Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria
Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria
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DOI：
10.1681/asn.2017040390
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发表时间：
2018-06-01
影响因子：
13.6
通讯作者：
Holmes, Ross P.
中科院分区：
文献类型：
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作者：
Fargue, Sonia;Milliner, Dawn S.;Holmes, Ross P.
内源性草酸盐合成有助于草酸钙结石病，并在遗传性原发性高草酸尿（PH）疾病中显著增加。关于草酸盐合成的不完整知识使新疗法的发现复杂化。羟脯氨酸（Hyp）代谢导致草酸和乙醇酸的形成。然而，低代谢对内源性草酸和乙醇酸合成的相对贡献尚不清楚。为了确定这一贡献，我们在9名健康受试者和19名PH值较高的个体中进行了稳定同位素[N-15，C-13(5)]-Hyp的连续静脉输注，并使用离子色谱耦合质量检测方法定量了尿中C-13(2)-草酸盐和C-13(2)-乙醇酸盐的水平。结果PH1、PH2、PH3组和对照组输注时尿草酸/肌酐比值分别为73.1、70.8、47.0、10.6 mg草酸/g肌酐。PH1、PH2和PH3患者的低代谢分别为12.8、32.9和14.8 mg草酸/g肌酐，而对照组为1.6 mg草酸/g肌酐。在对照组中，Hyp对尿草酸盐的贡献为15%，在PH1、PH2和PH3患者中分别为18%、47%和33%。在对照组中，Hyp对尿乙醇酸的贡献为57%，在PH1组中为30%
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 [N-15,C-13(5)]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary C-13(2)-oxalate and C-13(2)-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