Design and optimization strategies for the development of new drugs that treat chronic kidney disease

ABSTRACT

Introduction: Chronic kidney disease (CKD) is characterized by increased risks of progression to end-stage kidney disease requiring dialysis and cardiovascular mortality, predicted to be among the five top causes of death by 2040. Only the design and optimization of novel strategies to develop new drugs to treat CKD will contain this trend. Current therapy for CKD includes nonspecific therapy targeting proteinuria and/or hypertension and cause-specific therapies for diabetic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritides, Fabry nephropathy, hemolytic uremic syndrome and others.

Areas covered: Herein, the authors review the literature on new drugs under development for CKD as well as novel design and development strategies.

Expert opinion: New therapies for CKD have become a healthcare priority. Emerging therapies undergoing clinical trials are testing expanded renin-angiotensin system blockade with double angiotensin receptor/endothelin receptor blockers, SGLT2 inhibition, and targeting inflammation, the immune response, fibrosis and the Nrf2 transcription factor. Emerging therapeutic targets include cell senescence, complement activation, Klotho expression preservation and microbiota. Novel approaches include novel model systems that can be personalized (e.g. organoids), unbiased systems biology-based identification of new therapeutic targets, drug databases that speed up drug identification and repurposing, nanomedicines that improve drug delivery and RNA targeting to expand the number of targetable proteins.

KEYWORDS:

• Chronic kidney disease
• SGLT2
• diabetic kidney disease
• polycystic kidney disease
• nanomedicine
• drug repurposing

Article highlights

• Chronic kidney disease is projected to become one of the top five causes of death by 2040

• Only the design and optimization of novel strategies to develop new drugs to treat chronic kidney disease will contain this trend

• Development of new therapeutic approaches will rely on a smart combination of novel model systems, unbiased systems biology-based identification of new therapeutic targets and drug databases that speed up drug identification and repurposing

• SGLT2 inhibitors hold promise beyond diabetes

• Promising drug targets include inflammation, cell senescence and Klotho preservation

• Nanomedicines and RNA targeting strategies may overcome some limitations of current drugs

This box summarizes key points contained in the article.

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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

The authors are supported by the Fondo de Investigación Sanitaria (FIS)-Instituto de Salud Carlos III (ISCIII)/FEDER Funds: [PI16/02057, PI16/01900, PI17/00119, PI18/01366, PI18/01133]; the Instituto de Salud Carlos III (ISCIII)/FEDER Funds: [RETIC-REDinREN, RD016/0009]; Sociedad Española de Nefrología; Comunidad de Madrid en Biomedicina [B2017/BMD-3686 CIFRA2-CM]; the Fundación Iñigo Alvarez de Toledo (FRIAT) and ERA-PerMed-JTC2018 [AC18/00071; DTS18/00032]. A Sanz and MD Sanchez-Niño declare that they have also received salary support via a Miguel Servet Contract (Instituto de Salud Carlos III) while MV Pérez-Gómez has received support via a Juan Rodés Contract (Instituto de Salud Carlos III).