Neprilysin Inhibition and Effects on Kidney Function and Surrogates of Cardiovascular Risk in Chronic Kidney Disease
Authors: Matthew James, Braden Manns
Journal: Circulation (2018)

acubitril/valsartan is one of a new line of therapeutic agents for patients with heart failure.Given the relationships between kidney disease and structural heart disease, testing the impact of this new agent in patients with chronic kidney disease (CKD) is important.In this issue of Circulation, Haynes and colleagues 1 publish an article that assessed the effects of sacubitril/valsartan on kidney function in patients with CKD and albuminuria.Sacubitril is an inhibitor of neprilysin (neutral endopeptidase), an enzyme that degrades natriuretic peptides and other vasoactive peptides, including angiotensin II and bradykinin, leading to a variety of actions, including natriuresis, diuresis, vasodilatation, and counterregulation of the renal angiotensin system. 2 However, because it activates the angiotensin system (by raising angiotensin II levels), it is used in combination with angiotensin receptor blockers.The efficacy of sacubitril/valsartan in heart failure was established in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACE Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), a large randomized controlled trial of 8442 patients with class II or greater heart failure (ejection fraction <40%) who showed a reduction in death from cardiovascular causes or hospitalization for heart failure from 26.5% to 21.8%, when compared with treatment with angiotensinconverting-enzyme inhibition over a median follow-up of 27 months. 3Based on the results of this practice changing trial, in 2017, the Canadian Cardiovascular Society Heart Failure guidelines, 4 American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and Heart Failure Society of America updated their guidelines.The US guidelines now include sacubitril/valsartan as firstline therapy in conjunction with guideline-directed medical therapy 5 in patients with heart failure with reduced ejection fraction.The Canadian Cardiovascular Society Heart Failure and US guidelines recommend replacing an angiotensin-convertingenzyme inhibitors or angiotensin II receptor blockers with sacubitril/valsartan in patients with heart failure and reduced ejection fraction who remain symptomatic on angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers.It is important to note that patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m 2 were excluded from the PARADIGM-HF trial.Hence, the tolerability and efficacy of this medication in patients with more advanced CKD (eGFR <30 mL/min/1.73m 2 ) remains uncertain, although sacubitril/valsartan was noted to be effective in those with eGFR 30 to 60 mL/min/1.73m 2 (35% of patients within PARADIGM-HF).Indeed, cardiovascular disease and CKD frequently coexist, and cardiovascular events are more common than progression to end-stage kidney disease in patients with CKD. 6 Evidence of structural heart disease is present in the majority of patients with CKD by the time they reach end-stage kidney disease,