Search

The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors Trial (BENEFIT-EXT) study compared more or less intensive belatacept-based immunosuppression with cyclosporine (CsA)-based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.9% of patients received an expanded criteria donor kidney (United Network for Organ Sharing definition), 10.1% received a donation after cardiac death kidney, and 21.0% received a kidney with an anticipated cold ischemic time ≥24 h. Over 7 years, time to death or graft loss was similar between belatacept- and CsA-based immunosuppression, regardless of donor kidney subtype. In all three donor kidney cohorts, estimated mean GFR increased over months 1-84 for belatacept-based treatment but declined for CsA-based treatment. The estimated differences in GFR significantly favored each belatacept-based regimen versus the CsA-based regimen in the three subgroups (p < 0.0001 for overall treatment effect). No differences in the safety profile of belatacept were observed by donor kidney subtype., (© 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

In an earlier study, we were able to show that Tac monotherapy following 2 × 20 mg alemtuzumab induction is at least as effective as Tac-based triple-drug immunosuppression in cadaveric renal transplantation. We were interested to learn whether 1 × 30 mg of alemtuzumab is as effective as 2 × 20 mg. Patients of the initial study group (group A) received 20 mg alemtuzumab on days 0 and 2, and tac monotherapy from day 2 on. This group acted as control group for the new arm (group C), where patients were given only 1 × 30 mg alemtuzumab on day 0 followed by Tac monotherapy from day 2 on with the same target levels as in the control group. Frequency of rejection at 6 months was 15% in the control group compared to 6% in the study group and 20% at 12 months in group A versus 6% in group C (P = 0.034). Time to rejection was 4.9 months in group A and 0.8 in group C. One-year patient survival was 98.5% in both groups, graft survival 96.9% in group A, and 98.5% in group C. Safety profile was similar in both groups apart from more viral and bacterial infections in group C. Single shot alemtuzumab induction of 30 mg is as effective as 2 × 20 mg in cadaveric renal transplantation., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

The lymphocyte-depleting antibody alemtuzumab was evaluated in a prospective randomized multicenter trial in deceased donor kidney transplantation. The 65 patients in the study group received induction with alemtuzumab followed by delayed tacrolimus monotherapy, while the 66 patients in the control group were started on tacrolimus in combination with mycophenolate mofetil and steroids. Tacrolimus levels of 8-12 ng/mL for the first 6 months and 5-8 ng/mL thereafter were aimed for in both groups. At 12 months the biopsy-proven rejection rate was 20% in the study group and 32% in the control group (p = 0.09). Patient survival at 1 year was 98% for both groups. Graft survival was 96% for the study group versus 90% for the control group (p = 0.18). Graft function was identical in both groups. Adverse events were similar in both groups apart for more CMV infections in the study group. At the end of the first year 82% of the patients in the study group were steroid-free and 71% continued on tacrolimus monotherapy. These results suggest that alemtuzumab induction together with tacrolimus monotherapy is at least as efficient in renal transplantation as is a tacrolimus-based triple-drug regimen with a similar safety profile but more CMV infections.

Background: In January 1999 a new kidney allocation program was launched by the Eurotransplant Foundation, the 'Eurotransplant Senior Program' (ESP). Cadaveric donors above the age of 65 yr are allocated to kidney transplant recipients of the same age group., Methods: Using a single-center database, 91 patients who underwent first renal transplantation at the age of 65 yr and older in the years 1999-2002 were identified. Fifty-six patients were transplanted through ESP allocation (study group) and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS) procedure., Results: Age, sex and comorbid conditions did not differ by group. The rate of acute rejection episodes, primary non-function, delayed graft function, perioperative mortality did not differ by group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p=0.015) from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group, cumulative patient survival according to the Kaplan-Meier estimation was not statistically different at five yr., Conclusions: We did not find a relevant difference in the outcome between young and old kidney transplants in old recipients after this long observation period.

