# Uremic Toxins and Cardiovascular Disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $718,091

## Abstract

Chronic Kidney Disease (CKD) affects 15% of individuals in the U.S. and is an independent risk factor for
cardiovascular disease (CVD) in multiple meta-analyses and cohort studies. In late stage CKD/dialysis the
phenotype shifts to left ventricular hypertrophy (LVH), diastolic dysfunction, preserved ejection fraction heart
failure, and sudden cardiac death (SCD). Importantly, in patients with CKD, traditional Framingham risk factors
do not fully explain or predict the increased risk of LVH, diastolic dysfunction, or SCD in patients with CKD
supporting the importance of non-traditional risk factors specific to CKD, called uremic toxins as causative of
CVD in CKD. These toxins include 1) low molecular weight solutes including phosphate and parathyroid
hormone, both inducing arterial calcification and LVH, 2) middle molecules such as fibroblast growth factor 23
that induces LVH, and 3) protein bound uremic toxins that are generated from intestinal microbiota such as
indoxyl sulfate (IS) that are associated LVH and prolonged QT interval in patients. Indoxyl sulfate is a ligand for
the aryl hydrocarbon receptor (AhR) important in detoxification and regulation of inflammation and senescence.
Our model of progressive CKD, the Cy/+IU rat, spontaneously develops LVH, myocardial fibrosis, arrythmias,
heart and arterial calcification, and sudden cardiac death, emulating advanced human CKD. Our preliminary
data supports that dietary inulin (non-fermentable fiber) reduced the levels of indoxyl sulfate close to normal and
improved left ventricular mass index, and reduced heart fibrosis, senescence and oxidative stress. However,
inulin did not affect FGF23 nor normalize PTH and these toxins are known to cause LVH, arrythmias, suggesting
an additional contribution to CVD in CKD. We hypothesize that cardiovascular disease in CKD is due to
the interaction of PTH, FGF23 AND the gut microbiome derived uremic toxin indoxyl sulfate. To test this
hypothesis we will test the following specific aims: Aim 1: To determine if concomitant lowering of PTH and
FGF23 with a calcimimetic is additive to dietary inulin to lower indoxyl sulfate in improving cardiovascular
structure, function and arrythmias in a rat model of CKD. Aim 2: To confirm the cardiovascular effects of indoxyl
sulfate are mediated through the aryl hydrocarbon receptor (AhR) in the adenine mouse model of CKD. Primary
outcomes will be cardiac function measures of LVH and longitudinal strain by Echo and ECG in vivo, arrythmias
by optical mapping and left ventricular mass index ex vivo. Additional outcomes are blood levels of indoxyl sulfate
and CKD-MBD, cardiac pathology/gene and protein expression for fibrosis/hypertrophy and connexin,
senescence, oxidative stress, and inflammation. These studies examine clinically available treatments to lower
uremic toxins and determine if doing so results in a reduction of cardiovascular disease in CKD, the leading
cause of death.

## Key facts

- **NIH application ID:** 10878531
- **Project number:** 1R01HL170142-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Sharon M Moe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $718,091
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878531

## Citation

> US National Institutes of Health, RePORTER application 10878531, Uremic Toxins and Cardiovascular Disease (1R01HL170142-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878531. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*