# Clonal hematopoiesis, mild cognitive impairment and kidney function decline

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $602,674

## Abstract

PROJECT SUMMARY
Chronic kidney disease (CKD) is a predominantly age-related disorder and is associated with accelerated
cognitive function decline. Despite epidemiological evidence linking mild cognitive impairment (MCI) and
dementia with kidney function decline, we still have an incomplete understanding of the factors involved in their
pathogenesis suggesting that there are other unidentified age-related causal risk factors that drive the
development and progression of MCI, dementia, and kidney function decline. Recent data indicates that aging
humans accumulate leukemia associated somatic mutations in hematopoietic stem cells. These mutations
appear to provide a competitive growth advantage to the mutant cells, allowing progressive clonal expansion
which has been defined as clonal hematopoiesis (CH) and it is characterized by worsening chronic systemic
inflammation. CH is associated with several pathological conditions including cardiovascular disease, however,
its association with cognitive and kidney endpoints has not been explored. In addition, the underlying
mechanisms driving CH remain to be determined. Hence, our primary objective is to establish an association
between CH with MCI, dementia, and kidney disease progression. Given the interplay between CH and aging
related changes in the bone marrow (BM) fat microenvironment, a key secondary goal of this application is to
determine the role of BM fat in the evolution of CH. We will also examine blood metabolite signatures
associated with higher risk for clinically meaningful cognitive and CKD endpoints and higher BM fat content.
Our preliminary data demonstrated a significant occurrence of CH in patients with CKD. Also, we have shown
that BM adipocytes produce a local inflammatory signature including increased interleukin-6 that promotes CH.
These findings provide a strong premise for our hypothesis that CH associates with MCI, dementia and CKD,
and that BM fat plays a significant role in CH development. We will leverage the unique resources of the
Systolic blood Pressure Interventional Trial (SPRINT), including longitudinal data on assessment of cognitive
function and CKD, biospecimens, and DNA enabling assessment of CH. In a subset of 6,000 SPRINT
participants aged 50 or older with normal kidney function at baseline, we will determine CH at baseline using
our targeted sequencing panel and analytic pipeline for somatic mutation calling and assess whether CH
identifies those at highest risk for cognitive and kidney function impairment. We propose 3 aims; Aim 1: To
evaluate the prospective associations between CH and metabolomics with incident MCI and dementia events
among SPRINT participants with normal kidney function at baseline. Aim 2: To evaluate the prospective
associations between CH and metabolomics with kidney disease progression events among SPRINT
participants with normal kidney function at baseline. Aim 3: To define a link between BM fat and clonal
hematopoiesis in CKD. Understan...

## Key facts

- **NIH application ID:** 10626828
- **Project number:** 5R01AG077747-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Michel Benjamin Chonchol
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $602,674
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626828

## Citation

> US National Institutes of Health, RePORTER application 10626828, Clonal hematopoiesis, mild cognitive impairment and kidney function decline (5R01AG077747-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10626828. Licensed CC0.

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