Targeting pharmacotherapies for inflammatory and cardiorenal endpoints in kidney disease.

Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with CKD. Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardio-rheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit activation of the NLRP3 inflammasome and the downstream cytokines IL-1 and IL-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, SGLT-2 inhibitors, and GLP-1 agonists. Finally, emerging therapies in CKD such as IL-6 inhibition, small-interfering RNA against lipoproteins, AhR inhibitors, and therapies adopted from the renal transplant population including mTOR inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.