Original Article
Prevention of Acute Graft Rejection by the Prostaglandin E1 Analogue Misoprostol in Renal-Transplant Recipients Treated with Cyclosporine and Prednisone
N Engl J Med 1990; 322:1183-1188April 26, 1990
- Abstract
- 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 μg 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 μmol 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. (N Engl J Med 1990; 322: 1183–8.)
Media in This Article
Figure 1
Kaplan–Meier Survival Curve (Time to First Event) for Acute Graft Rejection.Figure 2
Kaplan–Meier Survival Curve (Time to First Event) for Acute Cyclosporine Nephrotoxicity.Article Activity
- Article
PROSTAGLANDINS of the E and I series exhibit immunosuppressive effects.1 2 3 4 5 Two factors, however, have restricted the study in humans of the immunosuppressive potential of prostaglandins: the need to administer pharmacologic doses to animals to achieve immunosuppression, and the unavailability of oral preparations of prostaglandins.
Prostaglandins of the E series alter renal function by regulating perfusion pressure and the distribution of renal blood flow.6 7 8 9 If renal injury is present, the inhibition of prostaglandin synthesis can further worsen renal function.10 11 12 In contrast, analogues of prostaglandin E1 or prostacyclin have been shown to reduce the renal injury that follows experimentally induced ischemia.13 , 14
Cyclosporine is a potent and effective immunosuppressive agent that has enhanced the success of organ transplantation.15 16 17 18 Its use is limited, however, by its nephrotoxicity.19 20 21 Clinical attempts to minimize the nephrotoxic effects of cyclosporine have been directed primarily toward reducing the dose of the drug or eliminating the use of it altogether.22 23 24 25 With these approaches, however, immunosuppression may be reduced, and acute rejection of the allograft can occur.26 The pathogenesis of cyclosporine nephrotoxicity is uncertain, but it may involve the inhibition of the synthesis of renal prostaglandins.27 28 29 30 In rodents, an analogue of prostaglandin E1 largely reverses the acute renal dysfunction induced by cyclosporine,31 confirming the findings of earlier experiments.32 33 34
In the clinical setting of renal transplantation, episodes of immunologic, ischemic, or toxic injury may impair allograft function. We hypothesized, therefore, that prophylactic treatment with misoprostol, a prostaglandin E1 analogue with oral bioavailability, would improve renal function after transplantation. Our study was designed to determine whether therapy with misoprostol would improve the function of renal allografts and reduce the incidence of acute rejection in patients whose immune function was suppressed with cyclosporine and glucocorticoids.
Methods
The study was a prospective, randomized, double-blind comparison of misoprostol with placebo in renal-transplant recipients. Misoprostol (Cytotec, G.D. Searle, Skokie, Ill.) is a racemic prostaglandin E1 analogue. Its chemical formula is (±)methyl-11α, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate. Misoprostol is currently approved for use in the prevention of gastric ulcers caused by nonsteroidal antiinflammatory drugs and is given in doses of up to 200 μg four times a day by mouth.
The protocol was reviewed and approved by the institutional review board of the University of Illinois. Written informed consent was obtained from each subject. Subjects were ineligible for entry if they had a medical or psychiatric condition that was judged to preclude compliance with the protocol. To minimize variability in immunosuppressive regimens, subjects were also excluded if a need for the long-term use of azathioprine could be reliably foreseen. In addition, subjects were ineligible if they were known to be pregnant or hypersensitive to prostaglandin analogues.
Stratification and Randomization
Subjects were stratified according to the source of the renal allograft — i.e., a cadaver or a living related donor. They were then randomly assigned in the order of their enrollment to receive either misoprostol or placebo, according to a computer-generated assignment schedule. Adherence to random assignment was confirmed by G.D. Searle and Company, which held the only master code. None of the investigators had access to the code until the study had been completed.
Immunosuppressive Regimen
Immunosuppression therapy was initiated with cyclosporine (Sandimmune [Sandoz, Hanover, N.J.], 14 mg per kilogram of body weight per day) administered orally 6 to 12 hours before transplantation. If the drug could not be given by mouth, it was given intravenously (1 to 3 mg per kilogram every 12 hours) for 24 to 72 hours. The oral dose was then gradually reduced in each subject with reference to the blood level of the drug, so that the dose was approximately 6 mg per kilogram per day after 16 weeks. Maintenance doses of cyclosporine were intended to keep trough blood levels between 200 and 400 ng per milliliter as measured by polyclonal radioimmunoassay (RIA, Sandoz) or between 100 and 150 ng per milliliter by high-performance liquid chromatography.
