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Comprehensive Analysis of Oxalate Homeostasis in Calcium Oxalate Kidney Stone Formers

Award Number: R01DK137784
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/18/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Comprehensive Analysis of Oxalate Homeostasis in Calcium Oxalate Kidney Stone Formers - SUMMARY Urinary oxalate excretion is a key risk factor in the formation of calcium oxalate kidney stones, the most common type of kidney stone, a disease that affects 9% of the US population. Therapeutic development for prevention of calcium oxalate kidney stone disease is hampered by our incomplete understanding of the factors leading to the increased urinary oxalate pool in many patients with calcium oxalate kidney stones. Environmental and lifestyle factors as well as dietary and metabolic, or endogenous, factors may all play a role, but the interplay between them has clouded the interpretation of the oxalate focused studies that have been done in kidney stone formers. Our preliminary data and published studies suggest there is both an increased synthesis of oxalate and a greater gastrointestinal absorption of oxalate in calcium oxalate kidney stone formers. These warrant confirmation and the underlying mechanisms need to be defined. The frequency of colonization with Oxalobacter formigenes, a gut commensal oxalate degrading bacterium, is substantially lower in calcium oxalate kidney stone formers and its absence has been linked with increased kidney stone risk. Colonization with Oxalobacter formigenes leads to reduced urinary oxalate excretion in healthy volunteers. Whether colonization with this organism is possible in calcium oxalate kidney stone formers and leads to reduced urinary oxalate excretion warrants study. Our hypothesis is that increased endogenous oxalate synthesis and increased gastrointestinal absorption of oxalate via greater transport capacity and higher bioavailablity due to decreased microbial oxalate degradation in the gut lead to a greater influx of oxalate and increased urinary oxalate excretion. This proposal aims to 1/ demonstrate that endogenous oxalate synthesis is increased in idiopathic calcium oxalate kidney stone formers using 13C-isotope oxalate infusion to quantify oxalate production and determine the contribution of different oxalate precursors by oral dosing with 13C-glycolate and 13C-ascorbic acid; 2/ confirm that gastrointestinal oxalate absorption is higher in idiopathic calcium oxalate kidney stone formers and define the driving mechanisms by using a combination of low and high oxalate diets and 13C-oxalate oral dosing coupled with sugar functional intestinal permeability tests that will identify gut segments and type of transport involved; 3/ demonstrate that the colonization of Oxalobacter formigenes in idiopathic calcium oxalate kidney stone formers is possible, sustainable, and results in a reduction of urinary oxalate excretion. We expect this proposal to identify mechanisms playing a role in the increased urinary oxalate pool in idiopathic calcium oxalate kidney stones patients; develop tools to investigate these mechanisms; provide a potential treatment for lowering urinary oxalate excretion by colonization with Oxalobacter formigenes. This in turn may lead to the development of targeted therapies to be tested in clinical trials for treating those afflicted with calcium oxalate kidney stones.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $589,796 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$589,796
														Subtotal = $589,796

Issue Date FY: 2024 ( Subtotal = $675,139 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/13/2023	NEW	$675,139
														Subtotal = $675,139

Grand Total All Awards = $1,264,935

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Comprehensive Analysis of Oxalate Homeostasis in Calcium Oxalate Kidney Stone Formers

Award Number: R01DK137784

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/18/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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