Chronic Kidney Disease Progression Mechanisms: Why They Matter in an Era of Novel Kidney Protective Therapies

Research over several decades has identified multiple factors that contribute to a complex pathway of mechanisms that drive the progression of chronic kidney disease (CKD) across all etiologies. These include glomerular hypertension and hyperfiltration, proteinuria, and tubulointerstitial fibrosis. These endeavors identified multiple therapeutic targets for achieving kidney protection, starting with angiotensin II, which led to the development of renin-angiotensin-aldosterone system inhibitors as the first effective kidney protective therapies. Following a long period of stagnation, several additional kidney protective drug classes have been developed, including sodium glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid antagonists, and glucagon-like peptide-1 receptor agonists. The effects of all of these drugs can readily be understood within the framework of previously described CKD progression mechanisms. The development of additional novel kidney protective drug classes has been informed by our understanding of progression mechanisms and include endothelin receptor antagonists, soluble guanylate cyclase stimulators or activators, and aldosterone synthase inhibitors. This review of novel therapies in the light of CKD progression mechanisms highlights the importance of ongoing research to identify new therapeutic targets as we seek to achieve complete arrest and even reversal of CKD progression.