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The association between estimated glomerular filtration rate (eGFR) and both death and end-stage renal disease (ESRD) strengthened significantly when cystatin C measurement was added to creatinine assessment, a meta-analysis showed.
In general-population cohorts, the proportion of people with eGFR <60 mL/min/1.73 m2 increased by 41% with the addition of cystatin C-based assessment of renal function versus creatinine alone.
In addition, reclassification to higher eGFR values was associated with a reduced risk of all-cause mortality, cardiovascular death, and ESRD, Josef Coresh, MD, PhD, of the Chronic Kidney Disease Prognosis Consortium Data Coordinating Center in Baltimore, and co-authors reported in the Sept. 5 issue of the New England Journal of Medicine.
"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," the authors concluded.
"We also found that the risk of death was increased when values for both cystatin C-based eGFR and eGFR based on combined creatinine cystatin C measurements were below a threshold of approximately 85 mL/min/1.73 m2," they added.
The results confirm the long-recognized ability of cystatin C to improve eGFR assessment, said Robert Gaston, MD, of the University of Alabama at Birmingham. However, two obstacles could limit the findings' generalizability.
"Cystatin C, compared with the current standards which are based on serum creatinine, is very expensive," Gaston told MedPage Today. "It's also not widely available, and up to this point in time, it has largely been used as a research tool."
Calculation of eGFR has long represented the clinical standard for evaluating kidney function. Although eGFR thresholds are used in classification and staging, values are estimated on the basis of serum creatinine, which has limitations for risk prediction, the authors noted in their introduction.
Several studies have suggested that combining cystatin C and serum creatinine improves risk classification of patients with respect to death, cardiovascular disease, and ESRD. However, the lack of a reference standard for cystatin C has posed an obstacle to comparison of results across the different studies, the authors continued.
Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKDEC) developed an international reference standard for cystatin C and published improved equations for estimating GFR. The developments afforded an opportunity to perform a meta-analysis of 16 studies involving diverse patient populations.
The analysis included 11 general-population studies with a total of 90,750 participants and five studies involving 2,960 patients with chronic kidney disease (CKD). Using the CKDEC equations, the authors calculated eGFR by serum creatinine, cystatin C, or the combination.
For the general-population cohorts, investigators computed pooled hazard ratios associated with a reference point of 95 mL/min/1.73 m2 for all-cause and cardiovascular mortality and 65 mL/min/1.73 m2 for ESRD. The reference point for patients with CKD was 50 mL/min/1.73 m2.
The primary outcomes were all-cause mortality, cardiovascular mortality, and ESRD.
For the general-population cohorts, mean values for creatinine, cystatin C, and the combination were 85, 85, and 84 ml/min/1.73 m2, respectively. Mean values for the patients with CKD were 38, 39, and 38 mL/min/1.73 m2.
Using the creatinine-based eGFR threshold of <60 mL/min/1.73 m2 to define CKD, the authors found that 9.7% of the general-population participants had CKD by creatinine alone, 13.7% by cystatin C alone, and 10% by the combination.
During a mean follow-up of 7.7 years, 13.6% of general-population participants died. The risk of death began to increase with eGFR below the reference point and became statistically higher compared with the reference point at a threshold of 88 mL/min/1.73 m2. Corresponding values for creatinine-based and combination-based estimates were 59 and 83 mL/min/1.73 m2. In the CKD cohorts, cystatin C and the combination had more linear associations with all-cause mortality than did creatinine alone.
Overall, net reclassification improvement for all-cause mortality by use of cystatin C was 0.21 (95% CI 0.17-0.26, P<0.001).
"In the general-population cohorts, across all the creatinine-based eGFR categories, reclassification to a lower eGFR was associated with a significantly higher adjusted risk of death," the authors reported.
"Conversely, across all categories of creatinine-based eGFR values, reclassification to a higher eGFR with the measurement of cystatin C was associated with a reduction in the adjusted risk of death," they added.
Results were similar for cardiovascular mortality. Risk increased significantly at thresholds of 69, 86, and 83 mL/min/1.73 m2 for creatinine, cystatin, and the combination.
The outcome of ESRD was based on two general-population cohorts (37,872 participants) and 2,955 participants in the CKD studies (mean follow-up 9.3 years). The authors found that risk of progression to ESRD was similar for the three methods of estimating GFR and similar between the general-population and CKD cohorts.
Echoing the observations of Gaston, the authors of an accompanying editorial pointed out that use of cystatin C to assess eGFR will require action on the part of clinical laboratories, but they expressed optimism about laboratories' adoption of the test.
"The increased use of cystatin C evaluation in such patients, and the current findings ... will probably push clinical laboratories to incorporate this kidney biomarker," wrote Julie R. Ingelfinger, MD, deputy editor of NEJM, and Philip A. Marsden, MD, of the University of Toronto. "The study ... effectively shows that the cystatin C-based eGFR offers the best means of predicting rates of death and end-stage renal disease across diverse populations."
The study was supported by the National Kidney Foundation, which receives support from Abbott and Amgen.
Coresh disclosed relationships with Amgen and Merck. One or more coauthors disclosed relationships with Gilead, Pharmalink, Amgen, and Novartis
Ingelfinger and Marsden reported no relevant disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
New England Journal of MedicineSource Reference: Shlipak MG et al "Cystatin C versus creatinine in determining risk based on kidney function" N Engl J Med 2013; 369: 932-943.
New England Journal of MedicineSource Reference: Ingelfinger JR, Marsden MA "Estimated GFR and risk of death -- Is cystatin C useful?" N Engl J Med 2013; 369: 974-975.