Robert Duca

Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfusions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

Immunologic factors determining survival of cadaver-kidney transplants. The effect of HLA serotyping, cytotoxic antibodies and blood transfusions on graft survival.

We assessed immunologic factors determining graft survival in 510 recipients of primary cadaver allografts at one center. The degree of HLA match grade did not directly affect graft survival (54 per cent in no-antigen match, and 42 per cent in three-antigen match, at two years). There was no correlation between the HLA match grade and the degree of stimulation of the mixed lymphocyte culture. Patients receiving more than five blood transfusions had a significantly better graft survival than nontransfused recipients (52 versus 23 per cent, respectively, at two years, P less than 0.001). The beneficial effect of transfusions was noted whether or not lymphocytotoxic antibodies were produced, provided adequate screening was performed before transplantation. Transfusions did not alter the degree of stimulation in the mixed lymphocyte culture. More liberal use of transfusions and frequent screening for cytotoxic antibodies would probably result in more effective cadaver-kidney transplantation.

Improved outcome following renal transplantation with reduction in the immunosuppression therapy for rejection episodes

Renal transplantation is superior to hemodialysis in terms of rehabilitation and cost, but it is offered to only a minority of patients with end-stage renal failure because of complications related to immunosuppression therapy. To reduce morbidity, we modified out therapy of patients with transplant rejection from high dose intravenous methylprednisolone (group A: January 1968--September 1972) to lower dose oral prednisone (group B: September 1972--December 1977). Patient survival in group B was significantly improved over that in group A, both in recipients of cadaver transplants (91 per cent versus 81 per cent, respectively, at one year, p less than 0.0009) and in recipients of transplants from living related donors (99 per cent versus 86 per cent, respectively, at one year p less than 0.001). The improvement in patient survival was the result of a significant decrease in the incidence of infections. Patients with multiple rejection episodes, a very high risk group, experienced an 18 per cent increase in patient survival in group B. With reduction and rapid tapering of corticosteroids for the treatment of patients with acute rejection and curtailment of the therapy of patients with multiple rejection episodes, survival after renal transplantation becomes comparable to that following hemodialysis; in addition, graft function is not compromised.

Do blood transfusions enhance the possibility of a compatible transplant

SUMMARY Blood transfusions prior to first cadaver kidney transplants have a significant beneficial effect on graft survival and, in this sense, appear to enhance the possibility of a compatible transplant. This desirable effect, however, occurs concomitantly with an increased degree of sensitization, which in turn reduces the likelihood of identifying a compatible kidney by direct crossmatch testing. This report illustrates that the beneficial effect is achieved with one to five transfusions prior to transplantation, but that more transfusions afford no additional benefits. In addition, the presence of cytotoxic antibodies per se does not have an adverse influence on graft survival. Liberal transfusion policies are therefore indicated in cadaver transplant candidates, but more than five transfusions prior to transplantation should probably be avoided unless clinically necessary.

Peptic ulcer disease in kidney transplant recipients

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.

1,500 renal transplants at one center: Evolution of a strategy for optimal success

From analysis of results of more than 1,500 renal transplants has evolved a plan for donor selection and immunosuppressive management whereby patients with end-stage renal disease can obtain maximum graft and patient survival. With superior results in both patient and graft survival with living-related transplantation, this modality should be considered initially. Pretreatment with third party blood transfusions appears effective in all donor categories. Donor-specific blood transfusions have afforded 1-haplotype mixed lymphocyte culture-incompatible recipients enhanced opportunity for successful transplantation. Current results with living-related transplantation suggest realistic expectations of 1 and 2 year graft survival rates of greater than 90 percent. Curtailment of steroid therapy has resulted in improved patient survival at 1 and 2 years: 98 and 97 percent for recipients of living-related grafts, and 91 and 88 percent for recipients of cadaver grafts. These results, in combination with proper donor selection and appropriate recipient pretreatment with blood transfusions, have made renal transplantation a very effective therapeutic method in patients with end-stage renal disease.

