of biopsy and complication costs of US$ 9116 per year.
     The results of such decision analyses are of immense importance to managers and providers of healthcare, as well as physicians. The cost burden of ESRD is extremely high and it is very tempting to develop a strategy to prevent it. It is well known that chronic renal insufficiency can develop and progress silently. It is equally humbling to realize that the currently available therapies do not stem the natural tendency of kidney disease to progress. They can only reduce the loss of GFR. Therefore, one would intuitively think that screening for proteinuria would lead to a cost-effective strategy for reducing morbidity and mortality. However, this analysis by Boulware et al. concludes that screening of US adults for the early detection of urinary protein is cost-effective only if directed towards high-risk groups (the elderly, and persons with hypertension and/or diabetes).
     It may be worthwhile to recapitulate the major variables in the screening and prevention paradigms in this study. The success of this strategy depends on the incidence of proteinuria, sensitivity and specificity of dipstick testing, cost and adherence to drugs, and variables associated with the management of ESRD. Since there are tremendous variations in the management of ESRD worldwide, the results of the study will not be easy to generalize outside the US, especially in the developing world. In the absence of regional or national registries, the exact incidence of ESRD in developing countries is not known. The reported annual incidence of ESRD from developing countries varies from 34 to 220 per million population, which is in contrast to an incidence of 98–198 per million population reported from ESRD registries maintained in developed countries.4 In the developing world, almost two-thirds of patients present to a nephrologist when they already have ESRD. Due to financial constraints, <10% of all patients with ESRD receive any kind of renal replacement therapy. The annual per capita income in India in 1999–2000 was US$ 279. The average expenses of the state on health costs amount to US$ 7.67 per capita per year. In contrast, the cost of renal transplantation is US$ 5000 and the cost of dialysis alone (excluding drugs) is US$ 2500 per year.4 These harsh facts make it obvious that the treatment of established ESRD is beyond the reach of an average Indian. This applies to most of the developing world. The dismal care of ESRD militates against the feasibility of a health utility value of 0.70 that was assigned in the current study. A tremendous reduction in the health utility value in subjects with ESRD will influence the results in favour of screening in a significant manner. With early mortality being almost inevitable in most patients with ESRD, the case for screening for proteinuria will be much more pertinent to the developing world.
     A substantial proportion of ESRD worldwide is due to diabetes, hypertension and obstructive uropathy. It is eminently possible to prevent these diseases and initiate renoprotective interventions. In a report from Chennai, a large, population-based, low-cost screening programme using a simple questionnaire, checking of blood pressure, testing for proteinuria using sulphosalicylic acid and for urine glucose by Benedict reagent, found evidence for renal disease in 0.86% of the population and only a third of them had prior knowledge of it.5 While all this and basic treatment in the Chennai project have been achieved at a very low cost, this does not conclusively prove its cost-effectiveness or benefits in terms of added QALY. In effect, the beneficial effects of ACEI or ARB, though well-established in the clinical setting for patients with various diseases, are not effective in populationwide screening for proteinuria. Some of the estimates used in the decision analysis provide an insight into the reasons for the cost-ineffectiveness of the intervention (Table I).

     It is obvious that the incidence and prevalence of proteinuria in subjects with hypertension and diabetes is 10 times more than that in subjects without these conditons. The annual decline in GFR in those with diabetes and proteinuria is 4 times more than that in subjects without diabetes. Screening for proteinuria in the general population in developed countries may remain cost-ineffective unless new therapeutic modalities are found which are more effective in reducing the risk of mortality and progression towards ESRD. Until this is accomplished, health resources are better directed at the high-risk population. There is a strong case for working on preventing diabetes and hypertension, which account for the bulk of ESRD and CVD worldwide.
     Considerations regarding the implementation of strategies that are deemed cost-effective should incorporate recognition of the limited resources available for the provision of healthcare services to society and should seek to allocate resources in a manner that allows the maximum net benefit from their use. Of course, screening from the perspective of an individual rather than society will have a different impact because the individual may be driven by totally different considerations. The perceived satisfaction of an individual in getting screened is evident from a survey carried out in the US in which >70% of respondents preferred to undergo a total-body computed tomographic scan for cancer screening instead of receiving US$ 1000 in cash. This enthusiasm was not dampened by the possibility of false-positive test results or unnecessary treatments.6
     In conclusion, this decision analysis suggests that early detection of proteinuria to slow the progression of CKD and decrease mortality is not cost-effective unless selectively directed towards high-risk groups (the elderly, and persons with hypertension and/or diabetes) or conducted at an infrequent interval of 10 years. The results may not apply to many populations outside the US, but the volume of evidence available to carry out such analyses is a great achievement of modern clinical research and information technology. It is imperative that developing countries gather enough data relevant to their health issues and develop practice guidelines based on the rigorous analysis shown in this paper.