Original Investigation 

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

Michelle M. Estrella, Shoshana H. Ballew, Yingying Sang, et al

JAMA Published Online: November 7, 2025

doi: 10.1001/jama.2025.17578

Key Points

Question  Do individuals with a cystatin C–based estimated glomerular filtration rate (eGFRcys) value at least 30% lower than their creatinine-based estimated glomerular filtration rate (eGFRcr) have higher rates of mortality, cardiovascular events, and kidney failure compared with individuals whose eGFRcys is not at least 30% lower than their eGFRcr?

Findings  In this individual participant–level meta-analysis of 821 327 participants from 23 cohorts, an eGFRcys at least 30% lower than eGFRcr was associated with higher mortality, cardiovascular events, and kidney failure with replacement therapy, compared with individuals whose eGFRcys was not at least 30% lower than their eGFRcr.

Meaning  An eGFRcys value at least 30% lower than eGFRcr was associated with higher rates of mortality, cardiovascular events, and kidney failure with replacement therapy.

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.