- Braden Manns, associate professor of medicine1234,
- Brenda Hemmelgarn, associate professor of medicine 1234,
- Marcello Tonelli, associate professor of medicine45,
- Flora Au, research analyst24,
- T Carter Chiasson, BHSc student4,
- James Dong, research analyst45,
- Scott Klarenbach, associate professor of medicine45
- on behalf of the Alberta Kidney Disease Network
- 1Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- 2Community Health Sciences, University of Calgary, Calgary
- 3Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary
- 4Alberta Kidney Disease Network, Calgary
- 5Department of Medicine, Division of Nephrology, University of Alberta, Edmonton, Alberta
- Correspondence to: B Manns, Foothills Medical Centre, 1403 29th St. NW Calgary, Alberta Canada T2N 2T9
- Accepted 2 September 2010
Objective To determine the cost effectiveness of one-off population based screening for chronic kidney disease based on estimated glomerular filtration rate.
Design Cost utility analysis of screening with estimated glomerular filtration rate alone compared with no screening (with allowance for incidental finding of cases of chronic kidney disease). Analyses were stratified by age, diabetes, and the presence or absence of proteinuria. Scenario and sensitivity analyses, including probabilistic sensitivity analysis, were performed. Costs were estimated in all adults and in subgroups defined by age, diabetes, and hypertension.
Setting Publicly funded Canadian healthcare system.
Participants Large population based laboratory cohort used to estimate mortality rates and incidence of end stage renal disease for patients with chronic kidney disease over a five year follow-up period. Patients had not previously undergone assessment of glomerular filtration rate.
Main outcome measures Lifetime costs, end stage renal disease, quality adjusted life years (QALYs) gained, and incremental cost per QALY gained.
Results Compared with no screening, population based screening for chronic kidney disease was associated with an incremental cost of $C463 (Canadian dollars in 2009; equivalent to about £275, €308, US $382) and a gain of 0.0044 QALYs per patient overall, representing a cost per QALY gained of $C104 900. In a cohort of 100 000 people, screening for chronic kidney disease would be expected to reduce the number of people who develop end stage renal disease over their lifetime from 675 to 657. In subgroups of people with and without diabetes, the cost per QALY gained was $C22 600 and $C572 000, respectively. In a cohort of 100 000 people with diabetes, screening would be expected to reduce the number of people who develop end stage renal disease over their lifetime from 1796 to 1741. In people without diabetes with and without hypertension, the cost per QALY gained was $C334 000 and $C1 411 100, respectively.
Conclusions Population based screening for chronic kidney disease with assessment of estimated glomerular filtration rate is not cost effective overall or in subgroups of people with hypertension or older people. Targeted screening of people with diabetes is associated with a cost per QALY that is similar to that accepted in other interventions funded by public healthcare systems.
End stage renal disease and its precursor chronic kidney disease are emerging public health problems because of their associated adverse clinical outcomes, poor quality of life, and high healthcare costs. Given that chronic kidney disease (defined as glomerular filtration rate below 60 ml/min/1.73 m2) is often not detected until it is advanced, screening programmes using blood or urine tests have been recommended.1 2 3 With population based screening, however, there are potential benefits (such as early identification and treatment of affected patients) and drawbacks (such as identification of patients with only mild disease, in whom additional treatment might not be warranted).4
Several studies have examined the effectiveness of screening for chronic kidney disease with estimated glomerular filtration rate or urinalysis.5 6 7 8 9 Previous studies of screening in high risk groups have found that it would identify one person with disease for every three to six people screened,5 6 7 8 9 10 whereas population based screening would detect one for every 16-21 people screened.10 11 Existing cost effectiveness studies have examined screening only with urinalysis.12 13 As only 26% and 3% of North Americans with glomerular filtration rate <30 ml/min/1.73 m2, and 30-60 ml/min/1.73 m2, respectively, have macroalbuminuria on urinalysis, this form of screening would be expected to miss a considerable proportion of people with chronic kidney disease.10
While clinical practice guidelines for chronic kidney disease from the National Kidney Foundation/Kidney Dialysis Outcomes Quality Initiative have recommended targeted screening of high risk patients, including those with diabetes or hypertension and aged >60,1 14 others have suggested a population based approach.4 15 16 The International Federation of Kidney Foundations recently surveyed its 28 member nations on the existence of screening programmes for chronic kidney disease, and 24 reported some form of screening activity.17 While most programmes entailed screening for disease among high risk groups, including those with hypertension, diabetes, and a family history of chronic kidney disease and older people, a few countries, including Hong Kong, Japan, and the Netherlands, have active population based screening programmes. Given the current interest in screening, as well as the controversy concerning its optimal use, we assessed the cost effectiveness of population based screening for chronic kidney disease based on estimated glomerular filtration rate alone (compared with no screening) in all adults and in subgroups of people defined by age, diabetes, and hypertension.
