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

Cystatin C-based GFR equations (eGFR_cys) 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 < .0001). In older adults, this difference was markedly attenuated (M/F ratio 1.0338, 95% CI 1.0132-1.0544). Across all adult subgroups, meta-regression indicated an age-related attenuation of the sex difference (β = -0.0011 per year). Between-study heterogeneity was substantial (I² = 98% in younger adults, 76% in older adults), likely reflecting true variability in population characteristics and analytical methods; however, the direction of the sex difference was highly consistent across studies. Sensitivity analyses using robust variance estimation, leave-one-out analysis, and trim-and-fill methods confirmed the robustness of pooled estimates and found no evidence of substantial publication bias. Plasma cystatin C exhibits a consistent, biologically plausible sex difference that varies across the life course, with a pronounced difference in adolescence and early to mid-adulthood that attenuates after 60 years of age. This pattern coincides with age-related changes in sex hormone exposure and, together with experimental and clinical evidence, supports a hormonal contribution to cystatin C regulation. These findings challenge the validity of both sex-neutral eGFR_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.