Glucocorticoids were also administered; an initial dose of methyl-prednisolone (500 mg) was given intravenously at the time of transplantation. Subsequently, prednisone was administered orally in a dose of 1.0 mg per kilogram per day, which was tapered gradually to approximately 0.3 mg per kilogram per day after 16 weeks.
Diagnosis and Treatment of Acute Cyclosporine Nephrotoxicity
An episode of acute nephrotoxicity was indicated by the presence of elevated cyclosporine blood levels and deteriorating renal function in the absence of other known causes of renal dysfunction. Most important, in the absence of other therapy, renal function had to improve within one week after reduction of the dose of cyclosporine. If necessary, percutaneous renal biopsy was performed to confirm the diagnosis of acute nephrotoxicity and to rule out acute graft rejection.35 , 36
Diagnosis and Treatment of Acute Graft Rejection
Episodes of rejection were routinely confirmed by percutaneous renal biopsy.37 However, if cyclosporine blood levels were elevated, the confirmatory biopsy could be delayed for several days after a reduction in the dose of cyclosporine. Rejection was treated initially with intravenous methylprednisolone (500 mg per day for 3 days) or with oral prednisone (2 mg per kilogram, rapidly tapered to 0.3 mg per kilogram over a period of 18 days). The use of the monoclonal antibody OKT3 (Muromonab-CD3 [Orthoclone OKT3], Ortho Pharmaceuticals, Raritan, N.J.) was reserved for treatment of episodes that were resistant to steroid therapy. Azathioprine could also be administered for a short period during OKT3 therapy.38
Experimental Drug Regimen
Misoprostol (200 μg four times a day by mouth) or placebo was administered simultaneously with the first dose of cyclosporine and continued thereafter for 12 weeks. The placebo tablets were identical in appearance to those of misoprostol but contained only excipients. The tablets were counted to assess compliance with the regimen. Twelve weeks after transplantation, both misoprostol and placebo were discontinued. While the subjects continued to receive cyclosporine and prednisone, they remained under observation for another four weeks.
Measurements of Cyclosporine Blood Levels
Trough cyclosporine blood levels were measured on days 1, 3, 5, and 7 during the first week after transplantation, then twice weekly through the fourth week and once weekly during weeks 5 to 16.
Measurements of Renal Function
Serum creatinine concentrations were measured daily during the initial hospitalization for transplantation. Subsequently, they were measured at least twice weekly for three weeks and monthly thereafter until the termination of the study 16 weeks after transplantation. The 24-hour creatinine clearances were measured after transplantation, initially on days 1, 2, 3, and 7, then weekly for three weeks, and monthly thereafter.
Physical Examinations and Laboratory Screening
Patients were followed with serial medical histories and physical examinations. Routine hematologic and chemical screening tests were performed. Women capable of childbearing underwent testing for pregnancy before transplantation and again after completing the study.
Concomitant Medications
The use of cimetidine and trimethoprim — drugs that may affect the tubular secretion or chemical measurement of creatinine — was avoided during the measurements of renal function. Nonsteroidal antiinflammatory drugs other than acetaminophen were also avoided. Antibiotic, diuretic, and antihypertensive agents were given as dictated by clinical circumstances.
Episodes of Acute Renal Dysfunction
Each episode of acute renal dysfunction was assigned to a single diagnostic category. An episode was characterized by a rise in the serum creatinine concentration of at least 18 μmol per liter (0.2 mg per deciliter) per day for two consecutive days, or more than 27 μmol per liter (0.3 mg per deciliter) in one day; or by oliguria (defined as the excretion of less than 600 ml of urine per day) that was unresponsive to a challenge with fluids or the intravenous administration of a diuretic. An episode was considered to have ended when the serum creatinine concentration returned to base line or rose to a new (higher) level that remained stable for at least three days.
The diagnostic categories of renal dysfunction were: (1) acute graft rejection, as described above; (2) acute cyclosporine nephrotoxicity, as described above; (3) primary renal nonfunction, occurring immediately after transplantation and, except as noted above, resolving spontaneously; (4) cytomegalovirus nephritis, diagnosed in an appropriate clinical setting associated with seroconversion, a fourfold rise in anti-cytomegalovirus IgG titer, or a positive culture, and in the absence of rejection on renal biopsy39; (5) prerenal azotemia, with acute oliguria responding to the administration of fluids; (6) obstructive uropathy, confirmed by renal scanning or ultrasonography; (7) vascular thrombosis, confirmed by scanning or arteriography; and (8) unknown or uncertain, a category employed when an episode could not be definitively assigned to one of the other seven categories.