Overview and validation
We carried out an incremental cost utility analysis of one-off screening for chronic kidney disease with estimated glomerular filtration rate compared with no screening in adults with no previous assessment of glomerular filtration rate. The box shows a high level overview of the modelling process.
Overview of analysis
The prevalence of undiagnosed chronic kidney disease in different subgroups of patients stratified by age (<65 or ≥65) and diabetes was determined from a North American population based survey10
The natural course of chronic kidney disease was then determined within the Alberta Kidney Disease Network,18 a large population based laboratory cohort of patients, with mortality rates and incidence of end stage renal disease estimated over a five year follow-up period
Screening for chronic kidney disease would be expected to identify patients with no previous diagnosis who could then receive angiotensin blockade
The relative risks of end stage renal disease and death associated with angiotensin blockade were taken from high quality published meta-analyses
This information was combined with decision analysis to examine the long term outcomes and costs for a strategy of screening for chronic kidney disease and subsequent management of patients compared with no screening (disease undiagnosed and untreated until detected incidentally during routine care)
In the base case analysis we used the perspective of the publicly funded healthcare system. Health benefits were measured in cases of end stage renal disease prevented and quality adjusted life years (QALYs) gained over a lifetime. We also assessed the incremental cost associated with screening for chronic kidney disease and measured the incremental cost per QALY gained. Costs and benefits were discounted at 5% annually. All costs were inflated to 2009 Canadian dollars (1 $C=£0.59=€0.67=US $0.83) by using the Canadian healthcare consumer price index.
Computer simulation model
We constructed a Markov model using decision analysis software (TreeAge Pro Suite 2007, Williamstown, MA) in accordance with existing guidelines for economic evaluation.19 Base case analyses were performed with Markov cohort simulation with transitions modelled on an annual basis, though we used first order Monte Carlo simulation to determine the incidence of end stage renal disease over time. We considered several health states in both the screening and no screening strategies, including people without chronic kidney disease, those with non-dialysis chronic kidney disease, patients receiving dialysis, and patients with a functioning transplant.
Model validity was established,20 including internal validation with primary clinical data (R2 between model outcomes and primary data was >0.97 for both end stage renal disease and mortality at five years) and external validity by comparing with other published reports.21 22 Among patients with chronic kidney disease, mortality and end stage renal disease was 24% and 2.7% at five years and 71% and 4.1% at 20 years, respectively. Several models were evaluated, and, given the excellent performance of all models, we used the simplest and most transparent model, where chronic kidney disease is represented as one health state (as opposed to modelling patients with varying severity of chronic kidney disease as three separate disease states1), in accordance with optimal modelling guidelines.20 Additional benefits of modelling with only one health state is that it offers increased flexibility to incorporate estimates of benefit (that is, relative risk for end stage renal disease and death) as reported in clinical trials, compared with models that use several distinct stages of chronic kidney disease based on severity of disease.
