Perturbations in iron homeostasis are associated with mortality, heart failure, and other adverse outcomes in patients with nondialysis-dependent chronic kidney disease (CKD), a new study finds. Fibroblast growth factor 23 (FGF23) appears to mediate some of these effects.

Among 3747 patients in the Chronic Renal Insufficiency Cohort Study, 27.1% were iron replete, 11.1% had iron deficiency, 7.6% functional iron deficiency, 6.3% mixed iron deficiency, and 9% excess iron (the remaining 38.8% were non-classified).

Iron deficiency compared with repletion was significantly associated with 28% and 34% increased risks for mortality and heart failure, respectively, Rupal Mehta, MD, of Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, and colleagues reported in Kidney International. Mixed iron deficiency was significantly associated with 61% and 33% increased risks for mortality and end-stage kidney disease (ESKD), respectively.

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High iron was significantly associated with 54%, 58%, and 41% higher risks for mortality, heart failure, and ESKD, respectively. Functional iron deficiency did not correlate with any outcome. The investigators found no associations between iron status and atherosclerotic cardiovascular disease.

In other analyses, FGF23 fully and significantly mediated the risks for mortality and heart failure in iron deficiency, Dr Mehta’s team reported. FGF23 mediated only 20% of the associated between mixed iron deficiency and mortality. It did not influence the association between high iron and outcomes. Emerging data demonstrate that iron is an important regulator of FGF23.

Hemoglobin accounted for only 23% of the association of iron deficiency with mortality, 31% of the association of iron deficiency with heart failure, and 5% of the association of mixed iron deficiency with mortality.

“The results of the current study suggest that increases in FGF23 induced by iron deficiency could magnify the cardiac toxicity of FGF23,” Dr Mehta’s team stated. “Further studies are needed to determine whether correction of iron deficiency can improve clinical outcomes in CKD, as it does in patients with heart failure and iron deficiency, who also manifest elevated FGF23 levels that are independently associated with worse outcomes.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Mehta R, Cho ME, Cai X, et al. Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease. Kidney Int. Published online July 30, 2021. doi:10.1016/j.kint.2021.07.013