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Antibody-mediated Rejection (antibody-mediated + rejection)
Kinds of Antibody-mediated Rejection Selected AbstractsAntibody-Mediated Rejection: Emergence of Animal Models to Answer Clinical QuestionsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010William M. Baldwin III Decades of experiments in small animals had tipped the balance of opinion away from antibodies as a cause of transplant rejection. However, clinical experience, especially with sensitized patients, has convinced basic immunologists of the need to develop models to investigate mechanisms underlying antibody-mediated rejection (AMR). This resurgent interest has resulted in several new rodent models to investigate antibody-mediated mechanisms of heart and renal allograft injury, but satisfactory models of chronic AMR remain more elusive. Nevertheless, these new studies have begun to reveal many insights into the molecular and pathological sequelae of antibody binding to the allograft endothelium. In addition, complement-independent and complement-dependent effects of antibodies on endothelial cells have been identified in vitro. As small animal models become better defined, it is anticipated that they will be more widely used to answer further questions concerning mechanisms of antibody-mediated tissue injury as well as to design therapeutic interventions. [source] A retrospective review of the outcome of plasma exchange and aggressive medical therapy in antibody mediated rejection of renal allografts: A single center experienceJOURNAL OF CLINICAL APHERESIS, Issue 6 2008Wisam Al-Badr Abstract Antibody-mediated rejection (AMR) has been recognized as a major cause of renal allograft loss. Protocols using plasma exchange (PE) to reverse rejection have mixed results. Methods: A retrospective chart review was performed to determine the clinical response to PE inpatients with AMR of renal allograft. A good response to treatment was defined as a decline in serum creatinine (SCr) to within 25% above the prerejection value or discontinuation of dialysis with a SCr <2 mg/dl within 3 months of discharge from the hospital and disappearance of donor-specific alloantibodies (DSA). Results: Twenty-two patients, treated with PE for biopsy proven AMR with or without acute-cellular rejection (ACR), were included in the study. Sixty-four percent of patients had concurrent AMR and ACR. Fifty-two percent of all patients had a good response to antirejection therapy, whereas 63% of patients with only AMR and 46% of patients with both AMR and ACR had a good response. Good response to PE did not correlate with the number of plasma volumes exchanged (P = 0.09), but correlated with a shorter period from transplantation to the rejection episode (P = 0.002). Conclusion: Only a shorter interval between transplantation and the acute rejection episode correlated with a good response to PE. J. Clin. Apheresis, 2008. © 2008 Wiley-Liss, Inc. [source] An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney TransplantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010P. F. Halloran Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury,repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell-mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury,repair response, including de-differentiation, cell cycling and apoptosis. The active injury,repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease. [source] De novo Thrombotic Microangiopathy in Renal Allograft Biopsies,Role of Antibody-Mediated RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010A. A. Satoskar The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody-mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR-associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR-related TMA because plasmapheresis treatment may be beneficial. [source] Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009C. D. Tan Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d, group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d, group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d, patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation. [source] C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in RatsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5p1 2006K. Minami Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complement-activating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days. [source] The role of B cells and alloantibody in the host response to human organ allograftsIMMUNOLOGICAL REVIEWS, Issue 1 2003Attapong Vongwiwatana Summary:, Some human organ transplants deteriorate slowly over a period of years, often developing characteristic syndromes: transplant glomerulopathy (TG) in kidneys, bronchiolitis obliterans in lungs, and coronary artery disease in hearts. In the past, we attributed late graft deterioration to ,chronic rejection', a distinct but mysterious immunologic process different from conventional rejection. However, it is likely that much of chronic rejection is explained by conventional T-cell-mediated rejection (TMR), antibody-mediated rejection (AMR), and other insults. Recently, criteria have emerged to now permit us to diagnose AMR in kidney transplants, particularly C4d deposition in peritubular capillaries and circulating antibody against donor human leukocyte antigens (HLA). Some cases with AMR develop TG, although the relationship of TG to AMR is complex. Thus, a specific diagnosis of AMR in kidney can now be made, based on graft damage, C4d deposition, and donor-specific alloantibodies. Criteria for AMR in other organs must be defined. Not all late rejections are AMR; some deteriorating organs probably have smoldering TMR. The diagnosis of late ongoing AMR raises the possibility of treatment to suppress the alloantibody, but efficacy of the available treatments requires further study. [source] The role of immunomodulation in ABO-incompatible adult liver transplant recipientsJOURNAL OF CLINICAL APHERESIS, Issue 2 2008Lucio Urbani Abstract Background: ABO-incompatible (ABO-i) liver transplantation (LT) is a high-risk procedure due to the potential for antibody-mediated rejection (AMR) and cell-mediated rejection. The aim of the current report is to illustrate the results of a retrospective comparison study on the use of immunomodulation with therapeutic plasma exchange (TPE) associated to high-dose immunoglobulins (IVIg) and extracorporeal photopheresis (ECP) in ABO-i adult LT patients. Patients and methods: