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The morphologic finding of transplant glomerulitis (g) forms important evidence of microvascular injury. Besides antibody-mediated rejection (ABMR), this morphological feature is also seen in acute cellular rejection (ACR) and vasculitis but not included in the grading criteria for cellular rejection. A systematic review was thus conducted to summarize the current evidence and shed light on the quantum of impetus to be given to this finding when encountered during evaluation of renal biopsies. Out of a total of 13 studies selected, 06 studies supported the histologic finding of glomerulitis in ACR and non-DSA ABMR morphologies with variable incidence ranging from 15 to 21%. Seven studies supported glomerulitis as an independent prognostic marker for graft outcome at 1 year post transplant with or without DSA with highest HR reported of 4.52 and lowest being 01. Reviewing the present literature revealed interesting insights into occurrence, nature, molecular expression, role in glomerular injury and long-term outcomes with glomerulitis. It is recommended to approach the treatment of such lesions with heightened caution, as there appear to be elevated rates of graft failure, delayed graft function and Transplant glomerulopathy. [ABSTRACT FROM AUTHOR]

The use of posttransplant cyclophosphamide has revolutionized the field of haploidentical hematopoietic stem cell transplant. The impact has been especially enhanced in low‑ and middle‑income countries. Unrelated donor pool in developing nations is often limited due to the lack of large unrelated donor registries. Donor‑specific antibodies (DSAs) are preformed immunoglobulin G anti‑human leukocyte antigen (HLA) antibodies against HLA antigens that are not shared with the donor. We present successful desensitization in a 13‑year‑old patient with classIII β‑thalassemia with very high MFI DSAs with flow crossmatch positivity, persisting after pretransplant immunosuppression. [ABSTRACT FROM AUTHOR]

The presence of preformed cytotoxic donor‑specific antibodies (DSAs) has been associated with inferior allograft outcomes in the immediate posttransplant period. Since the 1970s, the primary method for determining the presence of DSAs has been the complement‑dependent cytotoxicity crossmatch. Solid phase assays on the Luminex platform were introduced in India in 2010 in the form of human leukocyte antigen antibody screening, single antigen bead (SAB) assay and lysate‑based crossmatch (LumXM) to identify low titer antibodies, which are deleterious to allograft. Instead of SAB, LumXM has been popularly used in India to identify DSAs and also called DSA crossmatch, which is not recommended or validated in International literature for denying or accepting to transplant a patient due to its fallacies. We are reporting three cases which showcase the flawed nature of this test and the implications of this test on day to day practice in transplantation. [ABSTRACT FROM AUTHOR]

Anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) are associated with antibody-mediated rejection and chronic allograft nephropathy in kidney transplantation. The interpretation of immunological assays for DSAs can be challenging due to discordant results. In this report, we present two cases of kidney transplantation involving patients with anti-HLA-C DSAs. We discuss the interpretation of their immunological tests, including complement-dependent cytotoxicity (CDC) crossmatches, flow cytometry crossmatches, and donor-specific antigen using single-antigen bead (SAB) assays, which influenced therapeutic decisions. In the first case, the patient exhibited isolated B-cell-positive crossmatch and autoantibodies, prompting the consideration of polyclonal autoantibodies in the context of underlying hepatitis C infection. The SAB assay detected only one DSA against HLA-C 03:03:01 (mean fluorescence intensity - 27,127). After careful evaluation and confirmation of negative CDC crossmatch, transplantation proceeded, and the patient demonstrated good graft function. In the second case, the patient showed a positive T-cell crossmatch along with anti-Class I HLA DSAs against HLA C*07:01 and HLA C*07:02. Despite these findings, transplantation was performed based on the absence of complement-binding antibodies. The patient experienced good graft recovery with stable kidney function. The presence of HLA-C DSAs poses challenges in transplantation decision-making. Despite conflicting studies, the pathological nature of these antibodies has been demonstrated. Careful interpretation of immunological tests and consideration of the overall clinical context are essential in making therapeutic decisions. Further research is needed to understand the clinical significance of HLA-C DSAs and their impact on graft outcomes. [ABSTRACT FROM AUTHOR]

