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

Combined inhibition of neprilysin (NEP) and the angiotensin II receptor through angiotensin receptor-neprilysin inhibitors (ARNIs) has transformed heart failure management and is garnering increasing attention in nephrology. This article explores the renal role of NEP and critically reviews preclinical and clinical evidence on the use of ARNIs in CKD, following a bench-to-bedside approach. Experimental data show that NEP inhibition improves proteinuria, fibrosis, and endothelial function, with enhanced benefits when combined with renin-angiotensin-aldosterone system blockade. Randomized clinical trials in patients with heart failure (HF) (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], Prospective Comparison Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in Heart Failure with Preserved Ejection Fraction [PARAGON-HF], Prospective comparison of Angiotensin Receptor-neprilysin inhibitor with Angiotensin-Receptor Blockers Given following stabiLization In DEcompensated Heart Failure with preserved ejection fraction [PARAGLIDE-HF]) have demonstrated renal safety and potential benefit emerged in secondary end points and prespecified analysis. The only randomized clinical trial performed with primary kidney outcome, the UK Heart and Renal Protection III (HARP-III) trial, confirmed the tolerability of sacubitril/valsartan, 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, sacubitril/valsartan 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.