title: Neprilysin inhibition in chronic kidney disease.
abstract: 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with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn.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.
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
authors.forename: Parminder
authors.initials: P
authors.lastname: Judge
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Haynes
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Landray
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Baigent
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds; D002318:Cardiovascular Diseases / Q000503:physiopathology; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004338:Drug Combinations; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects; D009398:Nephrology / Q000639:trends; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000188:drug therapy; D011725:Pyridines / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000737:chemistry; D013841:Thiazepines / Q000627:therapeutic use; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011725:Pyridines; D013777:Tetrazoles; D013841:Thiazepines; C106266:omapatrilat; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: cardiovascular disease; chronic kidney disease; heart failure; hypertension; neprilysin inhibition