# Pathogenesis of Uric Acid Nephrolithiasis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $510,253

## Abstract

PROJECT SUMMARY
Patients with idiopathic uric acid nephrolithiasis (IUAN) exhibit multiple features of the metabolic syndrome and
the principal pathogenic abnormality of low urine pH. In previously completed NIH-supported studies, we have
identified: 1. Increased net acid load to the kidney and reduced ammoniagenesis by the kidney as the key
metabolic defects underlying low UpH in humans with IUAN and in rodent models of UA stone risk. 2. that the
peroxisome proliferator-activated receptor (PPAR) agonists thiazolidinediones (TZD) improve many of the
systemic and urinary abnormalities in IUAN. Preliminary studies show that modest weight loss (~5%) results in
further rise in UpH in TZD-treated IUAN patients, and that an intrarenal adiponectin autocrine/paracrine system
may mediate TZD-induced rise in renal ammoniagenesis and urine pH. Based on these findings, we will test
three hypotheses with three specific aims. Hypothesis 1: Weight loss + TZD independently and additively result
in durable changes in urine chemistry. In Aim 1, we will compare TZD, weight loss or both in combination on
urine acid-base parameters relevant to UA stone risk in IUAN patients. Hypothesis 2: While systemic TZD
certainly have beneficial effects through multiple mechanisms. There may be direct effects of TZD on the renal
tubule to alter urine acid-base parameters and reduces UA stone risk since PPAR is highly expressed in the
proximal tubule. In Aim 2, PPAR will be deleted from the renal tubules and the therapeutic effects of TZD will
be evaluated. Hypothesis 3: Activation of the recently discovered intrarenal adiponectin system in the renal
tubules mediates PPAR activation-induced changes in urinary parameters. In Aim 3, we will test the linear model
of PPAR activation → adiponectin activation → increased ammoniagenesis, we will genetically manipulate renal
PPAR and adiponectin using knock-out of each to test for necessity, and overexpression of each to test for
sufficiency. We will follow with primary cultured renal tubule cells from these animals to further confirm the linear
model in vitro. In summary, this proposal combined bench and clinical research to test a new model of how
PPAR activation improves urinary UA stone risk via activation of the newly discovered intrarenal adiponectin
system, and a novel regimen of TZD and weight loss in treating human IUAN.

## Key facts

- **NIH application ID:** 10437698
- **Project number:** 5R01DK081423-14
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ming-Chang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $510,253
- **Award type:** 5
- **Project period:** 2009-05-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437698

## Citation

> US National Institutes of Health, RePORTER application 10437698, Pathogenesis of Uric Acid Nephrolithiasis (5R01DK081423-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10437698. Licensed CC0.

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