A ten year experience with cadaver kidney preservation using cryoprecipitated plasma

Between August 1967 and January 1977, 699 cadaver kidneys were preserved and transplanted in our hospital after continuous perfusion with cryoprecipitated plasma. Overall graft survival of primary transplants was 55 +/- 2 per cent at one year and 41 +/- 2 per cent at four years. The results with ninety-six second transplants were similar. The number of HLA antigens shared and the duration of preservation did not influence graft survival. Patient survival among 426 cadaver graft recipients since September 1972, when lower dose immunosuppression was started, was 91 +/- 1 per cent at one year and 84 +/- 2 per cent at four years, significantly better than survival before then. Survival of fifty-two recipients of cadaver retransplants since September 1972 was 86 +/- 5 per cent at one year and 86 +/- 5 per cent at four years, which was better than before. The incidence of posttransplantation dialysis was 30 per cent and did not correlate with the length of preservation. Primary wound infections, primary ureteral extravasation, and vascular complications each occurred with an incidence of 1.1 per cent or less in patients treated with lower dose immunosuppression. Only four kidneys were lost because of complications, and in no instance was the need for transplant nephrectomy directly related to the method of preservation. Perfusion preservation with cryoprecipitated plasma gives excellent results compared with alternative methods.

An alternative to cadaver kidney transplants for patients with insulin-dependent diabetes mellitus.

The benefits of successful kidney transplants for patients with end stage renal disease associated with insulin-dependent diabetes mellitus are well known, and the potential advantages of earlier transplantation have been emphasized in other reports. Cadaver transplants, which are not always available for these patients, have not provided a high degree of success in many centers. This has discouraged the use of transplants unless well matched related donors are available. Most patients do not have well matched family members who are able to donate. We have attempted to increase the availability of related transplants for diabetic patients by using a new protocol in which related donors who are poorly matched by mixed lymphocyte culture (MLC) testing (stimulation index (SI) greater than or equal to 7) can often serve as the source of the transplant. This protocol of pretransplant donor-specific transfusions (DSTs) has been applied to 20 diabetic patients. Sixteen transplants have been performed after serial immunological studies following the DSTs detected no specific evidence of recipient sensitization to the respective transfusion donors. Only one of the transplants has been rejected, and this occurred in a patient who intentionally terminated immunosuppressive therapy. Graft survival for the group of 16 patients is 93 and 84% at 1 and 3 years, respectively. The quality of renal function for most of the patients is very good, with a mean serum creatinine of 1.9 and 1.5 ml/dl for those transplants at risk for 12 and 24 months. This new method has given encouraging results for poorly matched related transplants in diabetic patients and makes earlier transplantation possible by providing an alternative to cadaver transplants.

Dramatic improvement in the success rate for renal transplants in diabetic recipients with donor-specific transfusions.

The chance of achieving successful kidney transplants in diabetic patients was previously limited because few of them had optimally-matched (2-haplotype) related donors. Hence, transplants were usually not carried out until renal failure had already occurred. The application of donor-specific transfusions (DSTs) prior to transplantation to poorly matched donor-recipient pairs (1-hap-lotype) has been associated with a high success rate for type-I diabetic recipients in our center. The rate of graft survival for 35 consecutive transplants in this category was 88%, 80%, and 73% at 1, 2, and 5 years, respectively. Furthermore, the rate of patient survival was 94%, 90%, and 90% at 1, 2, and 5 years. These patient and graft survival data were without significant difference when compared with the corresponding data for 142 optimally-matched (2-haplotype) related transplants performed without DSTs for nondiabetic recipients, and also when compared with the corresponding data for 130 poorly matched (1 or 0-haplotype) related transplants involving nondiabetic recipients who were prepared for transplantation with DSTs. These good results with DSTs in diabetic recipients emphasize that earlier transplantation utilizing poorly matched related donors should be seriously considered for diabetic patients even before the onset of renal failure, as long as the transplants are carried out in association with DSTs.

Prognostic Features of Early Renal Transplant Rejections

In an analysis of 632 cadaver transplants, the early renal transplant course gave important prognostic information depending on temporal and/or renofunctional characteristics of rejection episodes. Two transplant rejections occurring within the first 2 mo posttransplant were associated with either 37%, 27%, or 6% 1-yr graft survivals depending on whether these episodes were separate, temporally back-to-back, or were without interrejection renofunctional recovery, respectively. This compares to 1-yr graft survivals of 89% or 73% in those patients who had no rejection or one with recovery early posttransplant. Patient survival in groups with multiple early rejections was also associated with a poor prognosis. Ninety to 93% 1-yr patient survival was noted when there was no or one rejection. There was only a 74%-83% 1-yr patient survival with two early treated rejections. Transplant rejection therapy must be individualized or even withheld in order to ensure optimum graft and patient survival.