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. 2025 Nov 7:e2517578.
doi: 10.1001/jama.2025.17578. Online ahead of print.

Discordance in Creatinine- and Cystatin C-Based eGFR and Clinical Outcomes: A Meta-Analysis

Michelle M Estrella  1 , Shoshana H Ballew  2 , Yingying Sang  2 , Morgan E Grams  3 , Josef Coresh  2 , Aditya Surapaneni  3 , Natalia Alencar de Pinho  4 , Johan Ärnlöv  5   6 , Hermann Brenner  7 , Juan-Jesus Carrero  8   9 , Teresa K Chen  1 , Debbie L Cohen  10 , Mary Cushman  11 , Ron T Gansevoort  12 , Shih-Jen Hwang  13   14 , Lesley A Inker  15 , Joachim H Ix  16   17 , Keiko Kabasawa  18   19 , Tsuneo Konta  20 , Jennifer S Lees  21   22 , Kevan R Polkinghorne  23   24 , Michael G Shlipak  1 , Robin W M Vernooij  25   26 , David C Wheeler  27 , Ashok Kumar Yadav  28 , Andrew S Levey  15 , Kai-Uwe Eckardt  29   30 ; Chronic Kidney Disease Prognosis Consortium Investigators and Collaborators
Collaborators, Affiliations

Discordance in Creatinine- and Cystatin C-Based eGFR and Clinical Outcomes: A Meta-Analysis

Michelle M Estrella et al. JAMA. .

Abstract

Importance: Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear.

Objectives: To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes.

Data sources: Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC).

Study selection: Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement.

Data extraction and synthesis: Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis.

Main outcomes and measures: The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy.

Results: A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]).

Conclusions and relevance: In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Estrella reported receiving grants from Bayer; personal fees from Boehringer Ingelheim outside the submitted work; and being an executive board member of the National Kidney Foundation (NKF). Dr Grams reported receiving grants from the National Institutes of Health (NIH) and NKF during the conduct of the study; travel support from KDIGO (Kidney Disease: Improving Global Outcomes), American Society of Nephrology, and Kidney Research Institute (KRI); serving on the scientific advisory boards of KRI and NKF; and serving on the community advisory board of US Renal Data System (USRDS) outside the submitted work. Dr Alencar de Pinho reported receiving grants to her institution from Agence nationale de la recherche (ANR-IA-COH-2012/3731), Ministry of Higher Education and Research (2023-1322), GSK, Boehringer Ingelheim France, Novo Nordisk, Fresenius Medical Care, and Vifor France outside the submitted work. Dr Ärnlöv reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Astellas, and Novartis outside the submitted work. Dr Cohen reported receiving funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; 5U01DK060984-25). Dr Kabasawa reported receiving Niigata Prefecture funding and grants from Japan Society for the Promotion of Science KAKENHI (17K15850, 23K09737, 23K07694) during the conduct of the study. Dr Konta reported receiving personal fees from Boehringer Ingelheim Japan, AstraZeneca Japan, Daiichi Sankyo, Pfizer, Chugai Pharmaceutical, Bayer, Mitsubishi Tanabe Pharma, Novartis, Mochida Pharmaceutical, Ono Pharmaceutical, MSD, Sanwa Kagaku Kenkyusho, Eisai, Kowa, Kyowa Kirin, and Fuji Yakuhin outside the submitted work. Dr Lees reported receiving personal fees from AstraZeneca and Boehringer Ingelheim outside the submitted work; and a Wellcome Trust Early-Career Award (301005/Z/23/Z). Dr Shlipak reported receiving grants paid to his institution from NIH during the conduct of the study; grants paid to his institution from NIH and Bayer; personal fees from Cardiovascular Health Study, Bayer, Boehringer Ingelheim, AstraZeneca, and Hagens Berman International Law Firm outside the submitted work; and serving as chair of the board for Northern California Institute for Research and Education. Dr Wheeler reported receiving personal fees from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Eledon, Pathalys, ProKidney, Vifor, and Vertex outside the submitted work. Dr Levey reported receiving grants to his institution from NIH and royalties from UpToDate outside the submitted work. Dr Eckardt reported receiving grants from Evotec and Travere; and personal fees from Akebia, AstraZeneca, Boehringer Ingelheim, CSL Behring, GSK, Medice, Novartis, Novo Nordisk, Vera, Vicore, and Bayer outside the submitted work. No other disclosures were reported.

Comment in

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