TY - JOUR
T1 - Endogenous oxalate production in primary hyperoxaluria type 1 patients
AU - Garrelfs, Sander F.
AU - van Harskamp, Dewi
AU - Peters-Sengers, Hessel
AU - van den Akker, Chris H. P.
AU - Wanders, Ronald J. A.
AU - Wijburg, Frits A.
AU - van Goudoever, Johannes B.
AU - Groothoff, Jaap W.
AU - Schierbeek, Henk
AU - Oosterveld, Michiel J. S.
N1 - Funding Information: S.F.G, M.J.S.O and J.W.G. report an unconditional grant from both Dicerna Pharmaceuticals and Alnylam Pharmaceuticals, during the conduct of the study. H. Peters-Sengers reports Research Funding from KOLFF personal grant of the Dutch Kidney Foundation (NSN). C. van den Akker reports Consultancy Agreements with Baxter, Nutricia Early Life Nutrition; and Honoraria from Baxter, Nutricia Early Life Nutrition, and Nestlé Nutrition Institute. J. Groothoff reports consultancy agreements with UniQure; and scientific advisor or membership with Alnylam. M. Oosterveld reports Honoraria from Apellis Pharmaceuticals. All remaining authors declare no conflicts of interests for the research, authorship and/or publication of this article. Funding Information: This work was funded by the Amsterdam UMC; personal PhD Scholarship S.F.G, Dicerna pharmaceuticals (unconditional grant), Alnylam pharmaceuticals (unconditional grant) and Metakids (grant ID: 2019-04-UMD). Publisher Copyright: © 2021 American Society of Nephrology. All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Glycolate
KW - Hyperoxaluria
KW - Kinetics
KW - Mass spectrometry
KW - Oxalate
KW - Stable isotope
UR - http://www.scopus.com/inward/record.url?scp=85120639108&partnerID=8YFLogxK
U2 - https://doi.org/10.1681/ASN.2021060729
DO - https://doi.org/10.1681/ASN.2021060729
M3 - Article
C2 - 34686543
SN - 1046-6673
VL - 32
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -