CAUSAL INFERENCE OF TESTOSTERONE’S ROLE IN THE ONSET OF MEMBRANOUS NEPHROPATHY: IMPLICATIONS FOR RENAL FUNCTION, PHYSICAL PERFORMANCE, AND SPORTS MEDICINE

Abstract

Background: Membranous nephropathy (MN) is a chronic glomerular disease characterized by immune complex deposition and thickening of the glomerular basement membrane, leading to renal dysfunction, fluid imbalance, and potential limitations in physical activity and athletic performance. Testosterone, a key androgenic hormone, plays a crucial role in muscle strength, metabolic regulation, and cardiovascular function, but its influence on renal pathology and sports-related physiological adaptations remains unclear. This study aims to investigate the causal relationship between testosterone levels and the onset of MN using a two-sample Mendelian randomization (MR) approach, providing new insights into the intersection of endocrine function, renal health, and physical performance. Methods: Publicly available genome-wide association study (GWAS) datasets were analyzed, incorporating case-control data on testosterone levels and MN incidence. Single nucleotide polymorphisms (SNPs) significantly associated with testosterone concentrations were selected as instrumental variables (IVs). Two-sample Mendelian randomization analyses, including Inverse Variance Weighted (IVW) and MR-Egger methods, were used to assess the potential causal effect of testosterone on MN risk. Sensitivity analyses, including heterogeneity tests, pleiotropy assessments, and stepwise elimination procedures, were conducted to ensure the robustness of findings. Results: A significant causal association between testosterone levels and MN development was observed. IVW analysis yielded an odds ratio (OR) of 3.02, indicating that higher testosterone levels are associated with an increased risk of MN, with consistent results across multiple analytical models. Sensitivity analysis confirmed no evidence of heterogeneity or pleiotropic bias, reinforcing the stability of these findings. Furthermore, reverse causality testing revealed that MN does not have a causal effect on testosterone levels, suggesting that the endocrine influence is unidirectional. Conclusion: This study provides genetic evidence supporting a causal role of testosterone in the development of MN, highlighting potential implications for renal function, metabolic balance, and physical performance in active individuals. Given the crucial role of testosterone in muscle physiology, recovery, and exercise capacity, understanding its influence on renal health and metabolic adaptation is essential for optimizing training protocols, athlete health monitoring, and prevention strategies in sports medicine. Future research should explore testosterone regulation, exercise interventions, and renal protective strategies to mitigate the impact of hormonal fluctuations on kidney function and athletic performance.