LAUSR

Previous epidemiologic data showed female has slower renal function decline compared to male and experimental studies showed the renoprotective effects of estrogen. Nevertheless, clinical studies that supports the beneficial effects of female sex hormone on chronic kidney disease (CKD) progression are limited. Middle age in women is the period of experiencing hormonal alteration. Therefore, we investigated that the associations of reproductive history with incident CKD in middle-aged women. A total of 4481 women aged ≥ 40 years with normal renal function were included in the study from the Korean Genome and Epidemiology Study database. The cohort consisted of community-based general population and were followed up from 2001 to 2016. Primary outcome was the incident occurrence of CKD (eGFR< 60 ml/min/1.73m2 and 25% decline from baseline creatinine). We additionally defined the endogenous estrogen exposure (menopausal age - age at baseline - 0.75 x each childbirth) to examine the effect of estrogen exposure on renal function. Multivariable Cox proportional hazards analysis was performed with time-varying covariates including childbirth, menopausal status, and hormone replacement therapy. The mean age of participants was 52.3 ± 8.9 years, and 51.5% (n=2306) of patients have reached menopause at baseline. The mean eGFR was 94.1 ± 12.7 mL/min/1.73 m2 and 7.0% (n=315) participants experienced childbirth during follow-up period. Age-adjusted Cox model showed that childbirth (HR 1.58, CI 1.24-2.02) and menopause (HR 1.31, CI 1.04-1.63) were significantly associated with high risk of incidental CKD, but not in hormonal therapy. These associations remained after multivariate adjustment (childbirth, HR 1.55, CI 1.21-1.98; menopause, HR 1.26, CI 1.01-1.57). Endogenous estrogen exposure ranged 0 to 14 years, and was categorized into no exposure (51.5%), moderated exposure (1-6 years), and high exposure (>6 years). High exposure group was associated with the lower risk of CKD compared to no exposure group (HR 0.74, CI 0.58-0.94). Restricted cubic spline analysis also showed the inverse relationship between estrogen exposure and the risk of incident CKD. In middle-aged women, menopause and childbirth were significantly associated with higher risk of incident CKD. These associations could be attributable to the reduction of endogenous estrogen exposure.