The mean interval from transplanta- are acute due to cytokine release, and others, such as tion to OKT3 treatment was Thirty-four The remaining 9 In the 34 responders, effects with OKT3 therapy.
This low percentage may be due the mean serum creatinine level before OKT3 administra- to our prophylactic regime, which includes high doses of tion decreased from 3. Table 1 shows the changes in not encountered any malignancies. Although our experi- creatinine level after OKT3 treatment with the 43 patients ence was not very short, longer follow up may be needed to grouped according to the Banff criteria for ARE severity.
Minor side effects of OKT3 treatment, namely fever, In conclusion, OKT3 therapy has proven to be valuable dyspnea, tachycardia, bradycardia were observed in 11 for rescuing kidney grafts with severe steroid-resistant Our data suggest that this agent is a good choice for acute pulmonary edema; one 2. Transplant Proc , 8. Transplant Proc , 1. Transplant Proc p 93 , 3. Clin Transplant in cadaveric renal transplantation for rejection that is unresponsive , to conventional anti-rejection therapy.
Am J Kidney Dis , 4. Transplantation , 6. Transplant short-term OKT3 therapy in the treatment of steroid-resistant Proc , renal allograft rejection. Transplant Proc , The role of basiliximab in the evolving renal transplantation immunosuppression protocol By Roberto Verzaro. Improved efficacy of basiliximab over antilymphocyte globulin induction therapy in paediatric renal transplantation By Grainne Walsh.
None of these postconversion complications resulted in patient death. Causes of graft loss after tacrolimus conversion There were 44 failures of tacrolimus conversion in this group of patients. Twenty-two patients had ongoing renal allograft rejection that was refractory to tacrolimus conversion. Eleven patients had repeat rejection episodes after initial successful rescue and lost their grafts. Page 6 Five of these 11 were late immunologic graft losses due to chronic rejection at 8, 24, 26, 28, and 48 months, respectively, following initial successful conversion in patients from the original series of 77 previously reported 4.
Six of 11 were among the 92 additional patients converted to tacrolimus since our original series, and they have experienced late immunologic graft loss, one each at 5, 6, 6, 9, 10, and 20 months following initial successful conversion. Eight patients with primary allograft nonfunction with superimposed rejection were not salvaged, two patients lost their graft due to noncompliance, and one patient died with a functioning graft.
Clearly, the utility of an agent which provides salvage of ongoing rejection must be proven in the long term and should have sustained efficacy in sufficient numbers of patients. Since our initial report in , we have experience with an additional 92 patients referred to our center for tacrolimus conversion. Significantly, this was with a mean follow-up of 30 months, reflecting the longevity of the salvage effect. The subset of 92 patients who were converted to tacrolimus since our original report were all referred from outside institutions where the patients were deemed to be losing their grafts owing to ongoing rejection.
In attempting to identify patients who would not benefit from conversion to tacrolimus, we stratified the patients according to initial biopsy findings. We have previously found that grafts with chronic rejection without any acute component are unlikely to benefit from tacrolimus conversion Another important feature that appears to be unique to tacrolimus as a salvage agent when compared with other agents 8,9,12 is its ability to provide graft salvage in patients who have been on dialysis owing to the severity of rejection.
Overall postconversion renal function in all of the patients salvaged in this series was 2. Furthermore, with follow-up up to 48 months, the SCR has continued to improve in patients successfully salvaged, perhaps indicating a beneficial effect of tacrolimus in preventing the onset of chronic rejection in some patients.
Another potential factor that may have influenced the likelihood of successful rescue was the interval between the time of NIH-PA Author Manuscript transplantation and tacrolimus conversion. In our earlier series we found no differences in the success rates whether tacrolimus conversion was performed before or after 2, 3, or 6 months following transplantation.
Conversion performed before or after 2 or 3 months following transplantation did not appear to influence the outcome. Probably more important than the timing of conversion are the findings on preconversion biopsy, in which the presence of chronic rejection or ACR with primary allograft nonfunction portends a worse prognosis 4, As a result of our expanded experience, we have learned that tacrolimus can provide effective salvage of ongoing renal allograft rejection for patients on conventional CsA-based immunotherapy.
However, there is a group of patients who experience refractory allograft rejection in whom CsA is no longer effective even when combined with antilymphocytic therapy to attempt rejection reversal 16, In addition to the now well-established graft salvage effects of tacrolimus, several other agents have shown initial promise as rescue agents, including mycophenolate mofetil 8,9 , deoxyspuergualin 12 , and perhaps sirolimus In the latter case report, sirolimus was effective in ameliorating rejection in a patient who was requiring dialysis therapy Further experience with this agent in primary and rescue therapy is anticipated.
Whether these agents will provide long- lived salvage rates and afford the opportunity to wean steroids after rescue such as is possible with tacrolimus remains to be determined. The reasons for the salutary effects of tacrolimus on established renal allograft rejection remain speculative but may include additional or distinct immunosuppressive activities of tacrolimus that have not yet been identified at the molecular level It is hoped that further investigation will elucidate the mechanisms by which tacrolimus appears to be unique in its ability to provide effective long-term reversal of renal allograft NIH-PA Author Manuscript rejection with what appears to be minimal attrition in the long term due to immunologic causes.
We currently recommend that tacrolimus conversion be considered an alternative to antilymphocycte preparations for steroid resistant rejection in CsA based regimens.
Tacrolimus is clearly also effective in salvaging rejecting grafts that have failed antilymphocyte therapy. With mandated reduction in costs and hospital lengths of stay upon us, minimizing the use of antilymphocyte preparations, both in terms of their expense and potential complications, would be most desirable, as long as equivalent graft survival rates can be achieved. Agents such as tacrolimus may provide a unique opportunity to address some of these concerns and may prove to be more cost effective than the traditional methods by which steroid resistant episodes have been treated in the past.
The addition of tacrolimus to the immunosuppressive armamentarium has provided transplant physicians with a much needed alternative to the conventional drugs used for renal allograft rejection therapy.
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