Statistical Analysis
Statistical analysis was performed with unpaired t-tests (two-sided), chi-square testing, Wilcoxon's nonparametric test, analysis of variance, logistic regression analysis, Kaplan–Meier survival analysis, and the log-rank test (SAS, SAS Institute Inc., Cary, N.C.). Data are shown for the entire population of subjects who were enrolled (the "intention-to-treat" cohort) and, as appropriate, only for the subjects who completed the study (the "study-completing" cohort). Results are expressed as means ±SEM.
Results
Characteristics of the Subjects on Entry
Between January 15, 1987, and January 1, 1988, 77 consecutive subjects were enrolled in the study at two study centers (University of Illinois Transplant Center sites in Chicago and Peoria). Only one eligible subject refused to participate. Thirty-eight subjects were assigned to receive misoprostol, and 39 to receive placebo. The two groups were well matched for demographic and immunologic characteristics (Table 1Table 1
Characteristics of the Study Groups at Entry.*). Of the 77 subjects who entered the trial, 65 completed the full 16 weeks of the study. Five subjects treated with misoprostol did not complete the study (one withdrew voluntarily, one was withdrawn because of noncompliance, one because of an adverse event unrelated to renal functioning, one because of a major protocol violation, and one because of irreversible acute rejection). Seven subjects in the placebo group did not complete the study (two because of noncompliance, one because of cancellation of the transplantation, three because of a nonrenal adverse event, and one because of irreversible acute rejection).Routine Immunosuppression
Cyclosporine and prednisone were administered in doses that were progressively tapered and that did not differ between the two groups. Cyclosporine blood levels were variably higher in the group receiving misoprostol; the differences were statistically significant during only 1 of the 16 weeks of treatment (week 3) as measured by high-performance liquid chromatography, but during none of 16 weeks as measured by radioimmunoassay (Table 2Table 2
Doses of Routine Immunosuppressive Agents and Cyclosporine Blood Levels in the Study Groups.*).Renal Function
During the early postoperative period there was no notable difference between the two groups. Within four weeks, however, serum creatinine concentrations were significantly lower in the group treated with misoprostol — an improvement in renal function that was sustained through the study. The changes in creatinine clearance reflected a similar improvement (Table 3Table 3
Renal Function after Transplantation.*).Episodes of Acute Renal Dysfunction
In the group given placebo, there were 62 episodes of acute renal dysfunction in 33 subjects. In the group given misoprostol, by contrast, there were 42 episodes in 29 subjects (Table 4Table 4
Episodes of Acute Renal Dysfunction during Treatment with Misoprostol or Placebo (Weeks 1 to 12).). The number of patients who had acute graft rejection was significantly lower in the misoprostol-treated group (10 of 38 [26 percent] vs. 20 of 39 [51 percent]; P = 0.02) (Fig. 1Figure 1Kaplan–Meier Survival Curve (Time to First Event) for Acute Graft Rejection.). Although the number of patients who had primary nonfunction was also lower in the misoprostol-treated group (9 of 38 vs. 16 of 39; P not significant), the incidence of acute nephrotoxicity due to cyclosporine was higher (13 of 38 vs. 8 of 39; P not significant) (Fig. 2Figure 2Kaplan–Meier Survival Curve (Time to First Event) for Acute Cyclosporine Nephrotoxicity.).Graft rejection adversely affected renal function in both study groups (Table 5Table 5
Serum Creatinine Concentrations after 12 Weeks, According to Treatment and the Occurrence of Acute Graft Rejection.*). Treatment with misoprostol, however, was associated with improved renal function whether or not rejection had occurred.Cyclosporine Blood Levels and Acute Renal Dysfunction
We explored further the relation between cyclosporine blood levels and the occurrence of acute graft rejection or acute cyclosporine nephrotoxicity. The finding of a difference in blood levels between the two groups during week 3 after transplantation was not associated with a significant difference in the rate of acute rejection or cyclosporine nephrotoxicity (Table 2 and Fig. 1 and 2). Furthermore, logistic regression analysis showed that the only significant predictors of acute rejection were a maximal value above 30 percent on previous testing for panel-reactive antibodies (indicating an increase in the rejection rate; P = 0.01) and treatment with misoprostol (indicating a decrease; P = 0.01). Cyclosporine blood levels were not predictive in themselves.
