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J. Clin. Med. 2015, 4(6), 1325-1347; doi:10.3390/jcm4061325

Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

1
Division of Nephrology and Hypertension and FRIAT, IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Av Reyes Catolicos 2, 28040 Madrid, Spain
2
REDINREN, Av Reyes Catolicos 2, 28040 Madrid, Spain
3
Nephrology Service and Research Unit, University Hospital Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010 Santa Cruz de Tenerife, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Desirée Luis
Received: 4 May 2015 / Revised: 4 June 2015 / Accepted: 8 June 2015 / Published: 18 June 2015
(This article belongs to the Special Issue Diabetic Nephropathy)
View Full-Text   |   Download PDF [251 KB, uploaded 18 June 2015]   |  

Abstract

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. View Full-Text
Keywords: chronic kidney disease; diabetes; diabetic kidney disease; inflammation; interleukin-1-beta; treatment chronic kidney disease; diabetes; diabetic kidney disease; inflammation; interleukin-1-beta; treatment
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MDPI and ACS Style

Perez-Gomez, M.V.; Sanchez-Niño, M.D.; Sanz, A.B.; Martín-Cleary, C.; Ruiz-Ortega, M.; Egido, J.; Navarro-González, J.F.; Ortiz, A.; Fernandez-Fernandez, B. Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade. J. Clin. Med. 2015, 4, 1325-1347.

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