Donor-specific antibody and sensitized patients in intestinal transplantation.

PURPOSE OF REVIEW: It has been well established that antibody to donor HLA pretransplant and the development of anti-human leukocyte antigen (HLA) antibodies posttransplant contribute to inferior graft survival outcomes. This article serves to review the current status of the management of pretransplant sensitized intestinal transplant candidate as well as to review posttransplant care of patients that harbor antidonor HLA antibodies. RECENT FINDINGS: The intestinal transplant candidate oftentimes presents for transplant listing with high levels of anti-HLA antibodies that necessitate a careful preoperative strategy to avoid a donor-recipient pair that would result in a positive crossmatch. In the end, donor intestine offer acceptance is based on a balance between recipient clinical needs and allowable immunologic risk tolerance. The use of virtual crossmatching (VXM) enables the transplant center to effectively gauge the immunologic risk of each potential donor-recipient pair far in advance of allocating resources toward pursuing a donor organ. In those candidates with high levels of preformed donor anti-HLA antibodies, desensitization with a novel technique of donor splenic perfusion has been described as well as a single-center experience with a conventional desensitizing protocol. Posttransplant, with the use of a denovo donor-specific antibody (dnDSA) monitoring and treatment protocol, the well known deleterious effects of dnDSA can potentially be ameliorated, thus improving outcome. Efforts to establish a formal histologic criteria for antibody-mediated rejection (ABMR) in the intestinal graft continues to evolve with recent findings describing the relationship between DSA and histopathologic findings. SUMMARY: Techniques such as the use of VXM, novel desensitization methods and protocols, monitoring and eradicating dnDSA, along with establishing new criteria for ABMR have all contributed to improving the outcomes in transplanting the immunologically challenging intestine.

Pre-empting Antibody-Mediated Rejection: A Program of DSA Monitoring and Treatment Can Effectively Prevent Antibody Mediated Rejection.

Antibody-mediated rejection (AMR) remains a problem without a reliable treatment in the care of kidney transplant patients. We proposed and tested a program of screening for donor specific antibodies (DSA) to initiate treatment of patients before AMR was detected and to prevent its occurrence. Starting in April 2012, we stratified patients into high-, medium-, and low-risk groups for the development of DSA and instituted a program of screening for and treatment of these antibodies. We used a historic control group of patients transplanted at our center as a comparator and looked at rates of DSA testing and development as well as rates of development of AMR, cell-mediated rejection, and graft loss. 614 patients were transplanted under the protocol compared with 266 patients in the control group. Length of follow-up was similar in both groups. The group undergoing DSA screening had lower rates of DSA development (17.6% versus 24.8%, p=0.016) and that DSA was found at a significantly earlier time post-transplant (147 versus 248 days, p=0.02). Incidence of AMR was dramatically lower in the screened group (1.3% versus 8.6%, p<0.0001) with no grafts lost due to AMR. AMR was found to occur at an average of 181 days post-transplant. Rates of acute cellular rejection did not decrease in a manner similar to AMR rates. In conclusion, a program of universal risk-stratified DSA testing in kidney transplant patients can dramatically reduce rates of AMR and virtually eliminate graft loss due to AMR.

Donor transmission of pineoblastoma in a two-yr-old male recipient of a multivisceral transplant: a case report.

Transplant-transmitted malignances are rare but devastating events. Primary brain tumors are the least common among reported donor-derived malignancies. We report a case of donor-transmitted pineoblastoma, a PNET, in a two-yr-old male recipient, who presented with a rapidly growing mass in the right mandible, four months after multiple visceral organ transplantation. The recipient had liver, pancreas, and small bowel transplants because of end-stage liver failure and short gut syndrome, which was secondary to large bowel resection for management of gastroschisis complicated by intestinal volvulus. The donor autopsy results became available seven wk after transplantation, which found a pineoblastoma with meningeal spread. Evaluation of eyes, adrenal glands, bone marrow, and other organs did not identify metastasis outside the CNS. A biopsy of the recipient's right mandibular mass revealed a malignant small round blue cell tumor with the immunohistochemistry profile of a PNET. Staging evaluation revealed the tumor in the right mandible with bone marrow involvement. Further investigation showed that recipient's tumor and donor's pineoblastoma shared the same immunophenotype and HLA type, suggesting the recipient's tumor is a donor-transmitted pineoblastoma. This is the first case report of donor-transmitted pineoblastoma post-organ transplant.

Paired kidney donor exchanges and antibody reduction therapy: novel methods to ameliorate disparate access to living donor kidney transplantation in ethnic minorities.

BACKGROUND: Currently ethnic minority patients comprise 60% of patients listed for kidney transplantation in the US; however, they receive only 55% of deceased donor renal transplants and 25% of living donor renal transplants. Ethnic disparities in access to kidney transplantation result in increased morbidity and mortality for minority patients with end-stage renal disease. Because these patients remain dialysis dependent for longer durations, they are more prone to the development of HLA antibodies that further delay the possibility of receiving a successful kidney transplant. STUDY DESIGN: Two to 4 pretransplant and post-transplant plasma exchanges and i.v. immunoglobulin were used to lower donor-specific antibody levels to less than 1:16 dilution; cell lytic therapy was used additionally in some cases. Match pairing by virtual cross-matching was performed to identify the maximal exchange benefit. Sixty candidates for renal transplantation were placed into 4 paired kidney exchanges and/or underwent antibody reduction therapy. RESULTS: Sixty living donor renal transplants were performed by paired exchange pools and/or antibody reduction therapy in recipients whose original intended donors had ABO or HLA incompatibilities or both (24 desensitization and 36 paired kidney exchanges). Successful transplants were performed in 38 ethnic minorities, of which 33 were African American. Twenty-two recipients were white. Graft and patient survival was 100% at 6 months; graft function (mean serum creatinine 1.4 g/dL) and acute rejection rates (20%) have been comparable to traditional live donor kidney transplantation. CONCLUSIONS: Paired kidney donor exchange pools with antibody reduction therapy can allow successful transplant in difficult to match recipients. This approach can address kidney transplant disparities.

The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure.

Donor-directed human leukocyte antigen (HLA)-specific allo-antibodies (DSAs) cause graft failure in animal models of hematopoietic stem cell transplantation (HCT). Archived pretransplantation sera from graft failure patients (n = 37) and a matched case-control cohort (n = 78) were tested to evaluate the role of DSAs in unrelated donor HCT. Controls were matched for disease, disease status, graft type, patient age, and transplantation year. Patients had acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; 98% received myeloablative conditioning regimens 100% received T-replete grafts, 97% received marrow, 95% HLA-mismatched, and 97% received calcineurin-based graft-versus-host disease prophylaxis. Among the 37 failed transplantations, 9 (24%) recipients possessed DSAs against HLA-A, B, and/or DP, compared with only 1 (1%) of 78 controls. Therefore, the presence of DSAs was significantly associated with graft failure (odds ratio = 22.84; 95% confidence interval, 3.57-infinity; P < .001). These results indicate that the presence of pretransplantation DSAs in recipients of unrelated donor HCT is associated with failed engraftment and should be considered in HCT donor selection.