We based the prevalence of non-dialysis chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) on the results of the National Health and Nutrition Examination Survey III, a representative survey of the North American population stratified by age and the presence of diabetes.10 In the survey, conducted by the National Center for Health Statistics in the United States, data (including estimated glomerular filtration rate) were collected with rigorous methods according to standardised protocols.23
We also used data from the Alberta Kidney Disease Network,18 a repository of laboratory data for routinely collected tests (including estimated glomerular filtration rate) for the entire province of Alberta, Canada. Patients in the laboratory repository are linked to provincial healthcare programmes, which care for all dialysis and transplant patients,24 and to provincial administrative data (using the unique provincial health number) to obtain demographic information (including death) and details regarding use of healthcare resources (physician claims, admission to hospital, and use of prescription drugs (for people aged ≥65)).18
Data from the network enabled us to estimate the annual incidence of end stage renal disease and death in a cohort of Albertans receiving routine care between May 2002 and December 2007 (table 1⇓). The initial and subsequent glomerular filtration rate for these patients was estimated with an equation from the Four Variable Modification of Diet in Renal Disease Study,25 with the baseline rate being defined by the mean estimated rate of all measurements during the first year. Diabetes mellitus was identified from hospital discharge records and physicians’ claims,26 and other chronic medical conditions were identified with validated algorithms.27 28 Proteinuria was defined as more than trace on a urine dipstick or if the urine protein:creatinine ratio was >23 mg/mmol (>200 mg/g).18
The cohort included 290 613 individuals, of whom 55 453 had chronic kidney disease and 30 277 had diabetes. All participants were followed to ascertain the incidence of death, end stage renal disease, and renal replacement therapy until 31 December 2007. Annual rates of these outcomes (stratified by age, presence of diabetes and presence of proteinuria) were estimated for up to five years after the index measurement of glomerular filtration rate, with censoring at end stage renal disease, death, or 31 December 2007 (table 2⇓ and table 3⇓).
For people without chronic kidney disease, age dependent population mortality rates were estimated from observed rates for Canadians.29 For people with chronic kidney disease, mortality rates were based on the annual rate observed within the Alberta Kidney Disease Network cohort after the initial assessment of estimated glomerular filtration rate. We accounted for age related increases in mortality in those with chronic kidney disease based on the observed mortality rates for patients in different age groups in the network (table 2⇑ and table 3⇑).
Adherence with screening and incidental case finding
We assumed that 50% of people would agree to screening, which requires venipuncture.30 As estimation of glomerular filtration rate can also occur during routine care, irrespective of screening, we assumed that a proportion of unscreened people would undergo such assessment each year. Using data from the network (to determine the number of people undergoing their first creatinine measurements each year) and the 2006 Canadian census (to define the total Alberta population31), we estimated the annual likelihood of undergoing incidental screening for chronic kidney disease in this previously unscreened population.
Diagnostic investigation for people in whom screening identified chronic kidney disease
We assumed that all people with newly diagnosed chronic kidney disease would undergo evaluation by a nephrologist, including a standard laboratory investigation (table 4⇓). This assumption was tested in a sensitivity analysis, in which we assumed that only 20% of patients were assessed by a nephrologist with the remainder managed by a primary care physician. Consistent with previous surveys of physicians,12 32 we also assumed that a kidney biopsy would be done in 5% and 20% of people with incident chronic kidney disease with and without diabetes.
Effectiveness of angiotensin blockade for people with chronic kidney disease
The benefit of screening for chronic kidney disease is assumed to be the detection of previously undiagnosed disease, enabling appropriate assessment and management. While detection of previously undiagnosed disease or undiagnosed severe glomerulonephritis requiring immunosuppression is possible, nearly all people detected by screening would have stage 3 chronic kidney disease unrelated to glomerulonephritis10; as such, management would focus on control of blood pressure through the use of angiotensin blockade, particularly in people with proteinuria.33 34 35 While it is possible that people with chronic kidney disease identified by screening would already be receiving angiotensin blockade, given that the target population consisted of people in whom glomerular filtration rate had not previously been measured, we assumed that this would not be the case.
We assumed that people found to have chronic kidney disease would receive an ACE (angiotensin converting enzyme) inhibitor or angiotensin blocker (if tolerated), with a target blood pressure of <130/80 mm Hg. We based the effectiveness of angiotensin blockade by conducting a focused literature search that identified relevant high quality meta-analyses and randomised trials in people with chronic kidney disease.33 35 36 37 38 39 40 41 42 As the effectiveness of angiotensin blockade at reducing end stage renal disease and death varies by diabetes and proteinuria status, we estimated the relative risk for these outcomes separately in these four subgroups (table 4).⇑
Costs related to screening
For people without chronic kidney disease, screening included a visit to a primary care physician and measurement of glomerular filtration rate, at a cost of about $C48 (table 5⇓). In patients found to have chronic kidney disease, the cost of screening was about $C83, accounting for an additional follow-up visit to a physician.
