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) greater-than-or-equal-to 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.