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 micromol/min baseline to 416+/-62 micromol/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 x min x 1.73 m2 x 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) microg/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.
Lipkin
G W
GW
Department of Nephrology, St. Bartholomew's Hospital, London, United Kingdom.
Thuraisingham
R
R
Dawnay
A B
AB
Harwood
S M
SM
Raine
A E
AE
D000328:Adult; D000368:Aged; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000097:blood; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D016572:Cyclosporine / Q000009:adverse effects*; D004231:Diuresis / Q000187:drug effects; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
D003509:Cyclohexanecarboxylic Acids; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; C060942:candoxatrilat; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015260:Neprilysin; D006152:Cyclic GMP