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.
“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]
The Discussion says accurate GFR assessment is clinically important and that GFR below the chronic kidney disease threshold for at least three months is a diagnostic criterion. It also says creatinine is affected by muscle mass and diet. It does not compare stable GFR values with transient biomarker elevations or discuss supplementation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGFR is considered the best overall indicator of renal function in both healthy individuals and patients with kidney disease.
“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]
The Discussion (page not available) says accurate GFR assessment is essential for detecting and managing kidney disease, and the introductory text says kidney-function assessment is routine care for adults. The paper does not call GFR the best overall indicator or explicitly make that comparison for both healthy individuals and patients with kidney disease. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAdding cystatin C to serum creatinine improves the accuracy of race-neutral eGFR equations.
“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]
The Results (Performance of New Equations in the Validation Data Set; page unavailable) report that the creatinine–cystatin C equation was more accurate than the creatinine-only equation. But the Results (Formulation of Equations; page unavailable) say adding race improved the combined equation’s performance, so the paper does not establish the claimed accuracy improvement specifically for race-neutral equations. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCyC has been validated as a marker of renal function in multiple large clinical cohorts comprising patients without acute disease.
“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]
The Methods (Study Design and Data Sources; page not provided) describe development and validation using cystatin C data from 18 studies involving 6,471 participants. The paper does not state that those cohorts comprised patients without acute disease, so that population qualifier is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThis helps explain the validated utility of CyC as a marker of renal function in patients without acute illness.
“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]
The paper’s introduction reports validation of a cystatin C–based equation for estimating GFR, and the Discussion describes its potential use in assessing chronic kidney disease. It does not establish that the validation specifically applies to patients without acute illness; that population qualifier is unsupported. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Associations between serum NfL and renal function were investigated using linear or logistic regression models adjusted for age, sex, and body mass index.
“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]
For the association between protein levels and liver function enzymes, eGFR, smoking status, the top 20 most prevalent diseases, and number of medications, regression models were individually fitted with age, sex and BMI along with technical factors as covariates.
“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]
eGFR was calculated using the CKD-EPI creatinine and cystatin C formula.
“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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12. Children and Adolescents: Standards of Medical Care in Diabetes—2018
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- 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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