Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients.

Introduction Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated and upcoming therapies require more reliable outcome parameters than currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo. Methods Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1-13C]glycolate, [U-13C2]oxalate and, in a subgroup, [D5]glycine. Isotopic enrichment of 13C-labelled oxalate and glycolate were measured using a new gas chromatography - tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively. Results Total daily oxalate rate of appearance (mean (SD)) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol per day in pyridoxine unresponsive patients, pyridoxine responsive patients, and controls, respectively (p=0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1-13C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in pyridoxine unresponsive, PH1 patients. Conclusion This stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans.