Methods

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From August 1991 to December 1992, kidney cadaveric donors were randomly allocated, in blocks of four, to receive BN 52021 (Institut Henri Beaufour, Le Plessis Robinson, France) or placebo. Donors were treated with BN 52021, 240 mg intravenously, or placebo in the surgical room just before kidney harvesting. The kidneys were perfused and stored at 4 °C using BN 52021, 0.08 mg per millilitre of University of Wisconsin solution or using placebo, respectively. Donors and recipients received the same substance (either BN 52021 or placebo). Following the same schedule, recipients receiving their first renal transplants were treated with either BN 52021 or placebo. In the BN 52021 group, the patients received 160 mg of BN 52021 intravenously 10 minutes before renal allograft blood reperfusion; 12 hours later they received 80 mg intravenously followed by 80 mg every 8 hours for 4 days. Patients received placebo according to the same schedule.

We excluded donors whose hearts were not beating and donors whose serum creatinine levels just before kidney harvesting were more than 200 µmol/L. Patients receiving kidney transplants (and their corresponding recipients) who were sent to other centers and patients receiving a second kidney transplant in our own hospital were not included in the study. The minimum follow-up period was 3 months.

All patients received the same immunosuppressive regimen consisting of cyclosporine, corticosteroids, and a short course of OKT3 during 6 days, as previously described [8]. Post-transplant renal failure was diagnosed when patients had increasing levels of serum creatinine that made dialysis necessary, after ruling out diagnoses of accelerated or hyperacute rejection, vascular complications, or urinary tract obstruction.

The diagnosis of acute rejection was based on classic clinical data, an increase in serum creatinine levels ( 30%), and in most instances on histologic criteria, especially when post-transplant renal failure was present. We assessed clinical tolerance of the study drug during hospital admittance and at each monthly visit.

The comparisons between the two groups were done using the nonparametric Mann-Whitney U-test for quantitative data and the Fisher exact test for qualitative data. Differences were considered significant at P < 0.05. The 95% CI estimates for the median differences between groups were calculated as previously described [9]. All P values were two-tailed.

Results

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Fourteen patients received allografts from 10 donors in the BN 52021 group, and 15 patients received grafts from 10 donors in the placebo group. The characteristics of the donors and the recipients were not significantly different (Table 1). Although the median donor age was younger in the BN 52021 group than in the placebo group, this difference was not statistically significant. Moreover, the mean level of serum creatinine in both donor groups was similar.

The occurrence of post-transplant renal failure was 0% (0 of 14) in the BN 52021 group and 33% (5 of 15) in the placebo group (P = 0.042) (Table 2). In the placebo group, the 5 patients with post-transplant renal failure required a mean number of seven hemodialysis procedures. Preoperative creatinine values were similar in the two groups. Mean values of creatinine decreased faster after transplantation in the BN 52021 group than in the placebo group. The median number of days to reach a serum creatinine level that was less than 300 µmol/L was slightly less in the BN 52021 group than in the placebo group (3 compared with 4 days, respectively; difference, 1 day; 95% CI, 0 to 10 days; P = 0.06). Median diuresis at the first day after transplantation was higher in the BN 52021 group (3585 mL) than in the placebo group (2770 mL) (P = 0.036) (Table 2). At 1 week after transplantation, the differences between the two groups in levels of cyclosporine (an immunosuppressive drug) were not statistically significant, but at the second week the BN 52021 group showed significantly higher (P = 0.035) levels of cyclosporine (Table 2).

The observed percentages of acute rejection episodes during the first 3 months were 33% (5 of 15) and 14% (2 of 14) in placebo and BN 52021 groups, respectively (P > 0.2). In the BN 52021 group, 2 patients had two rejections at 14 and 44 days after surgery, respectively. In the placebo group, 5 patients had five rejection episodes, between 13 and 36 days after transplantation. Two patients in the placebo group had biopsy-proven acute interstitial rejection on days 17 and 19 after transplantation while oliguria was present, and the patients had an improved response after receiving steroids. The remaining 3 patients in the placebo group had acute rejection episodes after their renal function improved in the post-transplant period. The only highly sensitized patient in the placebo group did not have either post-transplant renal failure or rejection. One patient without post-transplant renal failure in the placebo group lost his graft because of acute vascular rejection 40 days after transplantation. In the third month after surgery, the actual graft survival was 100% (14 of 14) in the BN 52021 group and 93% (14 of 15) in the placebo group. No adverse events related to the study drug were observed. No patients were lost to follow-up or died during the study period.

Discussion

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According to the preliminary results obtained in this double-blind randomized study, BN 52021 efficiently improves post-transplant renal function in patients receiving kidney cadaveric transplantation. Platelet activating factor antagonists appear to be useful in the prevention of ischemic-reperfusion injury in experimental animal studies [6, 10]. To our knowledge, the present study is the first showing the efficacy of a platelet activating factor antagonist in the prevention of organ ischemic-reperfusion injury in clinical transplantation. Our promising results obtained at a single center suggest that new large multicenter trials might be initiated to corroborate our findings and to define more precisely the treatment schedules.

Appendix

The BN 52021 Study Group in Renal Transplantation includes Josep M. Grino, MD; Josep M. Galceran, MD; Salvador Gil-Vernet, MD; Daniel Seron, MD; Alberto M. Castelao, MD; Jeroni Alsina, MD; Pere Domenech, MD; Lluis Riera, MD; Francesc Moreso, MD; Joan Torras, MD; Carlota Gonzalez, MD (L'Hospitalet de Llobregat, University of Barcelona, Barcelona, Spain); Philippe Guinot, MD; Joaquim Valles, MD; Rossend Obach, PhD (SA LASA Laboratorios, Institut Henri Beaufour, Paris, France); and Evgenii V. Berdyshef, PhD; Monique Braquet, PhD (Bio-Inova,^Paris, France).