# The role of functional iron deficiency in systemic complications of CKD

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2022 · —

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10683058
- **Project number:** 5I01CX001566-05
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** MONIQUE Eun Hee CHO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683058

## Citation

> US National Institutes of Health, RePORTER application 10683058, The role of functional iron deficiency in systemic complications of CKD (5I01CX001566-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10683058. Licensed CC0.

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