Costs related to managing chronic kidney disease with and without dialysis
The cost of managing people with chronic kidney disease was assumed to be the incremental costs resulting from a new diagnosis, including those of nephrologist care, the requirement for angiotensin blockade, and laboratory monitoring (table 5⇑). As admission to hospital in patients with stage 3-5 non-dialysis chronic kidney disease is usually because of comorbidity and because randomised trials of management of chronic kidney disease have not shown that interventions prevent admissions, we did not include the cost of admissions in our analysis. The annual cost of dialysis was estimated at $C64 218, assuming that nearly 81% of people were treated in haemodialysis centres.43 44 The cost of transplantation was estimated at $C84 531 for year one and $C35 545 for subsequent years.45
Valuing health benefits
Health benefits were measured in cases of end stage renal disease prevented and QALYs gained. We did not assume any difference in utility estimates for “diagnosed” and “undiagnosed” chronic kidney disease, as studies of antihypertensive therapy (the only additional treatment in people with diagnosed chronic kidney disease) suggest no significant impact on quality of life.46 We estimated utilities for relevant health states (dialysis and transplantation) based on contemporary Canadian studies.45 47
Sensitivity and scenario analyses
Sensitivity and scenario analyses were performed to determine the impact of uncertainty on the results of the model by varying all key parameters through plausible ranges. We conducted an additional scenario analysis examining the cost effectiveness of screening in people without diabetes but with known hypertension, reflecting an increased prevalence of chronic kidney disease in people with hypertension,10 as well as a doubling of the risk of progression to end stage renal disease among people with hypertension.48 As the cost of managing people with chronic kidney disease varies based on practice patterns, we also assessed the impact of using alternative cost estimates on results.
To address limitations in classic univariate sensitivity analysis, we performed Monte Carlo simulation, which allows for the simultaneous sensitivity analysis of all variables over their plausible range.49 50 It does so by replacing estimates of probabilities, utilities, and costs with specific probability distributions, which are based on the reported means and variances for each variable. Statistical distributions were created around all of the variables for which there was substantial uncertainty of measurement, including use of a β distribution for proportions (that is, the risk of end stage renal disease and mortality), use of a normal distribution for normally distributed variables (that is, certain costs, relative risks, and utility measures), and log normal distribution for skewed variables (that is, certain costs).
Compared with no screening, population based screening for chronic kidney disease was associated with an incremental cost of $C463 and a gain of 0.0044 QALYs per patient overall, representing a cost per QALY gained of $C104 900 (table 6⇓). In a cohort of 100 000 people, screening would be expected to reduce the number of people developing end stage renal disease over their lifetime from 675 to 657 (fig 1⇓). In subgroups of people aged <65 and ≥65, the cost per QALY gained associated with screening was $C200 100 and $C93 700, respectively (table 6).⇓
In subgroups of people with and without diabetes, the cost per QALY gained was $22 600 and $572 000, respectively. In a cohort of 100 000 people with diabetes, screening would be expected to reduce the number of people developing end stage renal disease over their lifetime from 1796 to 1741 (fig 1⇑). In people without diabetes with and without hypertension, the cost per QALY gained was $C334 000 and $C1 411 100, respectively (table 6).⇑
Tables 7⇓, 8⇓, and 9⇓ show the results of sensitivity analyses conducted for the model overall, while tables 10⇓ and 11⇓ show the results of sensitivity analyses on the effectiveness of angiotensin blockade in patients with and without diabetes, respectively. Sensitivity analyses showed that screening restricted to people with diabetes was generally associated with a cost per QALY gained of <$25 000, which was robust to changes in all plausible variables (tables 7-10). Screening in people without diabetes, however, was associated with a cost per QALY of around $50 000 only under scenarios where identification of chronic kidney disease would result in use of treatments that could improve survival by at least 15%, and when the risk of progression to end stage renal disease in the absence of treatment was substantially higher than in the base case (table 11).
