Inflammation as a therapeutic target to improve kidney and cardiovascular outcomes

Abstract

Chronic kidney disease (CKD) is a leading cause of premature death due to the loss of kidney function and development of kidney failure, and because of attendant major adverse cardiovascular events. High-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation, is associated with increased risks of cardiovascular events and CKD progression. CKD is characterized by a pro-inflammatory state with upregulation of inflammatory pathways and disruption of anti-inflammatory mechanisms. The resulting systemic inflammation, along with local tissue-based inflammatory mechanisms, are key contributors to kidney damage, atherosclerosis and cardiac dysfunction. As a result, a series of inflammatory pathways and mediators have emerged as potential therapeutic targets for CKD and its major cardiovascular complications. Investigational treatments that have targeted inflammation include inhibition of apoptosis signal-regulating kinase-1 (ASK1) by selonsertib, Janus kinase (JAK) 1/2 inhibition with baricitinib, protein kinase C-β (PKCβ) inhibition with ruboxistaurin, nuclear factor erythroid 2-related factor 2 (Nrf2) activation with bardoxolone, phosphodiesterase inhibition with pentoxifylline and monoclonal antibodies against IL-1β and IL-6. Furthermore, proven therapies for CKD, including renin–angiotensin–aldosterone system inhibitors, sodium–glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid antagonists, possess anti-inflammatory properties that might contribute to their previously established clinical benefits. Chronic kidney disease (CKD) is characterized by a pro-inflammatory state that contributes to kidney damage, atherosclerosis and cardiac dysfunction. This Review describes the epidemiology and pathogenesis of inflammation in CKD and outlines the therapeutic rationale for targeting inflammation to improve kidney and cardiovascular outcomes in patients with CKD.