Therapeutic Renin Inhibition in Diabetic Nephropathy-A Review of the Physiological Evidence.

Bianca Domingues Massolini,Stephanie San Gregorio Contieri,Paula Antoun Bellacosa,Andrei Brateanu,Luciana Aparecida Campos,Giulia Severini Lazarini,Ovidiu Constantin Baltatu,Mirela Dobre,Georg Petroianu

doi:10.3389/fphys.2020.00190

Abstract

The purpose of this systematic review was to investigate the scientific evidence to support the use of direct renin inhibitors (DRIs) in diabetic nephropathy (DN). MEDLINE was searched for articles reported until 2018. A standardized dataset was extracted from articles describing the effects of DRIs on plasma renin activity (PRA) in DN. A total of three clinical articles studying PRA as an outcome measure for DRIs use in DN were identified. These clinical studies were randomized controlled trials (RCTs): one double-blind crossover, one post hoc of a double-blind and placebo-controlled study, and one open-label and parallel-controlled study. Two studies reported a significant decrease of albuminuria associated with PRA reduction. One study had a DRI as monotherapy compared with placebo, and two studies had DRI as add-in to an angiotensin II (Ang II) receptor blocker (ARB). Of 10,393 patients with DN enrolled in five studies with DRI, 370 (3.6%) patients had PRA measured. Only one preclinical study was identified that determined PRA when investigating the effects of aliskiren in DN. Moreover, most of observational preclinical and clinical studies identified report on a low PRA or hyporeninemic hypoaldosteronism in DM. Renin inhibition has been suggested for DN, but proof-of-concept studies for this are scant. A small number of clinical and preclinical studies assessed the PRA effects of DRIs in DN. For a more successful translational research for DRIs, specific patient population responsive to the treatment should be identified, and PRA may remain a biomarker of choice for patient stratification.

Highlights

Diabetic nephropathy (DN) is the primary cause of chronic kidney disease
The following Medical Subject Headings (MeSH) were used in the search: diabetic nephropathy (DN) OR “diabetic kidney disease” AND “renin inhibitor” OR “aliskiren” OR “remikiren” OR “enalkiren” OR “zankiren.” We used filters to select the type of study, and we gathered data from clinical trials and from case–control and cohort studies and reviews, designed to assess the effects of Direct renin inhibitors (DRIs) on plasma renin activity (PRA) in DN
Of 920 potentially relevant papers initially identified through the PubMed search, after deduplication, we reviewed 918 titles and abstracts; from these, we included 878 in a full-text review

Summary

Introduction

Diabetic nephropathy (DN) is the primary cause of chronic kidney disease. Despite therapeutic advances, DN remains the principal cause of mortality in diabetic patients (Dugbartey, 2017).Renin–angiotensin system (RAS) has been classically involved in the progression of diabetic cardiovascular disease. Diabetic nephropathy (DN) is the primary cause of chronic kidney disease. DN remains the principal cause of mortality in diabetic patients (Dugbartey, 2017). The therapeutic drugs for DN currently consist mainly of angiotensin II (Ang II) receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) used for their antihypertensive and antiproteinuric measures (Bhattacharjee et al, 2016). Direct renin inhibitors (DRIs) acting on rate-limiting enzyme of the RAS offered probability of a greater inhibition of the system so as to have better therapeutic outcomes in patients with DN (Parving et al, 2008). Larger trials of the DRI aliskiren in combination with an ACE inhibitor or ARB in patients with DN did not reduce cardiovascular or renal outcomes (Parving et al, 2012)

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