Fabiola Del Greco M., Luisa Foco, Irene Pichler, Philipp Eller, Kathrin Eller, Beben Benyamin, John B. Whitfield, Peter P. Pramstaller, John R. Thompson, Cristian Pattaro, Cosetta Minelli

Iron depletion is a known consequence of chronic kidney disease (CKD), but there is contradicting epidemiological evidence on whether iron itself affects kidney function and whether its effect is protective or detrimental in the general population. While epidemiological studies tend to be affected by confounding and reverse causation, Mendelian randomization (MR) can provide unconfounded estimates of causal effects by using genes as instruments. We performed an MR study of the effect of serum iron levels on estimated glomerular filtration rate (eGFR), using genetic variants known to be associated with iron. MR estimates of the effect of iron on eGFR were derived based on the association of each variant with iron and eGFR from two large genome-wide meta-analyses on 48 978 and 74 354 individuals. We performed a similar MR analysis for ferritin, which measures iron stored in the body, using variants associated with ferritin. A combined MR estimate across all variants showed a 1.3% increase in eGFR per standard deviation increase in iron (95% confidence interval 0.4-2.1%; P = 0.004). The results for ferritin were consistent with those for iron. Secondary MR analyses of the effects of iron and ferritin on CKD did not show significant associations but had very low statistical power. Our study suggests a protective effect of iron on kidney function in the general population. Further research is required to confirm this causal association, investigate it in study populations at higher risk of CKD and explore its underlying mechanism of action.