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Introduction: The management of active antibody-mediated rejection (ABMR) is evolving, and optimal treatment remains uncertain due to incomplete understanding of pathogenesis. Bortezomib is found to be useful in the treatment of active ABMR. We studied the efficacy and safety of bortezomib in renal-transplant recipients with active ABMR. Materials and Methods: We retrospectively included renal-transplant recipients with active ABMR, who received bortezomib as main management. Results: Eighteen live-related renal-transplant recipients of active ABMR were included. C4d was positive in 14 patients and negative in eight patients. Patients with active ABMR had a mean improvement in glomerular filtration rate (GFR) of 7, 10.5, and 15 ml/min/1.73 m2 at 3, 6, and 12 months, respectively, from baseline GFR. Improvement was significant at 3 (P = 0.009) and 6 months (P = 0.018) of follow-up. Conclusion: Bortezomib may be a safe and effective therapy in patients with active ABMR in patients. [ABSTRACT FROM AUTHOR]

The occasion is when there is discordance between the results of the cell-based and virtual crossmatch and requires further workup before considering a patient for renal transplant. A case of the positive single-antigen bead (SAB) with donor-specific antibodies (DSA) against HLA-A*33:01 with negative complement-dependent cytotoxicity crossmatch and flow crossmatch was identified. The acid treatments of the beads were done to denature the antigen to understand the nature of identified DSA. There was variation in the Mean fluorescence intensity (MFI) observed in between patient sera with acid-treated beads (significantly increased) in contrast to regularly untreated SAB. This indicated additional antigens become available by the denaturation process. Hence, before making a final decision about the transplant in cases of ambiguity, SAB results should be interpreted in light of other compatibility results. [ABSTRACT FROM AUTHOR]

In renal transplant, the allograft is affected by many triggering agents such as innate and adaptive immune mechanisms, either mediated by macrophages and lymphocytes, or by soluble components antibodies and the complement system, which can ultimately lead to graft rejection. Antibody-mediated rejection (AMR) is a predominant cause of allograft failure. Donor-specific antibodies, mostly reactive to human leukocyte antigen antigens, are now considered by pathologists and clinicians as a significant cause of early and late graft dysfunction and failure. Complement 4d (C4d) is a fragment of the classical complement pathway (that is a part of component C4), which is activated by antigen-antibody complexes. The diagnosis of AMR improves by detection of the complement fragment C4d in renal biopsy, and it has included for diagnosis of AMR in the year 2003. There is more development about C4d after inclusion in the diagnostic criteria of AMR. This review aims to evaluate pathogenesis and current relevance of C4d in AMR. [ABSTRACT FROM AUTHOR]

The evaluation of donor-specific antibodies by Luminex single-antigen bead assay (in addition to other crossmatch tests) to assess pretransplant immunological risk should be performed in recipients (especially with a history of prior sensitization) even in resource-constrained settings as this approach can help in better risk stratification, to decide on transplant eligibility, selection of immunologically favorable donor, to plan desensitization protocol and induction therapy that can lead to the reduction of posttransplant rejection rates and better graft survival. Despite the cost, it is justified to use these sensitive assays in selected cases even in a cost-limited setting as this enables earlier and better-matched transplant, and avoidance of morbidity and poor graft survival. [ABSTRACT FROM AUTHOR]

Sensitized patients, who constitute a considerable proportion of kidney-transplant recipients, often have poor allograft outcomes. Only cell-based complement-dependent cytotoxicity (CDC) assays are typically used to quantify donor-specific antibodies (DSAs) in patients in developing nations, owing to financial restraints. We report the clinical outcomes of ten sensitized patients who were stratified and managed based on Luminex single-antigen beads (SAB) method for the DSA detection in a cost-limited set-up. Sensitization events included a history of blood transfusion, multiple pregnancies, and previous allograft loss. Anti-human leukocyte antigen antibodies, measured by SAB and reported as mean fluorescence intensity (MFI), were considered positive if the value was > 1000 MFI for single antigen. Three best approaches, (1) cadaveric transplants using virtual cross-match for kidney allocation in five patients, (2) desensitization before living donor transplants for four donor–recipient pairs with immunological incompatibility (high DSAs but cross-match compatible), and (3) combined kidney paired exchange with desensitization for one donor–recipient pair with cross-match incompatibility (positive CDC cross-match), resulted in successful allograft outcomes in all the 10 patients during follow-up (range: 3–55 months). DSA by SAB to assess pretransplant immunological risk (in a sensitized recipient) is useful even in cost-limited settings, largely due to reduction of posttransplant rejection rates and avoidance of mortality while on the waitlist. [ABSTRACT FROM AUTHOR]

