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

Abstract

Context: A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.

Objective: To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.

Design, setting, and participants: Prospective cohort study involving 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 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m(2) and ACR of either <30 or ≥30 mg/g.

Main outcome measures: All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.

Results: Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26,643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD 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, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the 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 1000 person-years; 95% CI, 28.7-40.5 vs 0.33 per 1000 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 1000 person-years, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (P < .001) and for end-stage renal disease was 6.4% (P < .001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.

Conclusion: Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Warnock reported that he is a consultant for Amgen Corp and has received research support from Amgen. Dr Cushman reported receiving research support from Amgen. Dr McClellen reported receiving research support from Amgen. Otherwise, no other conflicts of interest were reported.

Figures

Figure 1. Chronic Kidney Disease Definitions Using a Triple-Marker Approach of Creatinine, Cystatin C, and Albumin-to-Creatinine Ratio

The blue lines indicate normal results. Creatinine and cystatin C-based data refer to creatinine-based and cystatin C–based estimated glomerular filtration rate, mL/min/1.73 m2, respectively. ACR indicates albumin-to-creatinine ratio.

Figure 2. Association of Chronic Kidney Disease Definitions With All-Cause Mortality and End-Stage Renal Disease

Error bars indicate 95% confidence intervals; ACR, albumin-to-creatinine ratio. aNo chronic kidney disease (CKD) from all biomarker measures: 0.08 (95% CI 0.04–0.17) per 1000 person-years.