IRON DEFICIENCY INCREASES THE ACCUMULATION OF THE NEPHROTOXIC METAL CADMIUM

Cadmium (Cd) is a well-known nephrotoxic metal. Beyond its nephrotoxic effects, Cd also impacts other organs, including the cardiovascular system and liver. Uptake of Cd occurs partially through the divalent metal transporter 1 (DMT1), responsible for intestinal iron absorption. Iron deficiency may enhance Cd absorption and retention, while Cd exposure can aggravate anemia through hemolytic and erythropoietic effects. We investigated whether iron deficiency increases Cd accumulation in tissues and whether iron supplementation can mitigate Cd burden in experimental and clinical settings.

Male C57BL/6J mice were fed either a control (60 mg/kg) or an iron-deficient diet (6 mg/kg Fe) from 4-14 weeks of age. Mice received Cd (CdCl₂, 110 μmol/L) in drinking water from 6–14 weeks. A subset received a 0.2% adenine diet from 8-14 weeks to induce chronic kidney disease (CKD). Cd concentrations in blood, urine, liver, heart, and kidney were quantified using inductively coupled plasma mass spectrometry. Furthermore, plasma Cd levels were assessed in iron-deficient kidney transplant recipients (KTRs) who participated in a randomized trial. These KTRs received intravenous ferric carboxymaltose (FCM) regardless of anemia status, with Cd measurements at baseline and 24 weeks. Data are shown as medians per group. Group differences were tested with Mann–Whitney U tests with 10% FDR-adjusted p-values shown.

Iron-deficient mice developed overt anemia, with a median hemoglobin level of 5.2 g/dL (n=9) compared to 11.9 g/dL in controls (n=9, p<0.001). Similarly, iron-deficient CKD mice showed anemia, with a median hemoglobin level of 7.3 g/dL (n=6), versus 11.3 g/dL in CKD controls (n=6, p=0.01). Blood Cd levels were significantly higher in iron-deficient versus control Cd-exposed mice (Figure 1): 48.0 vs 16.2 µg/L in non-CKD, p<0.001 and 66.5 vs 46.3 µg/L in CKD, p=0.01. Liver Cd was significantly higher in iron-deficient control mice (9.7 vs 1.9 µg/g, p<0.001) and CKD mice (24.5 vs 9.6 µg/g, p=0.01). Heart Cd was similarly higher in iron-deficient versus control mice (1.02 vs 0.29 µg/g, p<0.001) and in CKD mice (1.35 vs 0.96 µg/g, p=0.01). Kidney Cd was higher in iron-deficient controls (11.1 vs 4.5 µg/g, p<0.001) and was comparable in CKD mice (7.8 vs 7.7 µg/g, n.s.). Urinary Cd was higher in iron-deficient compared with control mice (4.9 vs 1.4 µg/g, p<0.001) but not significantly different in CKD animals. CKD mice also had higher Cd levels in blood, liver, and heart than their corresponding non-CKD group (blood p=0.004 controls & p<0.001 iron-deficient; liver p=0.001 controls & p=0.03 iron-deficient; heart p=0.005 controls & n.s. iron-deficient). In human KTRs (n=64), plasma Cd was significantly lower at 24 weeks following intravenous FCM treatment (15.0[11.0-22.0] ng/L), compared to baseline (17.5[12.0-24.3] ng/L, p<0.001; Figure 2).

Iron deficiency substantially increases Cd accumulation, potentially due to enhanced uptake via shared transport mechanisms, such as DMT1. Conversely, iron supplementation reduces circulating Cd levels in humans, suggesting a protective role of iron repletion against Cd toxicity. Our findings highlight iron status as a key, modifiable determinant of Cd burden, with relevance for populations exposed to environmental Cd and at risk of iron deficiency or CKD.