Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria

Sonia Fargue, Dawn S. Milliner, John Knight, Julie B. Olson, W. Todd Lowther, Ross P. Holmes

Research output: Contribution to journalReview article

4 Citations (Scopus)

Abstract

Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection. Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and,13% in subjects with PH2 or PH3. Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.

Original languageEnglish (US)
Pages (from-to)1615-1623
Number of pages9
JournalJournal of the American Society of Nephrology
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2018

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Primary Hyperoxaluria
Oxalates
Hydroxyproline
glycolic acid
Creatinine
Calcium Oxalate
Intravenous Infusions
Isotopes

ASJC Scopus subject areas

  • Nephrology

Cite this

Fargue, S., Milliner, D. S., Knight, J., Olson, J. B., Lowther, W. T., & Holmes, R. P. (2018). Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. Journal of the American Society of Nephrology, 29(6), 1615-1623. https://doi.org/10.1681/ASN.2017040390

Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. / Fargue, Sonia; Milliner, Dawn S.; Knight, John; Olson, Julie B.; Lowther, W. Todd; Holmes, Ross P.

In: Journal of the American Society of Nephrology, Vol. 29, No. 6, 01.06.2018, p. 1615-1623.

Research output: Contribution to journalReview article

Fargue, S, Milliner, DS, Knight, J, Olson, JB, Lowther, WT & Holmes, RP 2018, 'Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria', Journal of the American Society of Nephrology, vol. 29, no. 6, pp. 1615-1623. https://doi.org/10.1681/ASN.2017040390
Fargue, Sonia ; Milliner, Dawn S. ; Knight, John ; Olson, Julie B. ; Lowther, W. Todd ; Holmes, Ross P. / Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 6. pp. 1615-1623.
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abstract = "Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection. Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15{\%} in controls and 18{\%}, 47{\%}, and 33{\%} in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57{\%} in controls, 30{\%} in subjects with PH1, and,13{\%} in subjects with PH2 or PH3. Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.",
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AB - Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection. Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and,13% in subjects with PH2 or PH3. Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.

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