Neprilysin inhibition in chronic kidney disease

Nephrol Dial Transplant. 2015 May;30(5):738-43. doi: 10.1093/ndt/gfu269. Epub 2014 Aug 18.


Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.

Keywords: cardiovascular disease; chronic kidney disease; heart failure; hypertension; neprilysin inhibition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aminobutyrates / chemistry
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Biphenyl Compounds
  • Cardiovascular Diseases / physiopathology
  • Clinical Trials as Topic
  • Disease Progression
  • Drug Combinations
  • Heart Failure / physiopathology
  • Humans
  • Hypertension / drug therapy
  • Kidney Failure, Chronic / drug therapy*
  • Kidney Failure, Chronic / metabolism*
  • Natriuresis / drug effects
  • Nephrology / trends
  • Neprilysin / antagonists & inhibitors*
  • Proteinuria / drug therapy
  • Pyridines / therapeutic use
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology
  • Tetrazoles / chemistry
  • Thiazepines / therapeutic use
  • Treatment Outcome
  • Valsartan


  • Aminobutyrates
  • Angiotensin-Converting Enzyme Inhibitors
  • Biphenyl Compounds
  • Drug Combinations
  • Pyridines
  • Tetrazoles
  • Thiazepines
  • omapatrilat
  • Valsartan
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination