Updates for Cardio‐Kidney Protective Effects by Angiotensin Receptor‐Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection

Abstract

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor‐neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin–angiotensin system inhibitors (RAS‐Is) in large clinical trials such as the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI [Angiotensin‐Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS‐Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM‐HF trial, ARNI was associated with more albuminuria compared with RAS‐I; thus, it is unclear whether long‐term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS‐I in patients with chronic kidney disease in the UK HARP‐III (United Kingdom Heart and Renal Protection‐III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS‐I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Updates on New Therapies for Patients with CKD

“… 62 , 63 Furthermore, there are no studies to evaluate the efficacy of ARNI over ACEi or ARB monotherapy in patients with CKD in the absence of HF. 64 Before randomization in the PARADIGM-HF and PARAGON-HF trials ( Supplementary Table S1 ), 42 , 57 approximately 10% to 15% of participants dropped out of the studies because of the adverse effects of hyperkalemia, renal dysfunction, or hypotension during the run-in period. After randomization, nearly 2% of the study participants had renal dysfunction defined as end-stage renal disease, a decrease of ≥50% in eGFR from the value at randomization or a decrease in eGFR of >30 ml/min per 1.73 m 2 .…”

Unraveling Chronic Cardiovascular and Kidney Disorder through the Butterfly Effect

“…Recent large-scale randomized controlled trials have brought attention to current therapeutic strategies. These include sodium-glucose cotransporter 2 (SGLT2) inhibitors [ 69 , 70 , 71 , 72 , 73 , 74 ], RAAS blockers [ 75 , 76 , 77 , 78 ], angiotensin receptor neprilysin inhibitors (ARNI) [ 79 , 80 ], mineralocorticoid receptor (MR) antagonists [ 81 , 82 , 83 ], and glucagon-like peptide 1 (GLP1) ± glucose-dependent insulinotropic peptide (GIP) receptor agonists [ 84 , 85 ]. These treatments show promise in preventing major adverse cardiac and kidney events (MACEs and MAKEs).…”

Renin–Angiotensin–Aldosterone System: From History to Practice of a Secular Topic

“…Natriuretic peptides (NPs) like atrial-NP, B-type NP or c-type NP are normally degraded by neprilysin. NEPis therefore increase the levels of these natriuretic peptides, promoting natriuresis and leading to improvement in myocardial relaxation, reduction in hypertrophy as well as blood vessel dilatation [36]. The two landmark trials PARADIGM-HF and PARAGON-HF demonstrated that ARNIs decrease CV death and heart failure hospitalization by 25-30% as compared to monotherapy with either ACEis or ARBs [35].…”