# Origin of Excess Acid in Uric Acid Urolithiasis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $449,722

## Abstract

Project Summary/Abstract
Uric acid urolithiasis composes up to about 10% of kidney stones and is increasing in prevalence
contemporaneously with the escalating prevalence of obesity, metabolic syndrome, and diabetes.
Uric acid urolithiasis is the renal manifestation of the multi-systemic disturbances in obesity,
metabolic syndrome and diabetes. The primary pathophysiologic feature of uric acid urolithiasis
is excessive aciduria. We propose a multi-organ pathogenic model of uric acid urolithiasis
traceable to intestinal organic acid generation by the gut microbiota (totality of the microbial fauna)
that escapes complete hepatic metabolism due to subtle defects in the liver from steatosis, which
then imposes an increased acid load on the kidneys. Defective ammoniagenesis in the kidney
from renal steatosis mandates excretion of the excess acid carried by alternative buffers including
urate which ultimately leads to uric acid precipitation and stones. In this model, the first step in
uric acid urolithiasis starts in the gut and liver. This proposal will use a combination of animal and
human studies to test the hypothesis of the gut and liver as pathogenic origin of uric acid kidney
stones. We propose three Aims to address: 1. Microbiota-phenotype association. Microbiome
(microbial genome) from uric acid stone formers, obese, and lean non-stone-formers will be
correlated with plasma and urinary parameters. 2. Microbiota-phenotype causation. Causality will
be tested by transplantation of the microbiota from the three groups of humans from Aim 1 into
germ-free mice and we will examine whether the appropriate phenotype is conferred. 3.
Microbiota-host interaction. We will test the hypothesis that increased acid production from the
microbiota is necessary but not sufficient to confer the disease phenotype. Additional host factors
need to be invoked; specifically impaired hepatic metabolism of the lumen-derived organic acids
from fatty infiltration of hepatocytes. We will use both animals and humans for all Aims drawing
expertise from a diverse synergistic team of human researchers, animal pathophysiologists,
microbiota biologists, and bioinformaticians to test our model. These experiments are the first to
explore the very origin of the acid load in uric acid urolithiasis, and take the study and treatment
of uric acid urolithiasis from empirical management by urinary alkalinization to a genuine and
thorough elucidation of its pathophysiology, and subsequent definitive therapy. The studies also
open up novel lines of investigation of the pathobiology of microbiota-host interaction in the
metabolic syndrome.

## Key facts

- **NIH application ID:** 10442425
- **Project number:** 5R01DK115703-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JEFFREY D BROWNING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $449,722
- **Award type:** 5
- **Project period:** 2019-09-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442425

## Citation

> US National Institutes of Health, RePORTER application 10442425, Origin of Excess Acid in Uric Acid Urolithiasis (5R01DK115703-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10442425. Licensed CC0.

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