Cystatin C-based estimated glomerular filtration rate and risk of stroke in the general population: a prospective cohort study

Lay Summary Previous research on the association between estimated glomerular filtration rate (eGFR) and stroke risk has produced mixed results, partly due to the use of serum creatinine-based eGFR (eGFR(cr)), which may be influenced by non-kidney determinants and therefore introduce bias. To address this issue, we investigated the linear and nonlinear associations of cystatin C-based eGFR (eGFR(cys)) with the incidence of total stroke, ischemic stroke, and hemorrhagic stroke in 429 566 community-dwelling UK Biobank participants. Our analysis revealed that eGFR(cys) below 75 mL/min/1.73 m(2) was associated with an increased risk of stroke, specifically ischemic stroke. Notably, the association between stroke and eGFR(cr) was weaker than that with eGFR(cys). Our findings highlight the importance of not underestimating stroke risk when an individual's eGFR is below 75 mL/min/1.73 m(2) in routine tests and suggest that eGFR(cys) is a superior marker for identifying those at increased risk of stroke. Background Previous results on the association between the estimated glomerular filtration rate (eGFR) and stroke are mixed. Most studies derived the eGFR from serum creatinine, which is affected by non-kidney determinants and thus has possibly biased the association with stroke risk. Methods In this cohort study, we included 429 566 UK Biobank participants (94.5% white, 54% women, age 56 & PLUSMN; 8 years) free of stroke at enrollment. The eGFR(cys) and eGFR(cr) were calculated with serum cystatin C and creatinine, respectively. Outcomes of interest were risk of total stroke and subtypes. We investigated the linear and nonlinear associations using Cox proportional hazards models and restricted cubic splines, corrected for regression dilution bias. Results During an average follow-up of 10.11 years, 4427 incident strokes occurred, among which 3447 were ischemic and 1163 were hemorrhagic. After adjustment for confounders, the regression dilution-corrected hazard ratios (95% confidence intervals) for every 10 mL/min/1.73 m(2) decrement in eGFR(cys) were 1.10 (1.05-1.14) for total stroke and 1.11 (1.08-1.15) for ischemic stroke. A similar pattern was observed with eGFR(cr), although the association was weaker. When either type of eGFR was below 75 mL/min/1.73 m(2), the risks of total and ischemic stroke increased exponentially as eGFR decreased. A U-shaped relationship was witnessed if eGFR(cr) was used instead. There was a null association between eGFR and hemorrhagic stroke. Conclusions The risks of total stroke and ischemic stroke increased exponentially when the eGFR(cys) fell below 75 mL/min/1.73 m(2).