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Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients
Journal of the American Society of Nephrology ( IF 13.6 ) Pub Date : 2021-12-01 , DOI: 10.1681/asn.2021060729
Sander F Garrelfs 1 , Dewi van Harskamp 1 , Hessel Peters-Sengers 2 , Chris H P van den Akker 1 , Ronald J A Wanders 1 , Frits A Wijburg 1 , Johannes B van Goudoever 1 , Jaap W Groothoff 1 , Henk Schierbeek 1 , Michiel J S Oosterveld 1
Affiliation  

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 [1-13C]glycolate, [U-13C2]oxalate, and, in a subgroup, [D5]glycine. Isotopic enrichment of 13C-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 [1-13C]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.



中文翻译:

原发性高草酸尿症 1 型患者的内源性草酸盐生成

背景

原发性高草酸尿症 1 型 (PH1) 是乙醛酸代谢的先天性错误,其特征是内源性草酸盐生成增加。草酸盐合成的代谢途径尚未完全阐明,即将到来的治疗需要比目前使用的血浆草酸盐水平和尿草酸盐排泄率更可靠的结果参数。因此,我们开发了一种稳定同位素输注方案来评估内源性草酸盐合成率和乙醇酸盐对体内草酸盐和甘氨酸合成的贡献。

方法

8 名健康志愿者和 8 名 PH1 患者(按吡哆醇反应性分层)接受了静脉内 [1- 13 C] 乙醇酸盐、[U- 13 C 2 ] 草酸盐和亚组中 [D 5 ] 甘氨酸的联合预注连续输注. 使用新的气相色谱-串联质谱 (GC-MS/MS) 方法测量13 C 标记的草酸盐和乙醇酸盐的同位素富集。稳定同位素稀释和掺入计算分别量化了出现率和合成率。

结果

在对吡哆醇无反应的患者、对吡哆醇有反应的患者和对照组中,每日总草酸盐出现率(平均 [SD])分别为 2.71 (0.54)、1.46 (0.23) 和 0.79 (0.15) mmol/d(P =0.002)。乙醇酸盐对草酸盐产生的平均 (SD) 贡献在患者中为 47.3% (12.8),在对照组中为 1.3% (0.7)。在甘氨酸中加入 [1- 13 C] 乙醇酸示踪剂显示,在对吡哆醇有反应的情况下,乙醇酸显着转化为甘氨酸,但在对吡哆醇无反应的 PH1 患者中则不然。

结论

这种稳定同位素输注方案可以评估新疗法的疗效,研究吡哆醇反应性,并作为进一步探索人类乙醛酸代谢的工具。

更新日期:2021-11-30
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