Sander Garrelfs1, Dewi van Harskamp2, Hessel Peters-Sengers3, Chris van den Akker4, Ronald Wanders5, Frits Wijburg6, Johannes van Goudoever7, Jaap Groothoff8, Henk Schierbeek9, Michiel Oosterveld10. 1. S Garrelfs, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands s.f.garrelfs@amsterdamumc.nl. 2. D van Harskamp, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 3. H Peters-Sengers, Center for Experimental Molecular Medicine, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 4. C van den Akker, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 5. R Wanders, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 6. F Wijburg, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 7. J van Goudoever, Emma Children's Hospital, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands. 8. J Groothoff, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 9. H Schierbeek, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands. 10. M Oosterveld, Emma Children's Hospital, Amsterdam UMC Location AMC, Amsterdam, Netherlands.
Abstract
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.
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.
Authors: Heike Hoyer-Kuhn; Sina Kohbrok; Ruth Volland; Jeremy Franklin; Barbara Hero; Bodo B Beck; Bernd Hoppe Journal: Clin J Am Soc Nephrol Date: 2014-01-02 Impact factor: 8.237
Authors: Christiaan S van Woerden; Jaap W Groothoff; Ronald J A Wanders; Jean-Claude Davin; Frits A Wijburg Journal: Nephrol Dial Transplant Date: 2003-02 Impact factor: 5.992