Probabilistic sensitivity analysis
Figures 2 and 3⇓ ⇓ show scatterplots of the incremental cost effectiveness of population based screening compared with no screening overall, highlighting uncertainty in the analysis, which is largely attributed to uncertainty regarding the impact of angiotensin blockade on mortality in people without diabetes and with chronic kidney disease. Given the current evidence of benefit for angiotensin blockade on both mortality and end stage renal disease in people with diabetes and chronic kidney disease, screening of people with diabetes led to better clinical outcomes in all simulations. Our analysis indicates a 37% probability that targeted screening for chronic kidney disease among people with diabetes is associated with a cost per QALY gained of <$20 000 and a 99% probability that the cost per QALY gained is <$50 000.
Population based screening for chronic kidney disease is unlikely to be cost effective in unselected people or in those without diabetes. Although the prevalence of chronic kidney disease might be high enough to make screening worthy of consideration, particularly among older people,10 most people who would be found to have chronic kidney disease under a population based screening strategy would not have diabetes and would be likely to have non-proteinuric chronic kidney disease, relatively slow loss of kidney function, and low potential to benefit from angiotensin blockade.39 Therefore, the overall benefit of detecting and treating asymptomatic chronic kidney disease among people without diabetes is low. On the other hand, in people with diabetes, rates of progression to end stage renal disease are much higher, and there is strong evidence that angiotensin blockade reduces such progression 33 36 42 and improves survival.51 Given this, our study found that screening for chronic kidney disease in people with diabetes is associated with a cost per QALY in a range that is generally considered acceptable.52 53 54
Strengths and limitations
We modelled progression of chronic kidney disease and mortality stratified by age, diabetes, and presence or absence of proteinuria using a large cohort of patients with chronic kidney disease followed over five years and estimated the benefit of screening from high quality meta-analyses of angiotensin blockade. Given that previous analyses examining the cost effectiveness of screening have used urine based screening methods,12 13 and as this might miss a considerable proportion of people with chronic kidney disease,10 we used estimated glomerular filtration rate to screen for the presence of chronic kidney disease. One limitation of our analysis is that we did not compare our results to a strategy of screening with urinalysis or a combined strategy of glomerular filtration rate and urinalysis, though all patients detected as having chronic kidney disease were assumed to undergo urinalysis. Proteinuria is a powerful predictor of an increased risk of end stage renal disease and death in people with chronic kidney disease.55 While screening with estimated glomerular filtration rate might identify more people than screening with urinalysis, most people identified are at lower risk of adverse outcomes and do not seem to gain additional benefit from angiotensin blockade.39
Our analysis was limited by the validity and availability of randomised trials (and meta-analyses) reporting the effectiveness of managing patients with chronic kidney disease. In general though, our analyses were guided by estimates of effectiveness from high quality meta-analyses. Screening in people without diabetes was unattractive given that angiotensin blockade does not seem to reduce mortality in people with non-diabetic renal disease.38 39 When we assumed that angiotensin blockade reduced mortality by 16% among people without diabetes (consistent with results of a large trial in which most participants did not have chronic kidney disease37), the cost per QALY for screening people without diabetes became more attractive ($40 800), though it is unclear whether this is a reasonable assumption. It could also be argued that people who are identified as having chronic kidney disease would be more likely to receive statins, which have been proved to improve survival in people with mild to moderate chronic kidney disease.56 57 58 59 In our analysis, however, we assumed that people at risk of cardiovascular events would already be receiving statins or aspirin (even without screening for chronic kidney disease). We therefore modelled only the impact of adding angiotensin blockade. In scenarios where we modelled the impact of treating identified patients with statins as well (resulting in a reduction in mortality of 16%58 at an additional cost of $620 a year), then the cost per QALY for screening in people without diabetes was $53 700.