Background: Various desensitization strategies are used to overcome immunologic barriers such as anti-human leukocyte antigen-donor-specific antibody (HLA-DSA) and anti-ABO blood group incompatibility. Materials and Methods: Three index cases of ABO-incompatible (ABO-i) kidney transplantation from living-related donors are discussed. Each recipient was evaluated by complement-dependent cytotoxicity crossmatch, flow cytometric crossmatch, lysate-based crossmatch, and single-antigen bead Luminex assay and anti-A, B isoagglutinin titer. The desensitization protocol included 500 mg of rituximab, followed by 2–10 sessions of plasmapheresis with basiliximab/antithymocyte globulin induction. Results: Case 1: A patient received the third transplant as ABO-i transplant, with no anti-HLA-DSA. Anti-ABO antibody titers were immunoglobulin M (IgM)/IgG 1:128/1:256. He had successful desensitization to anti-AB titer of <1:2 (IgM/IgG) with excellent outcome. Case 2: At the time of transplant, a patient had no anti-HLA-DSA. ABO titers were reduced to <1:8 (IgM/IgG) from baseline of IgM/IgG 1:128/1:1024 after desensitization. Posttransplant patient had severe acute graft dysfunction within 1 week, with rebound of anti-B titers to (IgM/IgG) 1:128/1:1024. Graft biopsy showed cortical necrosis resulting in graft loss. Case 3: His first ABO-compatible transplant was lost because of de novo anti-HLA-DSA, which developed within 1 week after transplant. The patient underwent the second ABO-i transplant. He also had anti-HLA-DSA against the second donor. Despite desensitization and anti-ABO titers coming down to <1:8, the patient developed severe acute graft dysfunction within 2 weeks, with rebound of anti-HLA-DSA antibody (titers increased >11000) resulting in graft loss. Conclusions: Careful evaluation of immunological barriers before ABO-i transplantation should be done, especially when both anti-HLA and ABO sensitization are present. [ABSTRACT FROM AUTHOR]

Abstract: Heart transplantation has become an important therapeutic option for the treatment of end-stage heart disease. Over the past 40 years, much has been learned about the immunologic responses to the allograft heart, including elucidation of the mechanisms of acute cellular rejection and antibody-mediated rejection (AMR). In AMR, damage to the allograft vasculature including capillaries and coronary arteries causes graft dysfunction and decreased survival. The recent recognition of AMR in cardiac transplantation has led to an evolution in the evaluation of the biopsy and graft surveillance. The use of serologic testing and both histologic and immunohistochemical criteria have improved the detection of AMR. [Copyright &y& Elsevier]

Copyright of Revista Médica Clínica Las Condes is the property of Editorial Sanchez y Barcelo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The positive complement-dependent cytotoxicity crossmatch (CDCXM) is considered as a contraindication for renal transplantation (RT) since long in an effort to avoid immediate rejection. There has been tremendous development in our understanding of transplant immunology today, and more sensitive and specific methods such as flow cytometry crossmatch (FCXM) and solid-phase antibody screening are used for detailed immunological assessment. We report successful RT in a 23-year-old girl with end-stage renal disease due to vasculitis on dialysis for 2 years. Before transplantation, the patient had Anti Human Globulin CDCXM positive while Dithioerythritol (DTT)-CDCXM was negative. The patient had no donor-specific antibodies examined by Luminex single-antigen beads and her FCMXM was negative. In the posttransplant period, there was no evidence of immune injury. Her serum creatinine was 0.7 mg/dl on the 3rd posttransplant day at the time of discharge. Induction immunosuppression was rabbit thymoglobulin (1.5 mb/kg) and methylprednisolone (500 mg, 3 doses) and maintenance immunosuppression was tacrolimus + prednisolone + mycophenolic acid. We found that even though CDCXM positivity has been traditionally considered as a contraindication for renal transplantation, in few carefully selected patients, we can still proceed to renal transplantation even if CDCXM is positive if more advanced and robust immunological tools such as FCMXM and donor-specific antibodies are negative. In our patient, AHG-CDCXM was positive while DTT-CDCXM was negative making it clear that antibodies of IgM origin were probably responsible for CDCXM positivity. [ABSTRACT FROM AUTHOR]

Background Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. Objective This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. Methods Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcεRI). Results Donor MHC class I– and MHC class II–specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcεRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. Conclusion These results demonstrate that MHC/HLA-specific IgE develops during an alloresponse and is functional in mediating effector mechanisms. Graphical abstract [ABSTRACT FROM AUTHOR]