Prevention of Acute Graft Rejection by the Prostaglandin E₁Analogue Misoprostol in Renal-Transplant Recipients Treated with Cyclosporine and Prednisone

Abstract

Prostaglandins of the E series have been shown to have immunosuppressive properties. To study the effects of the prostaglandin E1 analogue misoprostol on renal function and graft rejection after transplantation, we conducted a randomized, double-blind, placebo-controlled trial in 77 renal-allograft recipients. The subjects received misoprostol (200 micrograms four times daily by mouth; n = 38) or placebo (n = 39) for the first 12 weeks after transplantation, in addition to standard immunosuppression with cyclosporine and prednisone. They were then observed for an additional four weeks after the drug or placebo was discontinued. Treatment with misoprostol was associated with a significant improvement in renal function as judged by the mean (+/- SEM) serum creatinine concentration (128 +/- 7 vs. 158 +/- 11 mumol per liter after 12 weeks; P = 0.03) and creatinine clearance (84 +/- 6 vs. 69 +/- 5 ml per minute per 1.73 m2 of body-surface area; P = 0.05). There was a significant reduction in the incidence of acute rejection in the group treated with misoprostol as compared with the placebo group (10 of 38 vs. 20 of 39; P = 0.02), and there was less need for rehospitalization after transplantation (4 +/- 1 days with misoprostol vs. 10 +/- 2 days for placebo; P = 0.03). Although blood levels of cyclosporine did not differ significantly between the groups, they tended to be higher in the misoprostol group, as did the incidence of acute nephrotoxicity due to cyclosporine (13 of 38 vs. 8 of 39). Infectious complications tended to be fewer in the misoprostol-treated group (14 of 38 vs. 21 of 39). We conclude that misoprostol improves renal function and safely reduces the incidence of acute rejection in renal-transplant recipients treated concurrently with cyclosporine and prednisone.

Calcineurin Inhibitor Nephrotoxicity

“…In rats, it was shown that prostaglandin E2 reduces nephrotoxicity of cyclosporine, but this was likely mediated by an interaction between prostaglandin E2 and intestinal cyclosporine absorption (368). Misoprostol, a prostaglandin E1 analog, reduced CNI nephrotoxicity in vitro and in rats treated with chronic cyclosporine (369,370), and in a human study, misoprostol was shown to improve renal function (371). This effect in humans was, however, associated with a lower incidence of acute rejection with misoprostol treatment, misoprostol in itself did not prevent the development of CNI nephrotoxicity in humans (371).…”

“…Misoprostol, a prostaglandin E1 analog, reduced CNI nephrotoxicity in vitro and in rats treated with chronic cyclosporine (369,370), and in a human study, misoprostol was shown to improve renal function (371). This effect in humans was, however, associated with a lower incidence of acute rejection with misoprostol treatment, misoprostol in itself did not prevent the development of CNI nephrotoxicity in humans (371). Likewise, another study in patients with rheumatoid arthritis did not observe any effect of misoprostol treatment on acute CNI nephrotoxicity (372).…”

Baboon-to-human liver transplantation

“…[6][7][8] We now describe a baboon-to-human liver xenotransplantation in which FK 506 and cyclophosphamide were given as immunosuppressants, together with prednisone and prostaglandin, both of which help to mitigate preformed antigraft antibody syndromes and cellular rejection. 9,10 …”

Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function

“…[1][2][3] Suggested regimens include OKT3 induction in combination with azathioprine and steroids, with or without low doses of calcineurin inhibitors. [4][5][6] A new option in this circumstance is the use of daclizumab with mycophenolate mofetil (MMF) and steroids.…”