We assumed that the incidence of end stage renal disease and death, which was determined in a cohort of people with known chronic kidney disease, would be similar to a cohort of previously unidentified patients with chronic kidney disease who were detected through screening. Although this assumption might overestimate, or underestimate, the true risks, our results were robust to plausible changes in these variables. We also assumed that people with chronic kidney disease identified by screening would not be receiving angiotensin blockade, which seems reasonable given that they had not previously had their glomerular filtration rate measured. Of note, the results did not vary significantly when up to 20% of patients screened were already receiving angiotensin blockade. Finally, our results are most relevant to the Canadian setting. Given that our prevalence estimates are based on a large North American cohort study,10 our estimates of efficacy based on randomised trials conducted throughout the world, and that Canada has publicly funded healthcare and relative costs that are likely similar to Europe, we think that our results are likely to be valid in other countries.
Comparison with other studies
Previous studies have examined only the cost effectiveness of screening with urinalysis or urine based quantitative proteinuria.12 13 60 Like our study, these studies found that targeted screening of high risk groups (but not population based screening) might be cost effective.12 13 An analysis by Boulware et al suggested that screening for chronic kidney disease with measurement of proteinuria in patients with hypertension was associated with a cost per QALY of less than US $20 000.12 These analyses, however, assumed that angiotensin blockade would improve survival in people without diabetes,12 an assumption not supported by available data in patients with chronic kidney disease.38 39 A study examining the cost effectiveness of population based screening for urinary albumin excretion, with treatment of those noted to have albumin excretion >15 mg/day with fosinopril to prevent cardiovascular events, based on the PREVEND study cohort, reported a cost per life year gained of €16 700.60
Population based screening for chronic kidney disease has been advocated by some,4 15 16 and the National Kidney Foundation/Kidney Dialysis Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease have recommended screening for people at high risk of kidney disease, including those with diabetes and hypertension and aged over 60.1 14 Given that considerable resources would be required to set up a population based screening programme, our results are important. Our analyses suggest that screening for chronic kidney disease with estimated glomerular filtration rate is not cost effective in older people or in those without diabetes with hypertension but for people with diabetes is associated with a cost per QALY gained in the range of other funded interventions. We could not determine whether screening with urinalysis might be more cost effective overall or in certain subgroups compared with estimated glomerular filtration rate.
Our results suggest that population based screening for chronic kidney disease with assessment of estimated glomerular filtration rate is not cost effective overall or in subgroups of people without diabetes but with hypertension or in elderly people. Targeted chronic kidney disease screening with estimated glomerular filtration rate in people with diabetes is associated with a cost per QALY that is similar to other publicly funded interventions.
What is already known on this topic
Chronic kidney disease is common, and in many patients is asymptomatic and remains undiagnosed
Previous analyses have examined the cost effectiveness of screening with urinalysis rather than estimated glomerular filtration rate, the standard method for diagnosing chronic kidney disease
What this study adds
Population based screening for chronic kidney disease with estimated glomerular filtration rate assessment is not cost effective overall
Targeted screening of people with diabetes is associated with an acceptable cost per QALY in publicly funded healthcare systems.
Cite this as: BMJ 2010;341:c5869
Contributors: BM, SK, MT, and BH made substantial contributions to study conception and design, drafting, and critical revision. BM, SK, BH, FA, JD, and TCC were involved with data analysis and interpretation of data. BM is guarantor.
Funding: This study was supported by an operating grant from Alberta Heritage Foundation for Medical Research (now Alberta Innovates-Health Solutions). The infrastructure required for this research was also supported by the Alberta Heritage Foundation for Medical Research Interdisciplinary Team Grants Program (which supports the Interdisciplinary Chronic Disease Collaboration). The funding organisations played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. BM, MT, and BH are supported by New Investigator Awards from the Canadian Institutes of Health Research and MT, SK, BM, and BH are supported by salary awards from Alberta Innovates-Health Solutions.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: this project was supported by an operating grant from Alberta Heritage Foundation for Medical Research (now Alberta Innovates-Health Solutions) for the submitted work; no financial relationships with any companies that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: This study was approved by the Calgary Health Region ethics board.
Data sharing: No additional data available.
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