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Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C
Open accessAbstract
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 m(2) 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 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) 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 m(2), 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 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (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 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). 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.).
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“Stable GFR values are clinically more important than transient elevations in serum creatinine or other biomarkers, which may be influenced by extrarenal factors such as muscle mass, diet, or supplementation [1, 2].”
From Effect of creatine supplementation on kidney function: a systematic review and meta-analysis (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“GFR is considered the best overall indicator of renal function in both healthy individuals and patients with kidney disease.”
From Effect of creatine supplementation on kidney function: a systematic review and meta-analysis (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Adding cystatin C to serum creatinine improves the accuracy of race-neutral eGFR equations (476,477)”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [477]
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In the citing paper
“CyC has been validated as a marker of renal function in multiple large clinical cohorts54 comprising patients without acute disease.”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [54]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“helping to explain the validated utility of CyC as a marker of renal function in patients without acute illness.54”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [54]
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“Associations between serum NfL and renal function (serum creatinine, glomerular filtration rate estimated via the CKD-EPI equation (30), and glomerular filtration rate ≤ 60 mL/min/1.73 m2 as indicator of kidney disease) were investigated using linear or logistic regression models [adjusted for age, sex, and body mass index (31)], respectively.”
From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [30]
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“For the association between protein levels and liver function enzymes log[ALT] (field 30620); log[AST] (field 30650); estimated glomerular filtration rate (eGFR) calculated using the combined creatinine-cystatin C equation from the CKD-EPI study 56 , with relevant parameters obtained from fields 30700 (creatinine), 30720 (cystatin C), 21000 (ethnicity) in addition to age and sex; smoking status (f”
From Plasma proteomic associations with genetics and health in the UK Biobank (2023) · cites this paper as [56]
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“Reductions in body weight with tirzepatide would be expected to reduce skeletal muscle to some extent, which could influence creatinine dependent of changes in kidney function, and for this reason, we calculated eGFR using cystatin C in place of creatinine.”
In the citing paper
“Estimated glomerular filtration rate (eGFR) was calculated according to the CKD-EPI creatinine and cystatin C formula20, with CKD defined as eGFR <60 ml/min/1.73m2 (CKD stage 3 or beyond).”
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Metadata
- Authors
- Inker, L. A., Schmid, C. H., Tighiouart, H., Eckfeldt, J. H., Feldman, H. I., Greene, T., Kusek, J. W., Manzi, J., Van Lente, F., Zhang, Y. L., Coresh, J., & Levey, A. S.
- Affiliations
- Tufts Medical Center (US)
- University of Minnesota (US)
- University of Pennsylvania (US)
- University of Utah (US)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-07-05
- Volume
- 367
- Issue
- 1
- Pages
- 20-29
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4398023
- OpenAlex
- W2118625269
- Semantic Scholar
- 864b8e44b48f701b2cf2f7609bfcb54c52d74233
- Cited by
- 4,102
- References
- 29
- Citations by year
- 2026: 232 · 2025: 357 · 2024: 353 · 2023: 398 · 2022: 374 · 2021: 356 · 2020: 345 · 2019: 286 · 2018: 273 · 2017: 277 · 2016: 240 · 2015: 224 · 2014: 201 · 2013: 147 · 2012: 35
- FWCI
- 152.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u01dk053869-08, UL1TR000439)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK053869, U01DK067651, U01DK035073)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- glomerular filtration rate estimation, cystatin C, serum creatinine, chronic kidney disease, estimating equations, overdiagnosis
- MeSH terms
- Adult, Aged, Creatinine, Cross-Sectional Studies, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Biomarkers, Renal Insufficiency, Chronic, Cystatin C, Mathematical Concepts
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