Do Neprilysin Inhibitors Have a Role in Patients With CKD?

Tejas P. Desai, MD


December 14, 2018

Neprilysin inhibitors offer a new target for therapeutics. Neprilysin is an enzyme that degrades endogenous natriuretic peptides.[1] These peptides are secreted during times of fluid overload when the heart (specifically the atrium) is stretched. The peptides signal the kidneys to increase elimination of salt to help reduce the excess volume, but neprilysin curtails that response by degrading natriuretic peptides. Unfortunately, the body can overcome the effect of neprilysin inhibitors by increasing production of angiotensin II. Thus, a combination of inhibitors (ie, neprilysin inhibitor plus angiotensin II-receptor blocker) could potentiate the effect of these peptides and facilitate a greater amount/duration of natriuresis that can restore the patient to euvolemia.

Indeed, in the PARADIGM-HF trial, a combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II-receptor blocker) resulted in improved cardiovascular outcomes.[2] In a subgroup analysis, the combination pill seemed to retard the progression of kidney function decline and generated the hypothesis that dual therapy could preserve kidney function better than monotherapy with an angiotensin II-receptor blocker alone. These findings formed the basis for the UK HARP-III trial.[3]


In the UK HARP-III trial, 414 patients with kidney disease were randomly assigned to receive sacubitril/valsartan versus irbesartan alone.[3] The patients had relatively mild-moderate kidney disease (estimated glomerular filtration rate [eGFR] of 45-60 mL/min/1.73 m2 and a urine albumin:creatinine ratio [UACR] of 177 mg/g or greater, or an eGFR 20-44 mL/min/1.73 m2, irrespective of UACR) and were followed for 12 months. The primary outcome was the measured kidney function at the end of the study period.

Unfortunately, the positive results seen with cardiovascular outcomes in PARADIGM-HF were not seen observed in the UK HARP-III trial. The mean eGFR was 35.5 mL/min/1.73 m2 and fell to 29.8 and 29.9 ml/min/1.73 m2 in the dual-therapy and monotherapy arms, respectively (P = .86). In the prespecified subgroup analyses, there were no differences in the eGFR at study's end in either group when filtered for age, sex, magnitude of proteinuria, or etiology of chronic kidney disease. In fact, at no time point during the 12-month study period was the eGFR higher in the neprilysin arm than in the ARB arm.

What Are Your Thoughts on Neprilysin Inhibitors for CKD?

Despite the current negative findings, I wonder whether neprilysin inhibition can still have a role in patients with proteinuric kidney disease. While the majority of patients enrolled were assumed to have diabetic kidney disease, the mean proteinuria was 310 mg/g.

I also wonder whether a longer duration of treatment is required to see a difference in eGFR. I don't think we should shut the door on neprilysin inhibitors just yet as they relate to renal protection.

What do you think? Is the UK HARP-III trial a definitive trial on this subject? What type of patients would you like to see enrolled in a future trial that studies neprilysin inhibitors? Tell us in the comments section below.

Follow Tejas P. Desai, MD, on Twitter: @nephondemand

Follow Medscape Nephrology on Twitter for more nephrology news: @MedscapeKidney


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: