# Hepcidin-Ferroportin-Iron Axis in Cardiac Surgery-associated Acute Kidney Injury

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $165,104

## Abstract

Project Summary of Parent Grant
 Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major public health burden. Over
500,000 cardiac surgeries are performed annually in the U.S. alone, with as many as 64% complicated by
CSA-AKI. Those who develop CSA-AKI have a 6- to 18-fold higher acute mortality compared to those without
CSA-AKI. No pharmacologic therapy reliably prevents or treats CSA-AKI. Based on a strong pathophysiologic
rationale from both animal models and human studies, we propose that hepcidin and other heme/iron
regulatory proteins play a key role in CSA-AKI.
 In Aims 1 and 2, we will leverage the CABG Genomics Project, a large prospective cohort study of adult
patients who underwent cardiac surgery. CABG Genomics collected detailed clinical data and biospecimens,
including plasma/serum samples pre- and postoperatively at multiple time points. In Aim 1, we will measure
plasma hepcidin preoperatively in 2,000 patients to test its association with CSA-AKI. We will use multivariable
models to adjust for potential confounders, including plasma IL-6. We will externally validate our findings using
samples from the TRIBE-AKI study, which enrolled 1219 high-risk adults who underwent cardiac surgery at 6
sites in North America. In Aim 2, we will measure plasma hepcidin, free hemoglobin, haptoglobin, hemopexin,
transferrin saturation, and ferritin longitudinally in a nested 1:1 case-control study (n=600) to test whether early
changes in these markers are independently associated with CSA-AKI.
 In Aim 3, we will enroll 250 high-risk adult patients undergoing cardiac surgery at three major hospitals
in Boston. We will isolate peripheral blood mononuclear cells pre- and postoperatively to investigate the
relationship between monocyte expression of ferroportin and other heme/iron regulatory proteins, examined by
flow cytometry, with CSA-AKI. We will also assess whether early postoperative changes in monocyte
expression of ferroportin and other heme/iron regulatory proteins are associated with CSA-AKI.
 Investigating the hepcidin-ferroportin-iron axis and other heme/iron regulatory proteins in the setting of
CSA-AKI could have actionable implications for the design of future trials to prevent CSA-AKI. Unlike many
other markers previously examined in CSA-AKI, those proposed here are directly involved in the pathogenesis
of CSA-AKI and are targetable. This proposal will help determine the therapeutic strategy targeting disordered
iron homeostasis that has the highest likelihood of success. If low preoperative hepcidin is confirmed as an
independent risk factor for CSA-AKI, prophylactic administration of hepcidin agonists, which are currently in
development, could be tested in future studies of CSA-AKI prevention. Alternatively, if the proposed studies
reveal that other heme/iron regulatory proteins (e.g., haptoglobin, CD163, HO-1) have a greater influence on
CSA-AKI than hepcidin/ferroportin, therapeutic strategies targeting these proteins c...

## Key facts

- **NIH application ID:** 11097013
- **Project number:** 3R01DK126685-03S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** David Evan Leaf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,104
- **Award type:** 3
- **Project period:** 2022-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11097013

## Citation

> US National Institutes of Health, RePORTER application 11097013, Hepcidin-Ferroportin-Iron Axis in Cardiac Surgery-associated Acute Kidney Injury (3R01DK126685-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11097013. Licensed CC0.

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