Targeting inflammation in diabetic nephropathy: a tale of hope

ABSTRACT

Introduction: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Beyond the new anti-diabetic drugs that possess markedly cardiovascular and renal protective effects, no novel direct therapies for DN have become available on the market in the last twenty years. Recently well-designed clinical trials for the treatment of DN, with attractive pathogenetic rationale, e.g. bardoxolone and atrasentan, were canceled or stopped because of safety concerns or lack of reaching the end points, respectively.

Areas covered: In this review, we focus on the involvement of inflammation in the pathogenesis of DN. We update information from recent experimental and clinical studies that reported beneficial effects of several agents targeting chemokines, cytokines, transcription factors and kinases as well as several compounds with anti-inflammatory properties on DN.

Expert opinion: Inflammation plays a key role in the DN progression. Preclinical studies have identified several anti-inflammatory molecules that effective decrease albuminuria and/or proteinuria. However, limited clinical trials in humans have been performed to confirm these results. Inhibitors of CCL2/CCR2, IL-1β and JAK/STAT pathways, and Nrf2 inducers are promising therapeutic options to improve the renal outcome of patients with DN, but appropriate clinical trials are necessary.

KEYWORDS:

• Diabetic nephropathy
• albuminuria-proteinuria
• inflammation
• chemokines
• cytokines
• transcription factors
• kinase
• experimental models of diabetes

Article Highlights

• Despite the refining of treatment options for DN, based on RAAS system inhibition or new anti-diabetic drugs, an important number of DN patients progress to CKD and ESRD.

• Inflammation is a key player in the onset and progression of DN in T1DM and T2DM.

• In DN, activation of many transcription factors and kinases lead to the synthesis of pro-inflammatory chemokines, cytokines and adhesion molecules promoting leukocyte recruitment to the kidney.

• TNFR1/2 are currently the most reliable blood inflammatory biomarkers for DN outcomes.

• Experimental models of DN are important to identify novel therapeutic targets and to validate new anti-inflammatory treatments for this pathology.

• Anti-inflammatory molecules, including small compounds, monoclonal antibodies and synthetic peptides, resulted effective in reducing early kidney injury in pre-clinical studies.

• Observational clinical studies in humans have shown that targeting CCL2 and JAK kinases as well as pentoxifylline treatment ameliorate albuminuria in patients with DN, but studies on hard renal outcomes are needed.

• New anti-inflammatory therapy with Canakinumab, an anti-human IL1-β antibody, and Colchicine in patients with coronary artery disease, may boost the interest of pharmaceutical companies to pursuit targeting inflammation in DN and transform the tale of hope in reality.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors’ work has been supported by FEDER-FIS Funds [CP16/00017, PI16/01900, PI17/00130, PI17/00119, PI17/01495], Spanish Ministry of Economy and Competitiveness [SAF2015-63696-R, DTS17/00203], Spanish Society of Nephrology, Fundación Renal Iñigo Alvarez de Toledo (FRIAT), Red de Investigación Renal [REDinREN; RD16/009] and Comunidad de Madrid [B2017/BMD-3751 NOVELREN-CM]. FONDECYT Project N° [1160465, 21150768], CONICYT, Chile.