We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2 . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2 , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P  = .035), -0.08 (-12 to 0.29; P  = .43) and 0.01 (-0.21 to 0.19; P  = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P  = .40) and 0.35 (0.05-0.65; P  = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2 , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.

译文

:我们评估了阿曲生坦疗法对一组预定能反映糖尿病肾病患者线粒体功能的13种尿液代谢产物的作用。这项事后分析是使用RADAR研究期间收集的尿液样本进行的,这是一项随机,双盲,安慰剂对照试验,测试了阿特拉森坦对2型糖尿病和肾病患者白蛋白尿减少的影响。基线时,eGFR <60 mL / min / 1.73 m2的患者中,通过气相色谱质谱法定量的13种代谢物中有4种低于可检测水平,有6种减少。在eGFR <60 mL / min / 1.73 m2的患者中使用阿曲生坦治疗12周后,代谢物的单值指数变化了-0.31(95%CI -0.60至-0.02; P = .035),-0.08(在安慰剂中为-12至0.29; P = 0.43)和0.01(-0.21至0.19; P = 0.913),阿曲生坦分别为0.75和1.25 mg / d。与安慰剂相比,阿曲生坦0.75和1.25 mg / d的代谢物指数差异分别为0.13(-0.17至0.43; P = 0.40)和0.35(0.05-0.65; P = 0.02)。这些数据证实了2型糖尿病,肾病和eGFR <60 mL / min / 1.73 m2的患者线粒体功能障碍的先前发现,这表明阿曲生坦可以预防特定患者群体常见的线粒体功能障碍的发展。指出了未来使用阿曲生坦治疗更长的时间的研究。

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