Isotope Day 2023-Mass Spectrometry with Sonia Fargue, PhD

"Using Isotopes to Probe the Metabolism of Oxalate"
Dr. Sonia Fargue, an Assistant Professor in the Department of Urology at the University of Alabama, discusses her research on oxalate metabolism and its relation to primary hyperoxaluria and calcium oxalate kidney stone disease. She explains that oxalate, a small dicarboxylic acid, is a net product in humans with no known utility and is almost entirely excreted in the urine. Oxalate sources are evenly split between metabolism (endogenous synthesis) and dietary sources. Endogenous synthesis has both non-enzymatic and enzymatic pathways involving the metabolism of glyoxylate, a direct precursor to oxalate.
Dr. Fargue mentions that her group uses stable isotope tracers in human studies to understand oxalate metabolism, which has a long history dating back to the 1950s and 60s. She explains that there's been a renewed interest in oxalate metabolism due to primary hyperoxaluria, a rare disease caused by deficiencies in enzymes involved in oxalate or glyoxylate metabolism. She discusses the FDA approval of a new drug for treating primary hyperoxaluria type 1 by targeting glyoxylate metabolism.
Dr. Fargue outlines the specific questions her group aims to answer with isotope studies in humans, including the importance of specific precursors to endogenous synthesis in healthy volunteers, stone formers, and patients with primary hyperoxaluria. She describes the common methods used at UAB, such as dietary equilibration, fasting, infusions or oral dosing of isotopes, and collection of urine and blood samples.
She provides examples of studies using constant infusions to look at oxalate synthesis from its precursor hydroxyproline and glycolate. She mentions that hydroxyproline metabolism is a target for intervention in primary hyperoxaluria types 2 and 3, and glycolate metabolism is a target for primary hyperoxaluria type 1, which is what the new FDA-approved drug does.
Dr. Fargue discusses a study using oral dosing of labeled ascorbic acid to look at its contribution to oxalate synthesis, finding that ascorbic acid is the largest single source of oxalate in non-stone formers. She also mentions a study that infused labeled oxalate to calculate the synthesis rate of oxalate and found that even without a tracer, they could estimate the synthesis rate using natural abundance of isotopes.
Lastly, Dr. Fargue discusses using isotopes to look at dietary absorption of oxalate, finding that most oxalate is absorbed within six hours but there's also late absorption, suggesting both proximal and possibly colonic absorption. She concludes that stable isotope tracers have provided invaluable insights into oxalate metabolism, helping to piece together the puzzle of oxalate sources and their importance in different diseases. Despite some limitations and unknowns, her group is moving forward to study oxalate metabolism in primary hyperoxaluria, kidney stone disease, and possibly chronic kidney disease progression.
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