Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients.
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
01
06
2021
accepted:
16
08
2021
pubmed:
24
10
2021
medline:
9
2
2023
entrez:
23
10
2021
Statut:
ppublish
Résumé
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 the 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 . Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1- 13 C]glycolate, [U- 13 C 2 ]oxalate, and, in a subgroup, [D 5 ]glycine. Isotopic enrichment of 13 C-labeled 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. Total daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, 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- 13 C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive. 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.
Sections du résumé
BACKGROUND
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 the 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- 13 C]glycolate, [U- 13 C 2 ]oxalate, and, in a subgroup, [D 5 ]glycine. Isotopic enrichment of 13 C-labeled 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 rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, 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- 13 C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive.
CONCLUSIONS
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.
Identifiants
pubmed: 34686543
pii: 00001751-202112000-00023
doi: 10.1681/ASN.2021060729
pmc: PMC8638398
doi:
Substances chimiques
Oxalates
0
Pyridoxine
KV2JZ1BI6Z
glycolic acid
0WT12SX38S
Glycolates
0
Glycine
TE7660XO1C
Glyoxylates
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3175-3186Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Références
Cochat P, Rumsby G: Primary hyperoxaluria. N Engl J Med 369: 649–658, 2013
Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, et al.; OxalEurope Consortium: Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int 86: 1197–1204, 2014
Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, et al.; Rare Kidney Stone Consortium: Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26: 2559–2570, 2015
Fargue S, Rumsby G, Danpure CJ: Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1. Biochim Biophys Acta 1832: 1776–1783, 2013
Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, et al.; OxalEurope: Primary hyperoxaluria type 1: Indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 27: 1729–1736, 2012
van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA: Primary hyperoxaluria type 1 in The Netherlands: Prevalence and outcome. Nephrol Dial Transplant 18: 273–279, 2003
Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Hero B, Beck BB, et al.: Vitamin B6 in primary hyperoxaluria I: First prospective trial after 40 years of practice. CJASN 9: 468–477, 2014
Liebow A, Li X, Racie T, Hettinger J, Bettencourt BR, Najafian N, et al.: An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J Am Soc Nephrol 28: 494–503, 2017
Lai C, Pursell N, Gierut J, Saxena U, Zhou W, Dills M, et al.: Specific inhibition of hepatic lactate dehydrogenase reduces oxalate production in mouse models of primary hyperoxaluria. Mol Ther 26: 1983–1995, 2018
Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O’Riordan WD, Cochat P, et al.; ILLUMINATE-A Collaborators: Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 384: 1216–1226, 2021
Clifford-Mobley O, Sjögren A, Lindner E, Rumsby G: Urine oxalate biological variation in patients with primary hyperoxaluria. Urolithiasis 44: 333–337, 2016
Bergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, Hoppe B, et al.; IPHR Investigators: Transplantation outcomes in primary hyperoxaluria. Am J Transplant 10: 2493–2501, 2010
Knight J, Assimos DG, Callahan MF, Holmes RP: Metabolism of primed, constant infusions of [1,2-(1)(3)C(2)] glycine and [1-(1)(3)C(1)] phenylalanine to urinary oxalate. Metabolism 60: 950–956, 2011
Fargue S, Milliner DS, Knight J, Olson JB, Lowther WT, Holmes RP: Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. JASN 29: 1615–1623, 2018
Huidekoper HH: Inborn errors of metabolism. In: Mass Spectrometry and Stable Isotopes in Nutritional and Pediatric Research, edited by Schierbeek H, New York, John Wiley & Sons;, 2017, pp 258–283
Toledo FGS, Miller RG, Helbling NL, Zhang Y, DeLany JP: The effects of hydroxychloroquine on insulin sensitivity, insulin clearance and inflammation in insulin-resistant adults: A randomized trial. Diabetes Obes Metab 23: 1252–1261, 2021
Siebel AL, Trinh SK, Formosa MF, Mundra PA, Natoli AK, Reddy-Luthmoodoo M, et al.: Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial. Metabolism 65: 904–914, 2016
van Harskamp D, Garrelfs SF, Oosterveld MJS, Groothoff JW, van Goudoever JB, Schierbeek H: Development and validation of a new gas chromatography-tandem mass spectrometry method for the measurement of enrichment of glyoxylate metabolism analytes in hyperoxaluria patients using a stable isotope procedure. Anal Chem 92: 1826–1832, 2020
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al.; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
Huidekoper HH: In Vivo Kinetic Studies in Inborn Errors of Metabolism: Expanding Insights in (Patho)Physiology, Amsterdam, The Netherlands, University of Amsterdam, 2008
Te Braake FW, Schierbeek H, de Groof K, Vermes A, Longini M, Buonocore G, et al.: Glutathione synthesis rates after amino acid administration directly after birth in preterm infants. Am J Clin Nutr 88: 333–339, 2008
Vlaardingerbroek H, Vermeulen MJ, Rook D, van den Akker CH, Dorst K, Wattimena JL, et al.: Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 163: 638–644.e1–5, 2013
Steele R: Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82: 420–430, 2006
Watts RW, Veall N, Purkiss P: Sequential studies of oxalate dynamics in primary hyperoxaluria. Clin Sci (Lond) 65: 627–633, 1983
Clarke JT, Bier DM: The conversion of phenylalanine to tyrosine in man. Direct measurement by continuous intravenous tracer infusions of L-[ring-2H5]phenylalanine and L-[1- 13 C] tyrosine in the postabsorptive state. Metabolism 31: 999–1005, 1982
Thompson GN, Pacy PJ, Merritt H, Ford GC, Read MA, Cheng KN, et al.: Rapid measurement of whole body and forearm protein turnover using a [2H5]phenylalanine model. Am J Physiol 256: E631–E639, 1989
Elder TD, Wyngaarden JB: The biosynthesis and turnover of oxalate in normal and hyperoxaluric subjects. J Clin Invest 39: 1337–1344, 1960
Prenen JA, Oei HY, Dorhout Mees EJ: Indirect estimation of plasma oxalate using 14C-oxalate. Contrib Nephrol 56: 18–25, 1987
Holmes RP, Goodman HO, Assimos DG: Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int 59: 270–276, 2001
Hatch M, Freel RW: The roles and mechanisms of intestinal oxalate transport in oxalate homeostasis. Semin Nephrol 28: 143–151, 2008
Harris KS, Richardson KE: Glycolate in the diet and its conversion to urinary oxalate in the rat. Invest Urol 18: 106–109, 1980
Hockaday TD, Clayton JE, Frederick EW, Smith LH Jr: Primary hyperoxaluria. Medicine (Baltimore) 43: 315–345, 1964
Gersovitz M, Bier D, Matthews D, Udall J, Munro HN, Young VR: Dynamic aspects of whole body glycine metabolism: Influence of protein intake in young adult and elderly males. Metabolism 29: 1087–1094, 1980
Robert JJ, Bier DM, Zhao XH, Matthews DE, Young VR: Glucose and insulin effects on the novo amino acid synthesis in young men: Studies with stable isotope labeled alanine, glycine, leucine, and lysine. Metabolism 31: 1210–1218, 1982
Donini S, Ferrari M, Fedeli C, Faini M, Lamberto I, Marletta AS, et al.: Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism. Biochem J 422: 265–272, 2009