Despite extensive efforts in the fields of donor selection and management, standardisation of organ retrieval procedures, storage solutions, and novel immunosuppressive protocols, the rates of delayed graft function (DGF) after renal transplantation have been stagnating between 30% and 50%. As DGF exerts negative influences on acute rejection episodes and long-term organ function, the early phase of transplantation immediately following reperfusion deserves special interest. Several studies on machine-controlled reperfusion showed promising results in various organs, in experimental and clinical settings. Moreover, the flushing of organs with Carolina rinse solution (CR) immediately prior to reperfusion has been proven beneficial and is being clinically applied in human liver transplantation in recognised departments. In our study, we set up an autogenic porcine kidney transplantation model and assessed the normal values (control group) for creatinine clearance (ClCr) and urine output per hour (U/h) after "standard" reperfusion similar to clinical transplantation. Subsequently, kidneys of the experimental group 1 were reperfused at a blood pressure (RR) under the systemic level by means of a roller pump. Group 2 kidneys were rinsed with CR before controlled reperfusion, analogous to group 1. Both groups were compared with each other and with the assessed normal values. Our findings for Group 1 are that pressure-reduced reperfusion negatively affected immediate graft function. ClCr was reduced from 9.9 (control group) to 3.4 ml/min, U/h from 233 to 132 ml ( P<0.05). Group 2 showed that rinsing the kidneys with CR before reperfusion improved functional parameters highly significantly, compared with group 1 (ClCr: 13.5 vs 3.4 ml/min, U/h: 384 vs 132 ml; P<0.05) and even showed a positive trend compared with the control group (ClCr: 13.5 vs 9.9 ml/min, U/h: 384 vs 233 ml; P=0.0546). We can conclude that in a model of porcine renal autotransplantation, pressure-reduced reperfusion via a roller pump is detrimental to early kidney graft function. The flushing of organs with CR prior to controlled reperfusion significantly improves ClCr as well as urine output.

Acute myeloid leukemia following organ transplantation (PT-AML) is a rare event with only a few published cases in the literature. We present three patients who developed AML (FAB M1, M5, M4) after renal, double lung or liver transplantation. Molecular analysis detected a t(9;11) in one patient and documented the recipient origin of AML in a second patient. All patients were treated with chemotherapy. Immunosuppression was reduced to cyclosporin A (CsA) and prednisone in two patients and to prednisone alone in one patient. Two patients achieved a complete remission (CR), with a remission duration of 4.6 months in one patient, the other patient died from septicemia after 15.2 months in CR. One patient was refractory to chemotherapy and died from septicemia. This report together with the documented cases in the literature suggests that PT-AML (1) develops after a median interval of 5 years after transplantation with variable latency (range, <1-17 years); (2) is heterogeneous with respect to FAB classification; (3) shows chromosomal and molecular changes typical of therapy-related AML (t-AML: -7, +8, 11q23, inv16, t(15;17)); (4) standard chemotherapy is feasible after reduction of immunosuppression and produces a CR rate of 56% with a median remission duration of 4.6 months and an overall survival of 2.6 months; (5) the major complications are early death (25%), gram-negative septicemia, progressive disease or relapse. This review provides diagnostic and therapeutic experiences and guidelines for the management of this increasing group of post-transplant patients.

Primary non-function (PNF) of renal allografts has been attributed to various risk factors, among them immunological ones, as well as unfavourable preservation conditions. To investigate the impact of these risk factory on the occurrence of PNF, 1335 consecutive kidney transplants performed at a single centre over a 10-year period were analysed. All patients received immunosuppression based on cyclosporine. As the method of analysis a conditional stepwise logistic regression model was chosen, comparing each graft suffering PNF with its partner kidney retrieved from the same donor. Thus, all donor-related variables could be omitted from the analysis, as they are the same in every pair of grafts. Risk factors analysed included panel-reactive antibodies, number of pretransplant transfusions, pregnancies, number of prior transplants, cold and second warm ischaemia time, mismatches on HLA loci A, B and DR and recipient age. The overall incidence of PNF was 87 grafts (6.5%). One patient suffered immediate rejection due to transplantation of an ABO incompatible graft. This case was excluded from further analysis. PNF occurred three times in recipients of living related grafts, twice in recipients of en-bloc grafts and four times in grafts, in which the paired kidney was either not transplanted or shipped outside the Eurotransplant region, so that no paired graft was available for matched case-control analysis. Of the remaining 77 pairs, twice both organs of one donor failed immediately. The remaining 73 complete pairs were analysed. Two of the investigated risk factors have independently a significant impact on the occurrence of PNF. Increasing the number of pretransplant transfusions raises the relative risk of graft failure up to six fold (P=0.02), while a history of prior transplants bears a relative risk of 0.21E05 (P=0.005). Ischaemia has no significant impact on the occurrence of PNF. Our data strongly suggest that immunological rather than donor risk factors are responsible for the non-function of kidney grafts.

Summary: Belatacept is a second‐generation cytotoxic T lymphocyte antigen (CTLA)‐4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co‐stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA‐4 Ig compounds through binding to B7 molecules expressed on antigen‐presenting cells (APCs) and up‐regulation of indoleamine 2,3‐dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down‐regulates T cell immunity. So far it remains unknown whether belatacept up‐regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi‐centre, investigator‐initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103‐045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post‐transplant in liver transplant patients randomized to receive either belatacept or tacrolimus‐based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus‐treated patients in per‐protocol and in intent‐to‐treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus‐treated patients. [ABSTRACT FROM AUTHOR]