Prevention of acute cyclosporine-induced renal blood flow inhibition and improved immunosuppression with verapamil

Abstract

Pretreatment with calcium antagonists such as verapamil (VP) and isradipine prevents CsA-induced decrease in renal microcirculation in mice. Recently, in posttransplant cadaver renal transplant (CRT) recipients, we demonstrated a CsA-induced 70% reduction in renal parenchymal diastolic blood flow velocity (PDBFV). Using duplex Doppler scanning, this randomized study of forty CRT patients examines the effect of pretreatment with VP on renal blood flow velocity and posttransplant function. Patients with initially low PDBFV (less than 8.0 cm/sec) who received VP therapy prior to administration of CsA experienced prompt restoration of flow, and continued to improve during CsA administration. With CsA alone, PDBFV diminished from 8.9 +/- 2.4 (SD) to 5.3 +/- 2.7 cm/sec (P less than 0.002). Although blood CsA levels were significantly higher at 1, 4, and 7 days (68, 184, and 235 ng/ml, respectively), after CsA induction, during VP treatment than in control patients (39, 105, and 156 ng/ml, respectively) (P less than 0.001), with the same daily doses of CsA, serum creatinines at day 7 were lower during VP treatment (1.28 +/- 0.44 vs. 1.66 +/- 0.44 mg%) than in controls (P less than 0.01). When the glomerular filtration rate was less than 45 ml/min on day 1. VP-treated patients showed greater improvement in GFR at day 7 by 34.1 +/- 10.9 ml/min compared with the 18 +/- 13 ml/min in controls (P less than 0.02). Only 3 of the 22 VP patients had rejection episodes within 4 weeks, versus 10 of the 18 recipients randomized to no drug (P less than 0.005). We conclude that VP is beneficial in CRT because it improves renal blood flow characteristics and prevents CsA-induced inhibition of blood flow. VP also ameliorates CsA-induced acute nephrotoxicity, and is associated with improved immunosuppression and fewer early rejections.