Highly Human Leukocyte antigen sensitized patients have relatively fewer chances of being transplanted successfully and may remain dialysis dependent for a long time. In the last few years with the development of immunomodulatory therapies and advancements in immunological investigations, the chance s of transplantation in these sensitized patients have improved. Desensitization therapies in these patients include plasma exchange, intravenous immune globulins and immunomodulatory agents such as rituximab and bortezomib. These agents used together in desensitization protocols across the world have shown encouraging results in highly Human Leukocyte Antigen sensitized recipients awaiting renal transplant. We used a desensitization protocol using rituximab followed by bortezomib with concurrent plasma exchange sessions and Intravenous Immune Globulins. Our aim was to assess improvement in renal function and quality of life in these patients after desensitization and renal transplantation. To the best of our knowledge, this is the first account of desensitization prior to renal transplantation from Pakistan.

BACKGROUND:

Recipients of ABO-incompatible (ABOI) and positive crossmatch (PXM) kidney transplants are at high risk for antibody-mediated acute rejection. Despite aggressive immunosuppression in high-risk patients, the incidence of acute rejection remains considerably higher than in other groups. No published studies have examined plasma concentrations of anti-thymocyte globulin (ATG) in patients undergoing plasma exchange. The objectives of this study were to compare plasma ATG concentrations before and after plasma exchange in ABOI and PXM kidney transplant patients to determine the amount removed.

MATERIALS AND METHODS:

This prospective pharmacokinetic evaluation enrolled 10 patients undergoing ABOI or PXM kidney transplant at an academic medical center. Blood and waste plasma samples from 5 patients were assayed for total and active ATG concentrations. Patient records were monitored for renal function and rejection rates in the first 6 months post-transplant.

RESULTS:

Total ATG concentrations decreased a mean of 59.78 ± 13.91% after each plasma exchange session, and active ATG levels decreased a mean of 56.8 ± 17.08%. Mean daily concentrations reflect a lack of expected ATG accumulation. Only 1 of 4 patients had detectable ATG concentrations after 30 days. After 6 months, the incidence of acute rejection in this sample was 44% and graft survival was 89%.

CONCLUSIONS:

This is the first study to show that plasma exchange removes a substantial amount of ATG in high-risk kidney transplant patients. Based on these results, we believe these high-risk patients have been traditionally underdosed.

• ClinicalKey
• Elsevier Science

BACKGROUND:

Patients who are HLA-sensitized are at high risk for early antibody-mediated rejection (AMR) and worse outcomes. Therefore, it is crucial to detect the presence of donor-specific antibodies (DSAs) using pretransplant antibody identification and crossmatch assays. An error in antibody identification can lead to disastrous clinical outcomes. We present a case of acute AMR associated with preformed HLA-DPα and HLA-DPβ DSAs that were not identified before transplantation.

CASE PRESENTATION:

A 27-year-old woman received a second kidney transplant from a deceased donor. Her pretransplant panel-reactive antibody level was 94%. The complement-dependent cytotoxicity crossmatch was negative for T and B cells at the time of transplantation. She experienced early acute AMR proven by a kidney biopsy. Single antigen bead testing of the patient's serum at the time of rejection as well as the pre-second transplant serum revealed strong antibodies against the DPA1*01:03 and DPB1*02:01 alleles in the second donor. These antibodies were not identified by phenotypic bead assay during the patient's time on the waiting list. The patient was treated with plasmapheresis and anti-thymocyte globulin. However, she experienced abdominal pain on day 37 post-transplantation. Surgical exploration revealed a laceration on the transplanted kidney, which was then repaired. Subsequently, infected hematoma was suspected and the transplanted kidney was removed.

CONCLUSION:

The present case highlights the clinical significance of preformed HLA-DPα and HLA-DPβ DSAs. Accuracy in determination of HLA antibodies before transplantattion is critical for transplant outcome. HLA-DP typing and single antigen bead testing are recommended for a precise antibody interpretation, especially in highly sensitized patients. Careful interpretation of antibody testing results is essential for the success of organ transplantation.

• Europe PubMed Central
• PubMed Central
• BioMed Central

As the need for the organ donation increases, strategies to increase kidney transplantation (KT) through expanded living donation have become essential. These include kidney paired donation (KPD) programs and desensitization in incompatible transplantations. KPD enables kidney transplant candidates with incompatible living donors to join a registry with other incompatible pairs in order to find potentially compatible living donor. Positive cross match and ABO incompatible transplantation has been successfully accomplished in selective cases with several pre-conditionings. Patients who are both difficult-to-match due to broad sensitization and hard-to-desensitize because of donor conditions can often be successfully transplanted through a combination of KPD and desensitization. According to the existing data, KPD can increase the number of KTs from living donors with excellent clinical results. This is also a cost-effective treatment as compared with dialysis and desensitization protocols. We carried out 3-way KPD transplantation with one highly sensitized, positive cross match pair and with two ABO incompatible pairs. Herein we report our first successful 3-way KPD transplantation in a single center. To maximize donor-recipient matching and minimize immunologic risk, KPD programs should use proper algorithms with desensitization to identify optimal donor with simultaneous two-, three- or more complex multi-way exchanges.

