Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients

Background, Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function, Methods. Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study, Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation, Results, After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8 +/- 1.6 (mean +/- SEM) to 44.1 +/- 6.8 pmol/L (P < 0.001) in association with a threefold increase in urine cGMP excretion (573 +/- 195 pmol/min baseline to 1823 +/- 545 pmol/ min; P < 0.001), marked natriuresis (207 +/- 34 mu mol/min baseline to 416 +/- 62 mu mol/min; P < 0.001), fractional sodium excretion (3.3 +/- 0.5% baseline to 5.6 +/- 0.7%; P < 0.01), and diuresis (3.4 +/- 0.5 ml/min baseline to 7.4 +/- 1 ml/min; P < 0.001), All parameters remained elevated above baseline for the remaining 7-hr study period. In response to candoxatrilat, the glomerular filtration rate rose by 19% (P = 0.01), renal plasma flow by 7% (P = 0.04), renal blood flow by 13% (P = 0.03) in association with an increase in filtration fraction from 24 +/- 2% to 28 +/- 2% (P = 0.002) and small fall in renal vascular resistance from 0.38 +/- 0.04 to 0.30 +/- 0.04 mmHg.min.1.73 m(2).ml(-1) (P = 0.02), There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) mu g/min (P < 0.01). Conclusions, Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.