Age-Dependent Sex Differences in the Incidence of AKI among Patients with CKD: The OCKR Study

Background: While basic studies revealed a protective effect of female hormones against acute kidney injury (AKI), the Kidney Disease Improving Global Outcomes (KDIGO) guideline states that females have a higher risk of AKI. A meta-analysis of observational studies reported an inconsistent sex difference in AKI with a considerable degree of heterogeneity. Sex differences in AKI have not been studied in the chronic kidney disease (CKD) population. We investigated whether sex affects the incidence of AKI and its impact on the risk of kidney failure among patients with CKD. Methods: The Osaka Consortium for Kidney Disease Research (OCKR) is a retrospective, multicenter cohort study that includes patients who attended the outpatient departments of nephrology at five hospitals in Osaka, Japan, from January 2005 to December 2021. In the present study, 15,220 patients with an estimated glomerular filtration rate (eGFR) of 15-60 mL/min/1.73 m2 were included. AKI was defined as a ≥1.5 times increase in a serum creatinine level from its median value over the past year, according to the National Health Service England AKI algorithm. The association of sex with AKI and sex-specific relations of time-dependent AKI with kidney failure with replacement therapy (KFRT) were examined using time-dependent Cox proportional hazards models. Results: The mean (standard deviation) age and eGFR at baseline were 69 (14) years and 37 (13) mL/min/1.73 m2, respectively, and 62% were male. Over a median follow-up of 2.9 years, 1,974 (13.0%) patients developed AKI and 1,316 (8.6%) experienced KFRT. Males had a significantly higher hazard of AKI (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.07-1.33) after adjustment for potential confounders. This association was stronger in patients aged <50 (HR 1.51; 95% CI, 1.05-2.17) than in those aged 50 or older (HR 1.16; 1.03-1.30) (P for interaction=0.04). Males also had an 85%-higher hazard of KFRT (95% CI, 1.58-2.18) than females. In contrast, the hazard of KFRT associated with time-dependent AKI was similar between sexes (P for interaction =0.87). Similar trends were observed when analyzed according to AKI stages. Conclusion: Females had a lower incidence of AKI, especially in the younger population, but a similar hazard of KFRT after AKI, compared to males.