Dysregulated iron metabolism and kidney stone risk: an epidemiological and experimental study

Kidney stone disease is a major global health burden with high recurrence, closely linked to oxidative stress. While iron, a redox-active metal, can exacerbate oxidative stress via the Fenton reaction, population evidence on its association with kidney stone risk is scarce. Based on data from 4,370 adults in the National Health and Nutrition Examination Survey (NHANES 2017–2018), we conducted survey-weighted multivariable logistic regression to assess the associations between iron status indicators and kidney stone risk, and used restricted cubic splines to examine potential dose-response relationships. Animal tissues were analyzed via IHC, Western blot, and biochemical assays. After adjustment, each 10% increase in transferrin saturation correlated with a 26% lower likelihood of kidney stones (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.56–0.97, p = .04), while each 10 mg/day increase in dietary iron intake correlated with a 12% higher risk (OR 1.12, 95% CI 1.01–1.24, p = .036). Dose-response analysis revealed a U-shaped relationship for iron intake (inflection point: 11.7 mg/day). Animal experiments confirmed renal iron accumulation, elevated sTfR, and activated ferroptosis. This study first demonstrates a significant association between dysregulated iron metabolism and kidney stone risk, suggesting that systemic iron dysregulation and local renal ferroptosis may contribute to stone pathogenesis, offering new preventive insights.