# Novel Advances in the Pathophysiology and Treatment of the CKD-MBD

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $425,874

## Abstract

Abstract
Our recent studies have established a new paradigm that the chronic kidney disease – mineral bone disorder
(CKD-MBD) syndrome is partly caused by release of factors that are induced during attempted kidney repair into
the circulation. These studies have shown systemic activation of activin receptor type IIA (ActRIIA) in CKD and
identified ActRIIA signaling as a potential therapeutic target for the CKD-MBD and renal fibrosis. Chronic Kidney
Disease (CKD) is a pandemic associated with high cardiovascular mortality rates. The causes of the high
cardiovascular mortality risk include CKD-MBD components. The CKD-MBD syndrome is a uniform complication
of CKD beginning after significant kidney injury reduces GFR by 10% or more. The available therapeutic options
attacking the CKD-MBD - phosphate binders, vitamin D analogs, and calcimimetics, target late stages of the
syndrome and not its pathogenesis or the cardiovascular complications directly, and have failed to show
cardiovascular benefit in clinical trials. Thus, there is great need for discoveries related to CKD-MBD
pathogenesis and identification of therapeutic targets for the CKD-MBD cardiovascular components. CKD
modulates ActRIIA signaling in the vasculature, heart, skeleton and kidney. ActRIIA signaling contributes to
vascular, skeletal, and cardiac complications of kidney disease. The studies in this application propose to
identify the mechanism by which ActRIIA is activated in CKD focusing on ligand stimulation by Activin
A. Inducible knockdown strategies and monoclonal antibody to activin A will be used to determine the role of
activin A in ActRIIA activation in CKD. Vascular, skeletal and cardiac tissues will be studied for mechanism of
disease and mechanism of ActRIIA activation. The vascular aim 1 studies will validate ActRIIA as a therapeutic
target in the vascular calcification of the CKD-MBD. In skeletal aim 2 studies, the mechanism of CKD stimulated
osteoblast dysfunction and bone resorption and abnormal remodeling is sought. In the cardiac aim 3 studies, the
mechanism of CKD stimulated cardiac hypertrophy will be sought focusing on cardiac energetics and the
regulation by perioxosome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) confirming the role
of ActRIIA and validating it as a therapeutic target. Successful completion of the proposed studies will establish
that the vascular, skeletal and cardiac components of the CKD-MBD are caused by activin A as an ActRIIA
ligand, establishing it as a therapeutic target in the CKD-MBD and CKD, and support new clinical trials in the
CKD-MBD and in the progression of CKD.

## Key facts

- **NIH application ID:** 10440482
- **Project number:** 5R01DK127186-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** KEITH A HRUSKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,874
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440482

## Citation

> US National Institutes of Health, RePORTER application 10440482, Novel Advances in the Pathophysiology and Treatment of the CKD-MBD (5R01DK127186-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440482. Licensed CC0.

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