Cyclosporine-induced elevation in circulating endothelin-1 in patients with solid-organ transplants.
The long-term use of cyclosporine is associated with significant complications, including hypertension and renal failure. Recent data from animal experiments suggest that alterations in renal function induced by high-dose CsA may be mediated by endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor and mitogenic peptide. The aim of the present study was to determine the effect of oral CsA on circulating levels of ET-1 in patients receiving standard immunosuppressive therapy following solid-organ transplantation (13 renal, 7 heart, 1 heart-lung, 1 liver). Plasma levels of ET-1 were measured by radioimmunoassay over a 24-hr period beginning with the oral administration of a single daily dose of CsA in 18 patients (5.6 +/- 0.5 mg/kg), or similar immunosuppressive therapy without CsA in 4 patients. Blood levels of CsA (parent compound and metabolites) were measured in 10 of the patients by RIA. Predose levels of ET-1 were similar in the two groups (1.73 +/- 0.32 and 1.29 +/- 0.9 pg/ml, respectively). Patients not receiving CsA showed no change in plasma ET-1 over the 24-hr period. In contrast, in the CsA-treated group there was a significant increase in plasma ET-1, reaching a peak at 6 hr (2.45 +/- 0.56 pg/ml, P < 0.03) that followed the peak increase in CsA parent compound and preceded the peak increase in metabolites. No significant differences were found between peak and trough levels of ET-1 in patients with moderate renal dysfunction (creatinine (Cr) > or = 150 mumol/L) compared with those with near-normal renal function, or patients receiving renal compared with nonrenal grafts. However, patients with long-term grafts (> 60 days) showed an exaggerated response to CsA, with a fractional increase in plasma ET-1 of 3.67 +/- 0.52 (n = 8) compared with 2.16 +/- 0.28 (n = 10) for patients with more recent grafts (P < 0.05). Therefore, oral administration of CsA causes an increase in circulating ET-1 in patients with solid-organ transplants that might contribute to CsA-associated nephrotoxicity and hypertension, particularly during long-term immunosuppressive therapy.
Grieff
M
M
McGill Vascular Biology Group, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
Loertscher
R
R
Shohaib
S A
SA
Stewart
D J
DJ
D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D001794:Blood Pressure; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use*; D016232:Endothelins / Q000097:blood*; D005260:Female; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D016041:Heart-Lung Transplantation / Q000276:immunology / Q000502:physiology; D006801:Humans; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D016031:Liver Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use
D016232:Endothelins; D016572:Cyclosporine; D003404:Creatinine; D001379:Azathioprine; D011241:Prednisone