• Europe PubMed Central
• PubMed Central
• Korean Academy of Medical Sciences

The case of a 39-year-old highly sensitized woman who underwent second renal transplantation after being on warfarin because of a history of frequent thromboses of her left femoral arteriovenous graft (AVG) is reported here. The patient received a flow cytometric positive crossmatch kidney transplant from a deceased donor. Her posttransplant course was complicated by prolonged delayed graft function (DGF) lasting for 9 months. Antibody-mediated rejection occurred in the immediate postoperative period. This resolved after treatment, and resolution was confirmed by repeat biopsy. Despite this, she had persistent DGF and remained dialysis dependent. A computed tomography scan due to the development of perinephric hematoma after posttransplant biopsy demonstrated venous collateralization around the allograft. At 7 months posttransplant, a venogram during declotting of AVG revealed chronic thrombus in the inferior vena cava (IVC) above the level of native renal veins with a venous gradient of 26 mmHg. After declotting of the graft, iliac venoplasty, and subsequent IVC stent, her renal function continues to improve with a most recent creatinine of 1.4 mg/dL at 36 months posttransplant. Venous hypertension secondary to IVC thrombosis in presence of patent femoral AVG should be considered as a rare cause of prolonged DGF.

• Europe PubMed Central
• PubMed Central

• Wolters Kluwer
• Ovid Technologies, Inc.

BACKGROUND:

Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.

METHODS:

To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant.

RESULTS:

The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access.

CONCLUSIONS:

Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

• Europe PubMed Central
• PubMed Central

• Wolters Kluwer

• Wolters Kluwer
• Ovid Technologies, Inc.

BACKGROUND:

Global Kidney Exchange (GKE) offers an opportunity to expand living renal transplantation internationally to patients without financial means. These international pairs are entered into a US kidney exchange program that provides long-term financial support in an effort to identify opportunities for suitable exchanges for both these international pairs and US citizens.

OBJECTIVE:

While the promise of GKE is significant, it has been met with ethical criticism since its inception in 2015. This paper aims to demonstrate the selection process and provide >3 yr of follow-up on the first GKE donor and recipient from the Philippines.

DESIGN, SETTING, AND PARTICIPANTS:

The first GKE transplant occurred with a young Filipino husband and wife who were immunologically compatible, but lacked the financial means to continue hemodialysis or undergo a kidney transplant in their home country. The pair was enrolled in the Alliance for Paired Donation matching system, several alternative kidney exchanges were identified, and the pair subsequently underwent renal transplantation and donation in the USA financed by philanthropy. The resulting nonsimultaneous extended altruistic chain provided transplantation for the Filipino husband and 11 US patients.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

The Filipino donor and recipient were followed by transplant professionals in both the Philippines and the USA. Follow-up data were maintained as required by the Organ Procurement and Transplantation Network in the USA.

RESULTS AND LIMITATIONS:

The Filipino donor has normal blood pressure and renal function, and the Filipino recipient is doing well 3.5 yr after their donation and transplantation.

CONCLUSIONS:

While criticisms of GKE highlight concerns for possible exploitation of financially disadvantaged groups, these results demonstrate that these concerns did not come to fruition, and the outcome experienced by the GKE donor and recipient (and other US participants) was successful.

PATIENT SUMMARY:

The first Filipino Global Kidney Exchange (GKE) donor-recipient pair continues to be followed by both US and Filipino transplant centers. Both are in good health, support the GKE program, and advocate for its expansion.

• ClinicalKey
• Elsevier Science

Advances in immune suppression therapies and desensitization have made possible kidney transplantation regardless of HLA incompatibility. Single antigen bead assay (SAB) is a semi-quantitative estimation of the amount of human leukocyte antigen (HLA) antibodies present in the recipient plasma, and mean fluorescence intensity (MFI) generated gives this rough estimation of the antibodies present in the recipient. Here we present a case of successful kidney transplantation in a patient who expressed DSA with high MFI. A 33-yr-old male, diagnosed with chronic kidney disease (CKD) on regular maintenance hemodialysis, opted for second kidney transplant with his sibling as prospective donor and was referred to the department of Transplant Immunology for histocompatibility testing. Patient had HLA incompatibility with multiple DSA identified by SAB. Patient undergone 20 sessions of plasma exchange till discharge and finally till 6 months graft was functioning well. The authors thus conclude that the option of a high-risk HLA incompatible kidney transplant can be offered to recipients with high MFI DSA, who wish to undergo transplantation for end stage renal disease.

• ClinicalKey
• Elsevier Science