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 <i>via</i> 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 <i>via</i> 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, <i>p</i> = .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, <i>p</i> = .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.