Highlight
– In an individual-level meta-analysis from the Chronic Kidney Disease Prognosis Consortium (CKD-PC), 11% of outpatients and 35% of hospitalized patients had cystatin C–based eGFR (eGFRcys) at least 30% lower than creatinine-based eGFR (eGFRcr).
– Among outpatients, this large negative eGFR difference was associated with substantially higher rates of all-cause mortality (HR 1.69), cardiovascular mortality (HR 1.61), atherosclerotic events (HR 1.35), heart failure (HR 1.54) and kidney failure requiring replacement therapy (HR 1.29).
Background
Estimated glomerular filtration rate (eGFR) is the cornerstone metric for assessing kidney function in clinical practice. Historically, eGFR has been calculated from serum creatinine (eGFRcr) and, more recently, from serum cystatin C (eGFRcys) or combinations of both. Creatinine-based equations (eg, CKD-EPI) remain widely used because of accessibility and clinician familiarity, but creatinine is influenced by muscle mass, diet, and certain drugs. Cystatin C is less dependent on muscle mass and, in some settings, may better reflect true GFR or capture non-GFR risk signals related to inflammation or catabolic states.
Discordance between eGFRcr and eGFRcys is common in everyday practice. Prior single-cohort studies suggested that when eGFRcys is lower than eGFRcr, patients may have higher risk of adverse outcomes; however, the prevalence, determinants and strength of association across diverse settings were uncertain.
Study design
The investigators performed an individual-level meta-analysis using data from the Chronic Kidney Disease Prognosis Consortium (CKD-PC). Participants were included if they had concurrent measurements of serum creatinine and serum cystatin C and outcome ascertainment. The pooled dataset included 821,327 individuals from 23 outpatient cohorts and 39,639 individuals from 2 inpatient cohorts.
The primary exposure was a large negative eGFR difference (eGFRdiff), defined a priori as eGFRcys ≥30% lower than eGFRcr. The reference category was eGFRdiff between −30% and +30%. Outcomes evaluated included all-cause mortality (primary outcome), cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. Analyses used time-to-event models and were adjusted for key covariates; follow-up averaged 11 (±4) years among outpatients.
Key findings
Population characteristics: Outpatient participants had a mean age of 59 years, were 48% female, with 13.5% diabetes and 40% hypertension. Inpatient participants were older (mean age 67 years), more often male (69%), and had higher burdens of diabetes and hypertension.
Prevalence of discordance
Among outpatients, 11% had a large negative eGFRdiff (range across cohorts 3%–50%). Among inpatients, the prevalence was markedly higher at 35%, reflecting acute illness and physiologic perturbations common during hospitalization.
Association with adverse outcomes (outpatients)
At a mean follow-up of 11 years, individuals with eGFRcys at least 30% lower than eGFRcr had substantially higher unadjusted event rates and adjusted hazard ratios compared with those with concordant eGFR (eGFRdiff between −30% and +30%). Key results:
- All-cause mortality: 28.4 vs 16.8 events per 1000 person-years; adjusted 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).
- Kidney failure with replacement therapy: 2.7 vs 2.1 per 1000 PY; HR 1.29 (95% CI, 1.13–1.47).
In short, large negative eGFRdiff identified a subgroup at meaningfully higher cardiovascular, mortality and kidney failure risk, even after adjustment for traditional risk factors and baseline eGFRcr.
Patterns and determinants of discordance
The paper reports higher prevalence of large negative eGFRdiff in hospitalized patients and variability across cohorts. Although full covariate analyses are presented in the original report, established non-GFR determinants likely contribute: reduced muscle mass (low creatinine production) can spuriously elevate eGFRcr relative to true GFR; acute or chronic inflammation, thyroid dysfunction, corticosteroid therapy, smoking, obesity and malignancy can alter cystatin C levels. Age and sex distributions and differing laboratory methods may also influence observed discordance.
Absolute versus relative risk
Hazard ratios indicate a 29% to 69% relative increase in outcome hazard across endpoints. Absolute event rates were modest for kidney replacement therapy (2.7 vs 2.1 per 1000 PY) but substantial for mortality and cardiovascular events, reflecting the prognostic relevance of the discordance for long-term outcomes.
Expert commentary
This large pooled analysis provides compelling evidence that a substantial minority of outpatients — and a majority of inpatients — have clinically meaningful discordance between creatinine- and cystatin C–based eGFR, and that when cystatin C yields a lower eGFR by ≥30% the patient faces higher risk for death, cardiovascular events and progression to kidney failure. Several clinical implications follow.
Interpretation and biological plausibility
There are two non–mutually exclusive explanations for the observed associations. First, eGFRcys may more closely reflect true GFR in certain populations (eg, older adults or those with low muscle mass), so a lower eGFRcys identifies previously unrecognized kidney dysfunction. Second, cystatin C may capture systemic processes (inflammation, catabolism) that confer independent cardiovascular and mortality risk beyond kidney filtration. The observed associations with both cardiovascular outcomes and mortality support both mechanisms.
Clinical practice implications
Clinicians should be aware that discordance is common and prognostically important. Practical suggestions:
- Consider reflex or targeted cystatin C measurement when eGFRcr is near clinical decision thresholds (eg, CKD staging boundaries) or when patient factors likely distort creatinine (frailty, low muscle mass, obesity, recent hospitalization, unusual diet or muscle wasting).
- Interpret eGFRcys and eGFRcr together. A substantially lower eGFRcys should prompt closer cardiovascular risk assessment, medication review (dose adjustments as appropriate), and more frequent kidney monitoring.
- In hospitalized patients, high discordance may reflect acute illness; decisions about long-term CKD status or medication dosing should consider repeat testing after recovery.
Limitations and generalizability
This is a pooled observational analysis; therefore, causality cannot be established. Heterogeneity in cohort composition, laboratory assays, timing of measurements, and outcome ascertainment exist despite harmonization efforts. eGFRdiff was defined on a single pair of concurrent measurements; dynamic changes in either biomarker over time were not the primary focus. The effect sizes may differ in populations underrepresented in CKD-PC. The authors’ use of a 30% threshold is clinically reasonable and previously used, but alternative thresholds may have different operating characteristics.
Conclusion
The CKD-PC individual-level meta-analysis demonstrates that discordance between creatinine- and cystatin C–based eGFR is common and clinically consequential. An eGFRcys that is ≥30% lower than eGFRcr identifies outpatients at substantially higher risk of mortality, cardiovascular events, heart failure and kidney failure. Clinicians should consider cystatin C testing in patients with clinical scenarios that make creatinine-based estimates unreliable, and should integrate discordant results into risk stratification and management decisions. Prospective studies are needed to test whether systematic use of cystatin C to resolve discordance improves clinical outcomes and to refine thresholds for action in different clinical contexts.
Funding and clinicaltrials.gov
This article summarizes results presented in: Estrella MM et al. Discordance in Creatinine- and Cystatin C-Based eGFR and Clinical Outcomes: A Meta-Analysis. JAMA. 2025 Nov 7. For full details on funding sources, study sponsors and cohort-specific registrations, please consult the original publication and supplementary materials in JAMA.
References
1. Estrella MM, Ballew SH, Sang Y, et al.; Chronic Kidney Disease Prognosis Consortium Investigators and Collaborators. Discordance in Creatinine- and Cystatin C-Based eGFR and Clinical Outcomes: A Meta-Analysis. JAMA. 2025 Nov 7. doi:10.1001/jama.2025.17578 IF: 55.0 Q1 .
2. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):1–150.
3. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–612.
4. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C–based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749.
