The role of functional iron deficiency in systemic complications of CKD

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Veterans have disproportionately increased risks for cardiovascular (CV), diabetic, and chronic kidney diseases (CKD) compared to the general population. Abnormal iron homeostasis has recently been suggested to play a critical role in the pathogenesis of various metabolic and CV disorders. Iron metabolism disorder is highly prevalent in CKD, but its systemic extra-hematopoietic consequences, including diabetic, renal, and CV risks, have not been investigated. In CKD, induction of inflammatory signaling increases hepcidin, a key hepatic iron regulator which prevents oral iron absorption and mobilization of iron from reticuloendothelial stores. By reducing available circulating iron, hepcidin likely mediates the development of functional iron deficiency (FID), in which insufficient iron incorporation into erythroid precursors and other cell types occurs despite adequate body iron stores. Thus, FID is characterized by low serum transferrin saturation (Tsat), reflecting reduced available plasma iron for cellular uptake, and increased ferritin, reflecting adequate total body iron stores. Given that iron is essential not only for erythropoiesis but also for mitochondrial energy metabolism, inadequate iron supply to highly metabolic organs could lead to a wide range of adverse systemic effects. While anemia is the most recognized clinical consequence of FID, its effect on other organs has never been assessed in the CKD population. We hypothesize that hepcidin-induced FID in CKD leads to (1) iron deficiency at the tissue level, with increased risk for failure of highly metabolic organs most dependent on mitochondrial oxidative capacity, such as heart and kidney, and (2) enhanced new-onset diabetes risk due to insulin resistance associated with inadequate muscle mitochondrial respiration. The lack of knowledge on extra-hematopoietic consequences of FID in CKD has led to a singular focus on anemia management without regard to its potential harm to other organs. The current standard CKD management thus does not evaluate iron status in the absence of obvious anemia. Yet, iron deficiency without the presence of anemia has been associated with marked mortality risk in heart failure. Moreover, the joint thresholds of Tsat and ferritin defining FID have not been developed to predict extra-hematopoietic clinical events in CKD, undermining the ability of clinicians to accurately diagnose the problem. In addition, the relationship of hepcidin with FID has not been characterized in a large CKD cohort. Improved knowledge of the role of iron in systemic complications of CKD is critical to developing a more integrated strategy for risk stratification and identifying innovative therapeutic targets. We propose to address the above knowledge gap using two observational studies involving (1) a historical cohort using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) and (2) a complementary prospective cohort from the ongoing NIDDK-sponsored Chronic Renal Insufficiency Cohort (CRIC), a longitudinal observational study of 3,939 CKD patients with available biospecimens since 2003. We propose to access biospecimens from CRIC to measure serum hepcidin and iron indices. Using these assay results from CRIC and longitudinal data from both CRIC and VINCI, we will evaluate the relationship of FID and hepcidin with renal, diabetic, and CV outcomes in both cohorts. VINCI provides large statistical power to explore the joint thresholds of Tsat and ferritin defining FID and to evaluate the association between FID and clinical risks, with direct relevance to Veteran health. CRIC allows the ability to apply the VINCI results in an independent cohort to identify FID and to explore the role of hepcidin, which is not available through VINCI. This is the first study to examine (i) the iron thresholds defining FID most associated with heart failure risk and (ii) the role of FID and hepcidin in the renal, diabetic and CV complications of CKD. Positive findings from our study will identify iron status and hepcidin as novel modifiable risk factors with the potential to impact current CKD practice, which does not assess iron status in the absence of obvious anemia.