Cystatin C versus creatinine in determining risk based on kidney function

Abstract

Background: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.

Methods: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.

Results: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.

Conclusions: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

Figure 1. Distribution of the Estimated Glomerular Filtration Rate (eGFR) as Calculated with the Measurement of Creatinine, Cystatin C, or Both in 11 General-Population Cohort Studies

A total of 90,750 participants were included in the meta-analysis of 11 studies, with a kernel-density estimate showing the smoothed frequency for each 1 ml of the eGFR value. The vertical lines indicate current clinical thresholds for eGFR categories.

Figure 2. Adjusted Hazard Ratios for the Three Study Outcomes in the General-Population Cohort Studies

Shown are hazard ratios for death from any cause (Panel A), death from cardiovascular causes (Panel B), and end-stage renal disease (Panel C), according to whether the eGFR was calculated with the measurement of creatinine, cystatin C, or both. The graphs show associations by plotting the adjusted hazard ratio versus the reference points, which are indicated by black diamonds (at 95 ml per minute per 1.73 m²of body-surface area for death from any cause and death from cardiovascular causes and at 65 ml per minute per 1.73 m²for end-stage renal disease). The hazard ratios were adjusted for age, sex, race, body-mass index, systolic blood pressure, total cholesterol, presence or absence of a history of cardiovascular disease, smoking status, presence or absence of diabetes, and level of albuminuria. In each panel, solid circles indicate that the adjusted hazard ratio at the indicated eGFR level was significant, as compared with the reference point. For death from any cause, the meta-analysis included 11 general-population cohorts with 90,750 participants, of whom 12,351 died during follow-up. For death from cardiovascular causes, the meta-analysis included 10 general-population cohorts with 64,010 participants, of whom 3193 died from cardiovascular causes during follow-up. For incident end-stage renal disease, the meta-analysis included 2 general-population cohorts with 37,872 participants, in 357 of whom end-stage renal disease occurred during follow-up. Because there were fewer events of end-stage renal disease than deaths, several eGFR levels had nonsignificant associations with the outcome, despite point estimates that were similar to those for other eGFR levels that had significant associations with end-stage renal disease.

Figure 3. Net Reclassification Improvement in eGFR Based on the Measurement of Cystatin C, as Compared with Creatinine-Based eGFR, for the Three Study Outcomes in the 16 Study Cohorts

Shown are values for net reclassification improvement, a measure of the overall improvement in the association between the reclassified eGFR based on the measurement of cystatin C, as compared with the creatinine-based eGFR, and the study outcomes of death from any cause, death from cardiovascular causes, and end-stage renal disease. The size of the squares is proportional to the inverse of the variance of the net reclassification improvements. The horizontal line indicates the 95% confidence interval. A similar analysis of the net reclassification improvement in eGFR as calculated with the measurement of both creatinine and cystatin C (combination group) is provided in Figure S4 in the Supplementary Appendix. The full study names are provided in Table 1. CKD denotes chronic kidney disease.