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with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn.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: Parminder Judge, Richard Haynes, Martin J Landray, Colin Baigent
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 30 Issue 5 Pg. 738-43 (May 2015) ISSN: 1460-2385 [Electronic] England
• PMID: 25140014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.

Chemical References

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

Topics

• 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, metabolism)
• Natriuresis (drug effects)
• Nephrology (trends)
• Neprilysin (antagonists & inhibitors)
• Proteinuria (drug therapy)
• Pyridines (therapeutic use)
• Renin-Angiotensin System (drug effects, physiology)
• Tetrazoles (chemistry)
• Thiazepines (therapeutic use)
• Treatment Outcome
• Valsartan