Research Article: The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study

Date Published: October 10, 2017

Publisher: Public Library of Science

Author(s): Adam Shardlow, Natasha J. McIntyre, Simon D. S. Fraser, Paul Roderick, James Raftery, Richard J. Fluck, Christopher W. McIntyre, Maarten W. Taal, Giuseppe Remuzzi

Abstract: BackgroundTo reduce over-diagnosis of chronic kidney disease (CKD) resulting from the inaccuracy of creatinine-based estimates of glomerular filtration rate (GFR), UK and international guidelines recommend that cystatin-C-based estimates of GFR be used to confirm or exclude the diagnosis in people with GFR 45–59 ml/min/1.73 m2 and no albuminuria (CKD G3aA1). Whilst there is good evidence for cystatin C being a marker of GFR and risk in people with CKD, its use to define CKD in this manner has not been evaluated in primary care, the setting in which most people with GFR in this range are managed.Methods and findingsA total of 1,741 people with CKD G3a or G3b defined by 2 estimated GFR (eGFR) values more than 90 days apart were recruited to the Renal Risk in Derby study between June 2008 and March 2010. Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, we compared GFR estimated from creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys) at baseline and over 5 years of follow-up. We analysed the proportion of participants with CKD G3aA1 reclassified to ‘no CKD’ or more advanced CKD with the latter two equations. We further assessed the impact of using cystatin-C-based eGFR in risk prediction equations for CKD progression and all-cause mortality and investigated non-GFR determinants of eGFRcys. Finally, we estimated the cost implications of implementing National Institute for Health and Care Excellence (NICE) guidance to use eGFRcys to confirm the diagnosis in people classified as CKD G3aA1 by eGFRcreat. Mean eGFRcys was significantly lower than mean eGFRcreat (45.1 ml/min/1.73 m2, 95% CI 44.4 to 45.9, versus 53.6 ml/min/1.73 m2, 95% CI 53.0 to 54.1, P < 0.001). eGFRcys reclassified 7.7% (50 of 653) of those with CKD G3aA1 by eGFRcreat to eGFR ≥ 60 ml/min/1.73 m2. However, a much greater proportion (59.0%, 385 of 653) were classified to an eGFR category indicating more severe CKD. A similar pattern was seen using eGFRcreat-cys, but lower proportions were reclassified. Change in eGFRcreat and eGFRcys over 5 years were weakly correlated (r = 0.33, P < 0.001), but eGFRcys identified more people as having CKD progression (18.2% versus 10.5%). Multivariable analysis using eGFRcreat as an independent variable identified age, smoking status, body mass index, haemoglobin, serum uric acid, serum albumin, albuminuria, and C reactive protein as non-GFR determinants of eGFRcys. Use of eGFRcys or eGFRcreat-cys did not improve discrimination in risk prediction models for CKD progression and all-cause mortality compared to similar models with eGFRcreat. Application of the NICE guidance, which assumed cost savings, to participants with CKD G3aA1 increased the cost of monitoring by £23 per patient, which if extrapolated to be applied throughout England would increase the cost of testing and monitoring CKD by approximately £31 million per year. Limitations of this study include the lack of a measured GFR and the potential lack of ethnic diversity in the study cohort.ConclusionsImplementation of current guidelines on eGFRcys testing in our study population of older people in primary care resulted in only a small reduction in diagnosed CKD but classified a greater proportion as having more advanced CKD than eGFRcreat. Use of eGFRcys did not improve risk prediction in this population and was associated with increased cost. Our data therefore do not support implementation of these recommendations in primary care. Further studies are warranted to define the most appropriate clinical application of eGFRcys and eGFRcreat-cys.

Partial Text: The use of serum creatinine concentration to estimate glomerular filtration rate (GFR) has become widely adopted as the principal test for the diagnosis of chronic kidney disease (CKD). However, the dependence of serum creatinine on muscle mass and the tendency of creatinine-based equations to underestimate GFR at values close to the diagnostic threshold of 60 ml/min/1.73 m2 has raised concerns about the risk of over-diagnosis in otherwise healthy older populations when relying on this method and has prompted calls to identify more reliable endogenous filtration markers for the estimation of GFR [1]. Concern has also been expressed that the use of GFR estimated from creatinine but not corrected for age may result in under-diagnosis of CKD in younger people [2]. Cystatin C, a protein that normally crosses the glomerular filtration barrier, has been proposed as an alternative endogenous marker. Cystatin C is produced by all nucleated cells, and is therefore less influenced by muscle mass than creatinine [1,3,4]. Though estimation of GFR from cystatin C alone was found to be no more accurate than creatinine, estimated GFR (eGFR) derived from a combined creatinine and cystatin C equation was more accurate and showed greater precision than eGFR derived from creatinine or cystatin C alone [5].

Our results indicate that for the majority with CKD stage 3 (confirmed by 2 eGFRcreat values) in primary care, use of eGFRcys or eGFRcreat-cys results in lower estimates of GFR than eGFRcreat. The use of eGFRcys as recommended by NICE to confirm an eGFRcreat-based diagnosis of CKD G3aA1 resulted in reclassification of 7.7% as not having CKD, but a far greater proportion (59.0%) were reclassified as having more advanced CKD (G3b–G5). Thus, in a primary care setting, the potential benefit of reducing over-diagnosis of CKD with eGFRcys would be eliminated by the unintended consequence of greater reclassification to more advanced CKD requiring more frequent monitoring and increased referrals to secondary care. Additionally, the use of eGFRcys did not improve discrimination in risk prediction models in a primary care population. Overall estimated costs would be increased by £23 per patient with eGFRcys and £8 per patient with eGFRcreat-cys.



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