Disease-modifying effects of iron deficiency in mouse models of chronic renal failure

Chronic kidney disease (CKD) affects global health, contributing to 1 in 60 fatalities worldwide. Iron deficiency (ID), a common complication of CKD, is a major cause of years lived with disability. The combination of CKD and ID presents a particularly challenging health burden, as ID can exacerbate CKD-related complications and negatively affect patient outcomes. Despite the high prevalence of ID and anemia in patients with CKD, whether and how ID alters CKD-associated complications, such as systemic inflammation, organ fibrosis, vascular calcification, and cardiomyopathy, remains insufficiently understood. Using 2 distinct mouse models of CKD, adenine-induced nephropathy and Alport syndrome (<i>Col4a3</i> ^-/-), we induced moderate or severe ID in mice and investigated on how it modulates pathologic complications. At baseline, akin to patients with CKD, both adenine nephropathy and Alport models displayed systemic inflammation, vascular calcification, and kidney and cardiac injuries accompanied by fibrosis. Severe ID aggravated systemic inflammation, kidney fibrosis, and cardiac fibrosis in adenine-induced CKD, while having no significant effect on vascular calcification, kidney injury, kidney functional impairment, or pathologic cardiac remodeling in either model. Our study offers valuable insights into the pathophysiologic mechanisms driving CKD-related comorbidities and suggests that iron supplementation may be beneficial in mitigating specific aspects of inflammation-induced kidney damage.