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.
