Colm Magee

A prospective, randomized, clinical trial of intraoperative versus postoperative thymoglobulin in adult cadaveric renal transplant recipients

Background. Delayed graft function (DGF) is frequently observed in recipients of cadaveric renal transplants. Previous retrospective or nonrandomized studies have suggested that intraoperative administration of polyclonal antithymocyte preparations may reduce the incidence of DGF, possibly by decreasing ischemia-reperfusion injury. Methods. We performed a prospective randomized study of Thymoglobulin induction therapy in adult cadaveric renal transplant recipients. Between January 2001 and January 2002, 58 adult cadaveric renal transplant recipients were randomized to receive intraoperative or postoperative Thymoglobulin induction therapy. Three to six doses of Thymoglobulin (1 mg/kg/dose) were administered during the first week posttransplant. Baseline immunosuppression consisted of tacrolimus (54 of 58) or cyclosporine A (4 of 58), steroids, and mycophenolate mofetil. DGF was defined by the requirement for hemodialysis within the first week posttransplant. Results. There were no significant differences between the two groups in recipient demographics, donor age, cold ischemia time, or total number of doses of Thymoglobulin administered. Intraoperative Thymoglobulin administration was associated with significantly less DGF and a lower mean serum creatinine on postoperative days 10 and 14 (P <0.05). Posttransplant length of stay was also significantly shorter for the intraoperative Thymoglobulin patient group. The acute rejection rate was also lower in the intraoperative treatment group but this did not achieve statistical significance. There was no difference in the incidence of cytomegalovirus disease between the two groups. Conclusions. The results of this study indicate that intraoperative Thymoglobulin administration, in adult cadaveric renal transplant recipients, is associated with a significant decrease in DGF, better early allograft function in the first month posttransplant, and a decreased posttransplant hospital length of stay.

Gemcitabine-associated thrombotic microangiopathy

Gemcitabine‐associated thrombotic microangiopathy (TMA) is believed to be very rare, with an estimated incidence rate of 0.015%. Indications for gemcitabine are expanding, and comprehensive characterization of this complication is therefore important.

Renal Failure Associated with Cancer and Its Treatment: An Update

Kidney disease frequently complicates malignancy and its treatment. The spectrum of disease in this setting includes acute renal failure (ARF), chronic renal failure, and tubular disorders. Fortunately, these complications are often preventable or reversible with prompt diagnosis and treatment. This

Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig-treated murine cardiac allograft recipients.

BACKGROUND Optimal activation of T cells requires two signals: antigen engagement through the T cell receptor and a costimulatory signal. Previous studies have shown that blockade of the CD28:B7 costimulatory pathway using the soluble fusion protein CTLA4Ig can prevent acute rejection of organ and tissue allografts; however, long-term engraftment has not been seen universally. This study was undertaken to define the role of donor antigen in inducing long-term allograft survival in CTLA4Ig-treated recipients. METHODS A murine cardiac allograft model was employed using BALB/c donors and C57BL/6 recipients. Additional donor antigen in the form of donor splenocytes was given at the time of transplantation. Recipients were treated with a single dose of CTLA4Ig 2 days after transplantation. RESULTS We find that a single dose of CTLA4Ig prolongs cardiac allograft survival, but permanent engraftment is not observed unless the recipients receive an injection of donor-type splenocytes. Treatment of the donor cells with CTLA4Ig does not by itself prolong allograft survival, which indicates the need for systemic treatment of the recipient. Allografts from animals not receiving donor cells show classic histologic changes of chronic rejection, and most cease function from 1 to 4 months after transplantation. Lethal irradiation of the donor cells does not appreciably affect their ability to prevent late allograft loss. CONCLUSIONS Donor cells are required to synergize with CTLA4Ig and prevent late cardiac allograft loss in the murine system. The fact that pretreatment of the donor cells alone is not effective suggests a role for antigen presentation by recipient antigen-presenting cells in the initiation of rejection. As lethal irradiation of the donor cells does not affect their ability to promote long-term engraftment, our data suggest that long-term microchimerism is not required to prevent chronic rejection in this model.

Peptide-mediated immunosuppression

New insights into the mechanisms of allorecognition and the interactions of the TCR with the MHC molecule-peptide complex on antigen presenting cells have focused attention on developing novel biological strategies to modify the alloimmune response. Peptides derived from various regions of MHC class I and II molecules and structure-based peptides have demonstrated immunomodulatory effects both in vitro and in vivo. Their binding sites and mechanisms of action are under active investigation. Trials in human transplant recipients, with an MHC class I peptide have already begun.

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

INTRODUCTION To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. METHODS Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. RESULTS Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. CONCLUSION These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Transplantation across previously incompatible immunological barriers.

This article reviews recent advances, which allow the transplantation across or around previously incompatible immunological barriers such as a positive crossmatch or ABO blood group incompatibility.

Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study

Abstract:  25(OH) Vitamin D (calcidiol) is the major circulating form of vitamin D and is considered the most reliable measure of vitamin D status. Adequate vitamin D status is important for bone health but there is increasing evidence that low serum concentrations of calcidiol (<30 ng/mL) are associated with many adverse health outcomes in the general population. Little is known about calcidiol status at the time of renal transplantation, a period when bone loss is greatest and immunosuppression is highest. We prospectively measured serum calcidiol and parathyroid hormone immediately after transplant from March 2005 onwards. Of 112 patients studied, 29% had calcidiol deficiency (<10 ng/mL), 59% had calcidiol insufficiency (10–29 ng/mL) and only 12% of patients had a normal calcidiol concentration (>30 ng/mL). The prevalence of calcidiol deficiency in black recipients was extremely high at 41%. Serum calcidiol tended to be lower in winter than other seasons. In conclusion, the prevalence of 25(OH) vitamin D (calcidiol) deficiency/insufficiency at the time of renal transplant is very high. The clinical effects of this deficiency/insufficiency deserve further study.

Efficacy and Safety of Low‐Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Renal Transplant Recipients: A Single‐Center, Retrospective Analysis

Study Objective. To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients.

Renal Transplantation in Patients With Positive Lymphocytotoxicity Crossmatches : One Center's Experience

Background. Sensitization to human leukocyte antigens remains an important barrier to successful renal transplantation. Materials and Methods. Herein we describe our center’s experience with a plasmapheresis-based desensitization protocol for highly sensitized patients. Twenty-nine patients had a positive T-cell or positive B-cell lymphocytotoxicity crossmatch against their donors. In some cases, baseline crossmatches were of high titer (e.g., 11 had baseline titers ≥1:32). Results. Twenty-eight of 29 patients were rendered T-cell crossmatch negative and B-cell crossmatch negative/low positive and transplanted. None had hyperacute rejection but 11 (39%) had acute antibody mediated rejection. Median follow-up is 22 months: 25 of the 28 (89%) of allografts are still functioning with mean plasma creatinine 1.5 mg/dL. There was one death because of the transplant or immunsuppression, one case of cytomegalovirus disease and no cases of lymphoproliferative disease. Conclusion. This series provides further evidence of the high efficacy of plasmapheresis-based desensitization protocols. Even patients with high baseline crossmatch titers can be successfully desensitized and transplanted. Short- and medium-term outcomes are encouraging but longer-term data are needed.