Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality

Study Questions:

Would combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) improve identification of risks associated with chronic kidney disease (CKD) compared with creatinine alone?


The study cohort involved 26,643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into eight groups, defined by estimated glomerular filtration rate (eGFR) determined by creatinine and by cystatin C of either <60 or ≥60 ml/min/1.73 m2 and ACR of either <30 or ≥30 mg/g. The primary outcomes measured were the incidence of end-stage renal disease and all-cause mortality, with a median follow-up of 4.6 years.


The demographics of this prospective cohort (n = 26,643) include mean age of 65 years, 40% black, and 54% women; also, 1,940 died and 177 developed end-stage renal disease. Among those without CKD as defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0-5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2-4.7) for those with CKD defined by creatinine and cystatin C; and 5.6 (95% CI, 3.9-8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 16% (n = 3,863) had CKD detected by ACR or cystatin C. When compared with participants who did not have CKD by any measure, the hazard ratios (HRs) for mortality were 1.7 (95% CI, 1.4-1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9-2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4-3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1,000 person-years; 95% CI, 28.7-40.5 vs. 0.33 per 1,000 person-years; 95% CI, 0.05-2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure, but detected by both ACR and cystatin C (rate per 1,000 person-years, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (p < 0.001) and for end-stage renal disease was 6.4% (p < 0.001) after adding eGFR, cystatin C in fully adjusted models with eGFR, creatinine, and ACR.


The study authors concluded that adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.


Important considerations when evaluating and applying the results of diagnostic tests include: 1) Are the results valid? And, 2) Will the results help me in caring for my patients? (Heart Fail Clin 2009;5:ix-xii). This study indeed suggests that the three biomarkers (creatinine, cystatin C, and ACR), when used as a package compared to creatinine alone, enhance the ability to predict risk in CKD. Given the challenges of managing patients with cardiorenal syndrome, it would be interesting to determine whether combining these three ‘renal’ biomarkers with ‘cardiac’ biomarkers such as B-type natriuretic peptide, troponins, and tissue Doppler would enhance the ability to predict risk and manage patients with cardiorenal syndrome (J Am Coll Cardiol 2008;52:1527-39).

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Follow-Up Studies, Diagnostic Tests, Routine, Kidney Function Tests, Biological Markers, Cardio-Renal Syndrome, Kidney Failure, Chronic, Glomerular Filtration Rate, Creatinine, Renal Insufficiency, Chronic, Cystatin C

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