#2981 IRON DEFICIENCY AND CADMIUM LEVELS IN KIDNEY TRANSPLANT RECIPIENTS
Authors: Rawee Pien , Kremer Daan , Touw Daan , de Borst Martin , Bakker Stephan J L , Eisenga Michele 
Published: June 2023

Abstract

Background and Aims
A higher plasma level of cadmium, a nephrotoxic divalent heavy metal, has been associated with an increased risk of graft failure in kidney transplant recipients (KTRs). The drivers of cadmium toxicity in KTRs are incompletely understood. We hypothesize that iron deficiency (ID) increases cadmium absorption and accumulation by upregulation of divalent metal transporters. Here, we first investigated whether ID is associated with higher plasma cadmium levels. As increased cadmium levels have previously been associated with cancer, cardiovascular disease, and diabetes in other populations, we also examined whether plasma cadmium levels are associated with all-cause mortality in KTRs.

Method
We used data from stable KTRs ≥1 year after transplantation who participated in the TransplantLines Food and Nutrition Cohort study. Plasma cadmium and iron status parameters, i.e., ferritin, iron, and transferrin saturation (TSAT), were measured at baseline. ID was defined as TSAT&lt;20% and ferritin &lt;300 µg/L. Linear regression analyses were applied to study the association between iron status parameters and cadmium levels. Multivariable Cox regression analyses were used to investigate the association of plasma cadmium levels with all-cause mortality, adjusted for age, sex, BMI, smoking status, history of cardiovascular disease, glucose, HbA1c, systolic blood pressure, eGFR, cholesterol, and ID at baseline. In sensitivity analyses, we repeated these analyses using an alternative definition of ID, TSAT&lt;20% and ferritin&lt;100 µg/L (IDalt).

Results
We included 670 KTRs (age 53±13 years, 58% males, median 5.4 (IQR, 1.9-11.7) years after transplantation). KTRs with ID (30% of all KTRs, median plasma cadmium level 63 (IQR, 48-76) ng/L) had higher cadmium levels than KTRs without ID (median 56 (IQR, 42-75) ng/L, P = 0.01, Figure 1). ID was not associated with plasma cadmium after adjustment for age, sex, and smoking status. However, within the ID group, TSAT (β = -0.016, P = 0.01) and serum iron (β = -0.023, P = 0.01) were inversely associated with log-transformed cadmium levels, independently of age, sex, and smoking status. Sensitivity analysis yielded similar results: KTRs with IDalt (23% of all KTRs) had higher cadmium levels than KTRs without IDalt (median 61 (IQR, 49-76) ng/L vs median 57 (IQR, 42-75) ng/L, P = 0.03). Furthermore, in Cox regression analysis, KTRs in the highest tertile of plasma cadmium levels (70 ng/L to 330 ng/L) had an increased risk of mortality (hazard ratio 2.80, 95%CI 1.47-5.36, P = 0.01) compared to KTRs in the lowest cadmium tertile (19 ng/L to 48 ng/L) during a median follow-up of 4.9 (IQR, 3.5-5.5) years. No significant interaction by iron status was observed for the association between plasma cadmium and mortality.

Conclusion
KTRs with ID had higher cadmium levels than KTRs without ID, and higher plasma cadmium levels were independently associated with a higher mortality risk. The association of cadmium with mortality was not different between individuals with and without ID at baseline. Further investigations should determine whether ID correction prevents cadmium accumulation in KTRs.