Kidney stones, of which the most common are calcium oxalate (CaOx) stones, affect 7 to 12% of the United States population and are responsible for 3% of all end-stage renal disease cases. Urine oxalate is derived from approximately 50% dietary sources and 50% from endogenous synthesis through various pathways. Though it is well established that approximately 80% of the endogenous oxalate is produced in the liver, the pathways for oxalate production are not well characterized. Our hypothesis is that glycolate is a major source of oxalate and that the renal reabsorption of glycolate leads to renal synthesis of oxalate. Establishing the role of glycolate in renal and liver synthesis of oxalate has implications for patients with the hereditary disease primary hyperoxaluria (PH), in which excessive endogenous oxalate production leads to severe recurrent CaOx kidney stones. Establishing these pathways could lead to new treatments to inhibit glycolate oxidation, resulting in reduced oxalate production. This proposal will 1) test if the metabolism of glycolate contributes to endogenous oxalate synthesis by performing primed, steady state, continuous intravenous infusions of the stable isotope of glycolate, carbon- 13 glycolate, in healthy volunteers. 2) test the hypothesis that glycolate is metabolized to oxalate in proximal tubule cells using a human proximal tubule cell line and freshly isolated human proximal tubule fragments and 3) determine renal reabsorption and metabolism of glycolate using isolated rat kidney perfusions. The roles of the enzyme hydroxyacid oxidase 2 (HAO2) and glyoxylate reductase (GR) will be defined in the context of this conversion. The mentoring team and training plan associated with this proposal will ensure that the candidate reaches the level of expertise in analytical chemistry, metabolic research, and human and animal studies that are necessary to meet her goals. The candidate's long-term objective is to lead a strong independent research program in the field of oxalate metabolism and the clinical disorders associated with it, including the primary hyperoxalurias.
The goal of this project is to determine the contribution of glycolate to endogenous oxalate synthesis and to define the role of the kidney in metabolizing glycolate to oxalate. The knowledge gained on oxalate metabolism has the potential to be applied to patients with the inherited disease primary hyperoxaluria and and to patients with idiopathic calcium oxalate kidney stone disease.
|Fargue, Sonia; Milliner, Dawn S; Knight, John et al. (2018) Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria. J Am Soc Nephrol 29:1615-1623|