ACUTE REVERSAL OF CYCLOSPORINE NEPHROTOXICITY BY NEUTRAL ENDOPEPTIDASE INHIBITION IN STABLE RENAL TRANSPLANT RECIPIENTS

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Abstract
Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function. 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. 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 μmol/min baseline to 416±62 μmol/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 m2·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) μg/min ( P <0.01). Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.