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Therapeutic approaches to diabetic nephropathy—beyond the RAS

Key Points

  • Current therapy for diabetic kidney disease is based on blood pressure control and the antialbuminuric and antihypertensive effects of renin–angiotensin system (RAS) blockers

  • Diabetic kidney disease remains the most common cause of end-stage renal disease, indicating the need for additional therapeutic approaches beyond the RAS

  • In the past few years, several major trials have failed to show a favourable risk to benefit ratio of promising novel therapeutic approaches to diabetic kidney disease

  • Insufficient understanding of drug mechanisms and the pathogenesis of diabetic kidney disease, lack of a gold standard for diagnosis, heterogeneity of trial populations and a paucity of hard outcomes might underlie these failures

  • Ongoing clinical trials are testing novel approaches that target signalling pathways, inflammation and fibrosis in diabetic kidney disease

  • Unfortunately, the primary outcome of most of these trials is albuminuria (which might be dissociated from loss of renal function) or estimated glomerular filtration rate (GFR), which might not adequately represent actual GFR

Abstract

Despite improvements in glycaemic and blood pressure control, and the efficacy of renin–angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway—further research into the potential nephroprotective effects of novel glucose-lowering agents is required.

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Figure 1: Pathogenesis of diabetic kidney disease and targets for therapy.

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Acknowledgements

This work was supported by grants from the Spanish Ministry of Science (SAF 2012-38830 to C.G.-G.), Fondo de Investigaciones Sanitarias (FIS PS09/00447, FIS 10/0072, PI13/00047, FIS/PIE13/00051, ISCIII-RETIC REDinREN/RD06/0016 and 12/0021), Spanish Society of Nephrology, Comunidad de Madrid S2010/BMD-2378 and PRIORITY as well as ISCIII Rio Hortega to B.F.-F., Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A.O., Fundacion Lilly and Diabetes kidney connect (Health-F2-2013-602422) to J.E.

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All authors researched the data for the article, wrote the manuscript, contributed to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Jesus Egido.

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Fernandez-Fernandez, B., Ortiz, A., Gomez-Guerrero, C. et al. Therapeutic approaches to diabetic nephropathy—beyond the RAS. Nat Rev Nephrol 10, 325–346 (2014). https://doi.org/10.1038/nrneph.2014.74

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