Abstract
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.