Blood Pressure
The incidence of hypertension in this cyclosporine-treated population was high, as expected. Blood-pressure levels were similar in the two groups, and the number of classes of antihypertensive agents needed to achieve satisfactory control of blood pressure was also not different (data not shown).
Adverse Events
The two groups reported similar numbers of adverse events, most notably diarrhea, which occurred in 15 of the 38 patients given misoprostol and 13 of the 39 given placebo. Acidosis occurred in 11 patients given misoprostol and 16 given placebo. Despite the evidence of enhanced immunosuppression with misoprostol (Table 4 and Fig. 1), the incidence of infectious complications was not higher (misoprostol vs. placebo, 14 of 38 vs. 21 of 39; P not significant). As was consistent with the findings regarding acute graft rejection and infections occurring after transplantation, the period of rehospitalization was shorter in the misoprostol-treated group (4±1 vs. 10±2 days; P = 0.03).
Discussion
In the current study we tested the hypothesis that the prostaglandin E1 analogue misoprostol favorably influences renal function in cyclosporine-treated recipients of renal transplants. The observation of lower serum creatinine concentrations and correspondingly higher creatinine clearances supports the hypothesis that treatment with misoprostol improves renal function in such patients.
The incidence of acute graft rejection was significantly reduced, suggesting that misoprostol has an adjunctive immunosuppressive effect. Both endogenous and synthetic exogenous prostaglandins of the E series may alter immune responsiveness.1 2 3 4 5 Misoprostol has been shown to inhibit the proliferative response in mixed lymphocyte culture40 and to augment the inhibitory effect of steroids in this assay (unpublished data). Moreover, we have recently shown that in animals subjected to cardiac transplantation, misoprostol improves graft survival and reduces the need for cyclosporine.41 When administered by itself in the approved doses for humans, however, misoprostol does not manifest immunosuppressive activity.42 43 44 Therefore, the presence of another immunosuppressive agent appears to be important. Synergy between eicosanoids and other immunosuppressants has been demonstrated previously and may underlie the enhancement of immunosuppression that we observed in the current study.3 , 5
The reduced incidence of acute graft rejection was unrelated to cyclosporine blood levels, although these tended to be higher in patients treated with misoprostol. However, differences in cyclosporine levels of the magnitude that we observed are unlikely to account for a reduction in the rate of rejection from 51 percent to 26 percent.45 Thus, we cannot confirm in the clinical setting the observations in rodents that prostaglandin E analogues reduce cyclosporine absorption and result in a secondary impairment of immunosuppressive activity.46 In contrast, we actually observed a higher incidence of acute cyclosporine nephrotoxicity in patients treated with misoprostol, although this finding was not statistically significant.31 Renal function was nonetheless superior in the misoprostol-treated subjects whether or not acute rejection occurred.
In summary, our findings indicate that the prostaglandin E1 analogue misoprostol significantly improves renal function in recipients of renal allografts. In the presence of cyclosporine and prednisone, misoprostol reduces the incidence of acute graft rejection without increasing the risk of post-transplantation complications.
Supported by an educational grant from G.D. Searle and Co.
Presented in part at the 21st Annual Meeting of the American Society of Nephrology, San Antonio, December 1988.
In accordance with the Journal's policy, the authors have stated that Dr. Moran has stock options in Monsanto, Inc., and in its fully owned subsidiary, G.D. Searle and Co., which makes misoprostol; and that Dr. Pollak is a consultant to G.D. Searle and Co.
We are indebted to the nurses and staff of the transplantation units and clinics for their able assistance and to Dr. David Nitzberg and Dr. Jane Yardley for their thoughtful examination of the data.
Source Information
From the University of Illinois, Division of Transplantation (Chicago: M.F.M., R.P., O.J.; Peoria: B.K.) and the Department of Pharmacy Practice (M.S.M., S.V.), Chicago; and from Clinical Research and Development, G.D. Searle and Co., Skokie, Ill. (M.M., C.B., C.W.). Address reprint requests to Dr. Moran at Clinical R&D, A-3W, G.D. Searle and Co., 4901 Searle Pky., Skokie, IL 60077.
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