TY  - JOUR
A1  - Reichetzeder, Christoph
A1  - Tsuprykov, Oleg
A1  - Hocher, Berthold
T1  - Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies
JF  - Life sciences : molecular, cellular and functional basis of therapy
N2  - Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase Ill trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
KW  - Endothelin receptor antagonists
KW  - Kidney
KW  - Side effects
KW  - Safety
KW  - Water and salt retention
KW  - Clinical trials
Y1  - 2014
U6  - https://doi.org/10.1016/j.lfs.2014.02.025
SN  - 0024-3205
SN  - 1879-0631
VL  - 118
IS  - 2
SP  - 141
EP  - 148
PB  - Elsevier
CY  - Oxford
ER  -