Dysregulated Iron Metabolism and Kidney Stone Risk: An Epidemiological and Experimental Study
NHANES cross-section finds dietary iron intake and transferrin saturation independently associated with kidney stone formation
Journal: Renal Failure | Published: 2026-03-03 | Type: Cross-sectional epidemiological study + animal experiment | PMID:41775437Authors: Wan Wenlong, Yuan Dongfeng, Xun Yang, Yu Xiao (Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, China)
Funding/COI: Funding not disclosed. Authors report no conflicts of interest.
Summary
Using data from 4,370 U.S. adults in NHANES 2017–2018, this study found that two iron metabolism markers — transferrin saturation (TSAT) and dietary iron intake — were independently associated with kidney stone risk in opposite directions. The authors paired this epidemiological signal with mouse experiments showing iron accumulation and activated ferroptosis in renal tissue of stone-model animals. It's an interesting mechanistic hypothesis built on cross-sectional data, which means the causal arrow is entirely unestablished.
Claims
Among 4,370 NHANES participants (450 stone formers, 3,920 non-formers), weighted kidney stone prevalence was 10.6%
Each 10% increase in TSAT was associated with a 26% lower likelihood of kidney stones (OR 0.74, 95% CI 0.56–0.98, p=.04) in the fully adjusted model
Each 10 mg/day increase in dietary iron intake was associated with a 12% higher kidney stone likelihood (OR 1.12, 95% CI 1.01–1.25, p=.036)
Dose-response analysis found a U-shaped relationship between dietary iron intake and stone risk, with an inflection point at 11.7 mg/day
Soluble transferrin receptor (sTfR) was positively associated with stone risk in unadjusted and age/sex-adjusted models but did not survive full covariate adjustment
Mouse stone models showed elevated renal iron accumulation, elevated sTfR, and markers of ferroptosis compared to controls
Study Quality
This is a cross-sectional study using NHANES data, which means it captures a snapshot in time and cannot establish the direction of causation. The statistical approach is methodologically sound: proper survey-weighted logistic regression following NHANES analytical guidelines, three progressive covariate adjustment models, and restricted cubic splines for dose-response analysis. The covariates included — age, sex, BMI, race/ethnicity, smoking, sedentary time, calcium intake, and the systemic inflammation response index — are appropriate for this question.
The animal experiments add mechanistic texture but are descriptive rather than interventional. Male-only C57BL/6 mice were used, which is internally inconsistent with the mixed-sex NHANES population. Immunohistochemistry and Western blot results are presented without the statistical detail needed to evaluate robustness. The human and animal findings are being used to mutually reinforce each other, but they were generated independently and the mechanistic link between the epidemiological signal and the ferroptosis pathway remains speculative.
Red Flags
Cross-sectional design: Cannot determine whether iron dysregulation precedes stone formation or is a consequence of it — the authors themselves raise reverse causation as a possibility
Self-reported outcome: Kidney stone status was ascertained by a single interview question ("Have you ever had a kidney stone?"), with no imaging or medical record verification
Borderline significance: The key TSAT finding has a confidence interval nearly touching 1 (OR 0.74, 95% CI 0.56–0.98), and the dietary iron OR of 1.12 represents a modest effect size
Paradoxical findings: Low TSAT and high dietary iron both associate with stone risk, pointing in opposite directions — the authors acknowledge this contradicts a simple iron-deficiency or iron-excess model, and the proposed "gut-kidney axis" explanation is speculative with no data presented
Funding not disclosed: For a paper from a Chinese university hospital with no listed grants, absent funding information is a gap, not a minor omission
Sex mismatch in animal experiments: Male-only mice used to model findings from a mixed-sex human cohort, with no justification
Dietary iron assessed by 24-hour recall: A single 24-hour dietary recall is a notoriously noisy measure of habitual intake
Strengths
Large, nationally representative sample with appropriate survey-weighted analysis
Multiple iron status biomarkers assessed simultaneously rather than relying on a single indicator
Dose-response analysis adds granularity beyond simple association
Novel question — the authors are correct that population-level data on iron metabolism and kidney stones is sparse
Combining epidemiological and mechanistic (animal) approaches in a single paper, even if the linkage is imperfect, gives the hypothesis more substance than either approach alone
Verdict
This paper raises a legitimate hypothesis — that iron metabolism is involved in kidney stone pathogenesis via oxidative stress and ferroptosis — but the evidence base is too fragile to support strong conclusions. The key findings are cross-sectional, self-reported, borderline-significant, and internally contradictory in a way the authors don't fully resolve. The animal data is consistent with the hypothesis but not designed to test it rigorously. Worth reading as hypothesis generation; not ready to inform clinical reasoning. The missing funding disclosure is a minor irritant on an otherwise reasonably conducted observational study.