Hypertensive Disorders of Pregnancy and Maternal Long-Term Kidney Dysfunction: A Mendelian Randomization Analysis

Background: Observational studies have demonstrated a potential association between hypertensive disorders of pregnancy (HDPs) and an elevated risk of subsequent kidney impairment. The present study aimed to evaluate the possible causal relationship between HDPs and future renal dysfunction using a genetic approach. Methods: This two-sample Mendelian randomization (MR) analysis, conducted between October 2023 and January 2024, examined the effects of HDPs—both overall and by subtype (gestational hypertension and preeclampsia/eclampsia)—on chronic kidney disease (CKD), albuminuria, and estimated glomerular filtration rate (eGFR). Genetic data were sourced from publicly available genome-wide association studies (GWAS) provided by the FinnGen, CKDGen, UK Biobank, GIANT (Genetic Investigation of ANthropometric Traits), deCODE, and DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies) consortia. The primary method employed was inverse-variance weighting, supplemented by sensitivity analyses and instrument-strength validation to ensure causal robustness. Results: This study included approximately 300,000 to 600,000 individuals per kidney function trait, with around 15,000 HDP cases. Genetically predicted HDPs showed a weak but statistically significant association with albuminuria odds ratio (OR): 1.02; 95% confidence interval (CI): 1.00–1.03; p = 0.01. This association remained consistent after adjustments for body mass index (BMI), smoking, and type 2 diabetes (T2D) in the multivariable MR analysis (OR: 1.03; 95% CI: 1.01–1.04; p < 0.001). No significant associations were observed between HDPs, including for the subtypes, and the presence of CKD or eGFR. These results demonstrated robustness across diverse sensitivity analyses. Conclusions: The genetic proxy for HDPs was identified as causally associated with maternal long-term albuminuria, independent of BMI, smoking, and T2D. These results offer novel insights bolstering the causal relationship between HDPs and long-term maternal kidney dysfunction.