• Michelle J Pena, Dick de Zeeuw, Dennis Andress, John J Brennan, Ricardo Correa-Rotter, Blai Coll, Donald E Kohan, Hirofumi Makino, Vlado Perkovic, Giuseppe Remuzzi, Sheldon W Tobe, Robert Toto, Hans-Henrik Parving, Shoba Sharma, Tom Corringham, Kumar Sharma, and Hiddo J L Heerspink.
• Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
• Diabetes Obes Metab. 2017 May 1; 19 (5): 749-753.

AbstractWe 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.© 2016 John Wiley & Sons Ltd.

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