The sex difference in plasma cystatin C is age-dependent: a systematic review and meta-analysis

Cystatin C–based GFR equations (eGFRcys) are inconsistent; some include a sex-adjustment factor while others do not. This reflects ongoing uncertainty about whether cystatin C concentrations differ between sexes in healthy individuals without kidney disease and how any such difference varies with age. We performed a systematic review and meta-analysis to address this discrepancy. We conducted a PRISMA-compliant systematic review (PubMed, Scopus, Embase) of studies reporting sex-specific cystatin C data in healthy adults. From 21 studies comprising more than 46,000 healthy adults, 52 unique subgroups (k = 52) were extracted. Analyses comprised: (1) a meta-regression of all subgroups by mean age; (2) a random-effects model for younger and middle-aged adults (k = 32, age ≤ 60 years); and (3) a separate model for older adults (k = 13, age ≥ 60 years). A qualitative review of pediatric data provided life-course context. The qualitative pediatric review confirmed a consistent 12–15% sex difference (men > women) emerging during adolescence. In younger and middle-aged adults, men had 8.6% higher cystatin C concentrations than women (pooled M/F ratio 1.0860, 95% CI 1.0587–1.1133; p cys equations, which may underestimate kidney function in younger men, and uniform sex-adjustment equations, which may overcorrect in older adults. Our results support the development of age-dependent, sex-specific approaches to cystatin C–based kidney function assessment.