With variable potencies atrial-, brain-type and c-type
natriuretic peptides (NP)s, best documented for
ANP and its analogues, promote
sodium and water excretion, renal blood flow, lipolysis, lower blood pressure, and suppress
renin and
aldosterone secretion through interaction predominantly with cGMP-coupled NPR-A receptor. Infusion of especially
ANP and its analogues up to 50 ng/kg/min in patients with high risk of
acute kidney injury (cardiac vascular bypass surgery, intraabdominal surgery, direct kidney surgery) protects kidney function (GFR, plasma flow, medullary flow,
albuminuria,
renal replacement therapy, tissue injury) at short term and also long term and likely additively with the
diuretic furosemide. This documents a pharmacologic potential for the pathway.
Neprilysin (NEP,
neutral endopeptidase) degrades NPs, in particular
ANP, and
angiotensin II. The drug
LCZ696, a mixture of the
neprilysin inhibitor
sacubitril and the ANGII-AT1 receptor blocker
valsartan, was FDA approved in 2015 and marketed as Entresto®. In preclinical studies of kidney injury,
LCZ696 and NPs lowered plasma
creatinine, countered
hypoxia and oxidative stress, suppressed proinflammatory
cytokines, and inhibited
fibrosis. Few randomized clinical studies exist and were designed with primary cardiac outcomes. The studies showed that
LCZ696/
entresto stabilized and improved glomerular filtration rate in patients with
chronic kidney disease.
LCZ696 is safe to use concerning kidney function and stabilizes or increases GFR. In perspective, combined AT1 and
neprilysin inhibition is a promising approach for long-term renal protection in addition to AT1 receptor blockers in
acute kidney injury and
chronic kidney disease.