Angiotensin Receptor and Neprilysin Inhibitors in CKD: Opportunity or Concern?

: Combined inhibition of neprilysin and the angiotensin II receptor through Angiotensin Receptor-Neprilysin inhibitors (ARNI) has transformed heart failure management and is garnering increasing attention in nephrology. This article explores the renal role of neprilysin and critically reviews preclinical and clinical evidence on the use of ARNIs in CKD, following a "bench to bedside" approach. Experimental data show that neprilysin inhibition improves proteinuria, fibrosis, and endothelial function, with enhanced benefits when combined with RAAS blockade. Randomized Clinical Trials (RCTs) in Heart Failure patients (PARADIGM-HF, PARAGON-HF, PARAGLIDE-HF) have demonstrated renal safety and potential benefit emerged in secondary endpoints and prespecified analysis. The only RCT performed with primary kidney outcome, the UK HARP-III trial, confirmed the tolerability of Sac/Val, and reported a significant reduction in proteinuria. No clear nephroprotective effect was observed; however, the trial design may not have been adequately structured to detect such an effect. On the other hand, real-world data indicate that ARNIs have an acceptable risk profile when patients are appropriately monitored, as Renin-Angiotensin-Aldosterone System blockers. Moreover, the benefits of the treatment clearly outweigh the adverse effects. Therefore, Sac/Val may emerge as a promising therapeutic option in nephrology, especially in patients with cardiorenal disease, pending further trials to better define its role in CKD.