Male reproductive surgeries and long-term kidney outcomes: a Mendelian randomization and meta-analysis of UK Biobank and FinnGen.

The long-term renal implications of conditions leading to male reproductive surgeries remain unclear. This study evaluated the potential causal relationships between genetic liability to undergoing these surgeries and kidney diseases. Genetic variants associated with four surgery-related phenotypes-testicular hydrocele surgery, testicular or scrotal surgery, circumcision, and vasectomy-were selected as instrumental variables. Mendelian randomization, meta-analysis, and exploratory mediation analyses were used to assess associations with 20 kidney outcomes. Results showed genetic liability to testicular hydrocele surgery was associated with higher odds of chronic kidney disease, IgA nephropathy, glomerulonephritis, cystic kidney disease, tubulo-interstitial nephritis, and kidney injury, and with lower odds of benign kidney tumors and renal stones. Genetic liability to testicular or scrotal surgery was associated with increased odds of renal colic, gout, malformations of the renal pelvis or ureters, renal stones, and kidney infections. Genetic liability to circumcision was associated with higher odds of congenital obstructive malformations, hypertensive heart/renal disease, malignant kidney neoplasms, and increased kidney volume, and with lower odds of kidney cysts, benign tumors, and chronic renal failure. Genetic liability to vasectomy was linked to reduced odds of pyelonephritis and malignant kidney neoplasms. Mediation analyses suggested partial contributions of immune and metabolic traits. This study provides evidence that genetic liability to undergoing male reproductive system surgeries-reflecting the underlying biological or pathological indications-is associated with distinct patterns of kidney disease susceptibility. Findings suggest that individuals with underlying conditions predisposing them to testicular hydrocele or scrotal surgery may benefit from attention to long-term kidney health.