Cystatin C Reveals Hidden Kidney Risk That Creatinine Tests Miss

Kidney function is routinely estimated using creatinine, but creatinine levels are influenced by muscle mass, diet, and other non-kidney factors. Cystatin C, a protein filtered by the kidneys largely independent of muscle mass, offers an alternative measure. When the two estimates diverge significantly, it signals either that creatinine is artificially elevated by non-kidney factors or that cystatin C is capturing kidney impairment that creatinine misses. This large international study sought to quantify how often this divergence occurs and whether it predicts worse clinical outcomes.

Researchers from the Chronic Kidney Disease Prognosis Consortium (CKD-PC) conducted an individual participant-level meta-analysis drawing on 23 outpatient cohorts (821,327 participants; mean age 59 years; 48% female) and 2 inpatient cohorts (39,639 participants; mean age 67 years; 31% female). The primary exposure was a 'large negative eGFR difference' — defined as eGFRcys at least 30% below eGFRcr. Outcomes included all-cause mortality, cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy (KFRT), tracked over a mean follow-up of 11 years in outpatients.

Among outpatient participants, 11% met the threshold for large negative discordance, ranging from 3% to 50% across individual cohorts. In hospitalized patients, the proportion rose to 35%. Characteristics associated with greater discordance included older age, female sex, lower body mass index, diabetes, and lower baseline eGFRcr — suggesting muscle wasting and metabolic conditions drive creatinine underestimation. Individuals with large negative discordance had substantially higher rates of all-cause and cardiovascular mortality, atherosclerotic events, heart failure, and KFRT compared with those whose eGFRcys and eGFRcr were within 30% of each other — even after adjusting for eGFRcr and albuminuria levels. The excess risk was consistent across subgroups defined by age, sex, diabetes status, and baseline kidney function category.

These findings carry major clinical implications. Current guidelines already recommend confirmatory cystatin C testing when eGFRcr falls in borderline ranges (60–90 mL/min/1.73 m²), but this study demonstrates that discordance is common across a wider range of kidney function and is independently associated with adverse outcomes far beyond kidney failure alone. Patients whose creatinine-based eGFR appears reassuringly normal but whose cystatin C-based eGFR is substantially lower may be systematically undertreated or under-monitored.

Several caveats apply. As a meta-analysis of observational cohorts, causality cannot be established. Cystatin C itself can be elevated by non-kidney factors including obesity, thyroid disease, corticosteroid use, and inflammation, which could confound discordance classifications. Additionally, cystatin C measurement is not yet universally available or standardized across clinical laboratories, and the cost-effectiveness of routine dual biomarker testing has not been established. Nonetheless, the consistency of findings across 25 diverse international cohorts strengthens confidence in the conclusions.