Reporter: Aviva Lev-Ari, PhD, RN
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C
Lesley A. Inker, M.D., Christopher H. Schmid, Ph.D., Hocine Tighiouart, M.S., John H. Eckfeldt, M.D., Ph.D., Harold I. Feldman, M.D., Tom Greene, Ph.D., John W. Kusek, Ph.D., Jane Manzi, Ph.D., Frederick Van Lente, Ph.D., Yaping Lucy Zhang, M.S., Josef Coresh, M.D., Ph.D., and Andrew S. Levey, M.D. for the CKD-EPI Investigators
N Engl J Med 2012; 367:20-29 July 5, 2012
BACKGROUND
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.
METHODS
Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.
RESULTS
Mean measured GFRs were 68 and 70 ml per minute per 1.73 m2 of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m2 with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m2 with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m2, respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m2, the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m2 or greater than or equal to 60 ml per minute per 1.73 m2 (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 as having a GFR of 60 ml or higher per minute per 1.73 m2.
CONCLUSIONS
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
Supported by grants (UO1 DK 053869, UO1 DK 067651, and UO1 DK 35073) from the National Institute of Diabetes and Digestive and Kidney Diseases.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was updated on July 5, 2012, at NEJM.org.
We thank Dr. Aghogho Okparavero for providing assistance with communications and manuscript preparation. (Additional acknowledgments are provided in the Supplementary Appendix.)
SOURCE INFORMATION
From Tufts Medical Center, Boston (L.A.I., C.H.S., H.T., Y.L.Z., A.S.L.); the University of Minnesota, Minneapolis (J.H.E.); the University of Pennsylvania School of Medicine, Philadelphia (H.I.F.); the University of Utah, Salt Lake City (T.G.); National Institutes of Health, Bethesda, MD (J.W.K.); Johns Hopkins University, Baltimore (J.M., J.C.); and Cleveland Clinic Foundation, Cleveland (F.V.L.).
Address reprint requests to Dr. Inker at the Division of Nephrology, Tufts Medical Center, 800 Washington St., Box 391, Boston, MA 02111, or at linker@tuftsmedicalcenter.org.
Additional investigators in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are listed in the Supplementary Appendix, available at NEJM.org.
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I’m not convinced of the study, regardless of it being published in NEJM.
1119 participants from 5 different studies in which GFR had been measured – the measurement of GFR is prone to more errors than any of the equations, and could not be carried out in most hospitals because of urine specimen collection errors.
Bette Seamonds was strongly interested in the cyclosporin C as long as 8 years ago. There was not much done then, but she saw features that noone else saw, and thought that it would replace calculated ClCr. I knew that it was cost to run and was on one instrument with exclusive rights.
I’m not sure if the study was wasted, except it really is a move forward. The College of American Pathologists were opposed to the eGFR, even as it was mandated in state after state. The issue was that it was not accurate at higher eGFR, in which case, it made little difference. It needs to be highly accurate at Stage 1,2,3. This study indicates improvement in the lower ranges, but the CV gets to be a nightmare at below 20 ml/min/1.73.
It is correct to validate and cross-validate. The problems with measured creatinine by the rate Jaffe (this was the best when introduced by Beckman, by Nathan Gochman) are more disconcerting than what you get with Cystatin-C. In the end, one test adjusted for the failure of the other.
The equation requires adjustments for age, gender, and race. The assumption for the race correction is that negro men are more muscular. It is a problem today with race being inaccurate in the medical record, and the mix of black race in the populations would have to be adjusted before doing a meta-analysis. Beyond that, we have no way of really knowing the truth in our diverse population, with white, black, hispanic, Asian, Indian subcontinent, native americans, and substantial intermarriage. Then throw in obesity to top it of, possibly with sarcopenia.
Cyclosporin-C is still not widely available, and I couldn’t predict when that will be the case.
May I suggest that this comment will be submitted by yourself to the Editor of NEJM to be published there ad a Discussion.
When I used Werner et al in NEJM September 2005, for my research, there was in December 2005 issue a big discussion about this study.