New therapeutic targets in chronic kidney disease progression and renal fibrosis

ABSTRACT

Introduction

The current therapeutic armamentarium to prevent chronic kidney disease (CKD) progression is limited to the control of blood pressure and in diabetic patients, the strict control of glucose levels. Current research is primarily focused on the reduction of inflammation and fibrosis at different levels.

Areas covered

This article examines the latest progress in this field and places an emphasis on inflammation, oxidative stress, and fibrosis. New therapeutic targets are described and evidence from experimental and clinical studies is summarized. We performed a search in Medline for articles published over the last 10 years.

Expert opinion

The search for therapeutic targets of renal inflammation is hindered by an incomplete understanding of the pathophysiology. The determination of the specific inducers of inflammation in the kidney is an area of heightened potential. Prevention of the progression of renal fibrosis by blocking TGF-β signaling has been unsuccessful, but the investigation of signaling pathways involved in late stages of fibrosis progression could yield improved results. Preventive strategies such as the modification of microbiota-inducers of uremic toxins involved in CKD progression is a promising field because of the interaction between the gut microbiota and the renal system.

KEYWORDS:

• Therapeutic target
• CKD
• chronic kidney disease
• inflammation
• renal fibrosis
• oxidative stress
• microbiota
• epithelial to mesenchymal transition
• SGLT2 antagonists

Article Highlights

• Besides hypertension and proteinuria, no other targets to stop glomerular filtration rate decrease exist in the nephrologist’s armamentarium.

• SGLT2 and GLP1 antagonists are promising new available medications that may soon assist in the cessation of CKD progression in diabetic patients.

• Inflammation, oxidative stress, and fibrosis are three new targets that show promising results in experimental models and clinical trials.

• Antagonists of TGF-β for the slowing of fibrosis have yielded conflicting results. Intervention in pathways in late fibrotic stages can be more effective.

• The use of antioxidants holds therapeutic potential. Bardoxolone results in phase 3 clinical trials were disappointing, although the compound is still under development and new trials are underway.

• The modification of the microbiota or the use of miRNA offer interesting preclinical results. Renal patients have altered microbiota, and some of the uremic toxins that drive renal fibrosis can be generated by those bacteria. This opens a new avenue that can be explored.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no 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 work of the authors was supported by the ISCIII and FEDER funds PI18/00610, and REDinREN RD016/009. Sandra Rayego-Mateos was supported by The ‘Juan de la Cierva de Formacion’ training program of the Ministerio de Economía, Industria y Competitividad, Gobierno de España (FJCI-2016-29050).