Sex differences in associations between creatinine and cystatin C-based kidney function measures with stroke and major bleeding

PURPOSE: We sought to explore whether adding kidney function biomarkers based on creatinine (eGFR(Cr)), cystatin C (eGFR(Cys)) or a combination of the two (eGFR(Cr-Cys)) could improve risk stratification for stroke and major bleeding, and whether there were sex differences in any additive value of kidney function biomarkers. METHOD: We included participants from the UK Biobank who had not had a previous ischaemic or haemorrhagic stroke or major bleeding episode, and who had kidney function measures available at baseline. Cause-specific Cox proportional hazards models tested associations between eGFR(Cr), eGFR(Cys) and eGFR(Cr-Cys) (mL/min/1.73 m(2)) with ischaemic and haemorrhagic stroke, major bleeding (gastrointestinal or intracranial, including haemorrhagic stroke) and all-cause mortality. FINDINGS: Among 452,879 eligible participants, 246,244 (54.4%) were women. Over 11.5 (IQR 10.8–12.2) years, there were 3706 ischaemic strokes, 795 haemorrhagic strokes, 26,025 major bleeding events and 28,851 deaths. eGFR(Cys) was more strongly associated with ischaemic stroke than eGFR(Cr): an effect that was more pronounced in women (men – HR: 1.16, 95% CI: 1.12–1.19; female to male comparison – HR: 1.11, 95% CI: 1.05–1.16, per 10 mL/min/1.73 m(2) decline in eGFR(Cys)). This interaction effect was also demonstrated for eGFR(Cr-Cys), but not eGFR(Cr). eGFR(Cys) and eGFR(Cr-Cys) were more strongly associated with major bleeding and all-cause mortality than eGFR(Cr) in both men and women. Event numbers were small for haemorrhagic stroke. DISCUSSION: To a greater degree than is seen in men, eGFR(Cr) underestimates risk of ischaemic stroke and major bleeding in women compared to eGFR(Cys). The difference between measures is likely explained by non-GFR biology of creatinine and cystatin C. CONCLUSION: Enhanced measurement of cystatin C may improve risk stratification for ischaemic stroke and major bleeding and clinical treatment decisions in a general population setting, particularly for women.