New Pharmacologic Agents That Target Inflammation and Fibrosis in Nonalcoholic Steatohepatitis–Related Kidney Disease

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Abstract

Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)-related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver-kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver-kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti-inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin-converting enzyme-2 activators are new renin-angiotensin axis modulators that showed incremental advantages over angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator-activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll-like receptor-4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti-inflammatory therapies include inhibitors of NOD-like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor-κB, and of vascular adhesion protein-1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin-3 antagonists, and inhibitors of rho-associated protein kinase and of epidermal growth factor activation. The evidence, merits, and limitations of each approach for the treatment of NASH and CKD are discussed.

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