Between January 1996 and December 2005, 19 patients underwent ABO-i LT. The study was designed for a comparison between two groups of ABO-i LT. Group 1 (control group) consisted of 11 patients treated with TPE only. Group 2 (study group) included eight patients treated with TPE and IVIg. Moreover, all Group 2 patients received acute rejection prophylaxis with ECP. Results: The graft survival at 6, 12, and 18 months was 63.6, 54.4, and 45.5% for Group 1 vs. 87.5, 87.5, and 87.5% for Group 2 (P , 0.001). In Group 1 there were 3(27.3%) cases of AMR; 5 (45.4%) biopsy-proven acute rejections (BPAR); 1 (9.1%) chronic rejection and 3 (27.3%) ischemic-type biliary lesions (ITBL). In Group 2 there were no cases of AMR, BPAR, chronic rejection, or ITBL (P = 0.013). Conclusion: At median follow-up of 568 days, TPE in combination with IVIg and ECP appears to protect the graft from AMR in ABO-i liver transplantation. Continued patient enrollment will allow validation of these preliminary observations or the opportunity to devise newer AMR-avoidance policies. J. Clin. Apheresis 2008. © 2008 Wiley-Liss, Inc. [source] B-cell surface marker analysis for improvement of rituximab prophylaxis in ABO-incompatible adult living donor liver transplantationLIVER TRANSPLANTATION, Issue 4 2007Hiroto Egawa Although the effectiveness of rituximab has been reported in ABO blood group (ABO)-incompatible (ABO-I) organ transplantation, the protocol is not yet established. We studied the impact of the timing of rituximab prophylaxis and the humoral immune response of patients undergoing ABO-I living donor liver transplantation (LDLT), focusing on clinicopathological findings and the B-cell subset. From July 2003 to December 2005, 30 adult patients were treated with hepatic artery infusion (HAI) protocol without splenectomy for ABO-I LDLT. A total of 17 patients were treated only with HAI (no prophylaxis), and the other 13 were treated with rituximab prophylaxis at various times prior to transplantation. For B-cell study of the spleen, another 4 patients undergoing ABO-I LDLT both with HAI after prophylaxis and eventual splenectomy, and 3 patients with ABO-compatible LDLT with splenectomy were enrolled. The mortality of the 30 patients with HAI, without splenectomy, and with/without rituximab prophylaxis was 33% and the main cause of death was sepsis. Peripheral blood B cells were completely depleted, anti-donor blood-type antibody titer was lower, and clinical and pathological antibody-mediated rejection was not observed in patients with prophylaxis earlier than 7 days before transplantation (early prophylaxis). Early rituximab prophylaxis significantly depleted B cells and memory B cells in the spleen but not in lymph nodes. On the other hand, B cells and memory B cells increased and memory B cells became dominant during antibody-mediated rejection. In conclusion, early prophylaxis with rituximab depletes B cells, including memory B cells, in the spleen and is associated with a trend toward lower humoral rejection rates and lower peak immunoglobulin (Ig)G titers in ABO-I LDLT patients. Liver Transpl 13:579,588, 2007. © 2007 AASLD. [source] Review article: Luminex technology for HLA antibody detection in organ transplantationNEPHROLOGY, Issue 2 2009BRIAN D TAIT SUMMARY Since its inception in the early 1960s, the serologically based complement-dependent cytotoxicity (CDC) assay has been the cornerstone technique for the detection of human leucocyte antigen (HLA) antibodies, not only in pre-transplant renal patients, but also in other forms of organ transplantation. Recently, solid phase assays have been developed and introduced for this purpose, and in particular the Flow-based bead assays such as the Luminex system. This latter assay has proved to be far more sensitive than the CDC assay and has revealed pre-sensitization in potential transplant recipients not detected by other methods of HLA antibody detection. However, the clinical implications of this increased sensitivity have not been convincingly demonstrated until recently. This technology for HLA antibody detection permits the evaluation of the clinical importance of antibodies directed at, for example, HLA-DPB1 and HLA-DQA1, which has not been possible to date. There are Luminex issues, however, requiring resolution such as the ability to distinguish between complement fixing and non-complement fixing antibodies and determination of their relative clinical significance. Luminex technology will permit a re-evaluation of the role of HLA antibodies in both early and late antibody-mediated rejection. [source] C4d in pediatric renal allograft biopsies: A marker for negative outcome in steroid-resistant rejectionPEDIATRIC TRANSPLANTATION, Issue 4 2006Regina Vargha Abstract:, Recently, deposition of C4d, reflecting complement activation via the classical pathway, has been established as marker of antibody-mediated rejection. As C4d can be detected in paraffin sections, it allows for retrospective analysis in populations with low case loads, such as in pediatric transplantation. In this study we re-evaluated consecutive renal transplant biopsies obtained since 1990 in 36 children (18 boys, 18 girls) who had received their allograft (nine living, 27 cadaveric) at an age of 10.12±4.4 yr. Clinical indications for biopsy were 16 acute steroid resistant rejections (ASRs), 11 chronic rejections and nine other diagnoses. Overall, C4d deposition was found in nine cases (25%), eight of them with diagnosed ASR. Six out of these eight allografts were lost during 36 months of clinical follow-up, a significantly higher rate than in C4d-negative biopsies (p<0.05). C4d status therefore turned out to be an excellent predictor for inferior graft survival following ASR. None of the other histopathologic markers were sensitive for humoral rejections. In conclusion, the high prevalence of C4d-positive staining in ASR demonstrates the importance of the humoral part of the immune system in pediatric transplantation. The worse outcome of C4d-positive rejections despite massive immunosuppressive therapy clearly indicates the need for innovative therapies in this high-risk population. [source] The Molecular Phenotype of Kidney TransplantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010P. F. Halloran Microarray studies of kidney transplant biopsies provide an opportunity to define the molecular phenotype. To facilitate this process, we used experimental systems to annotate transcripts as members of pathogenesis-based transcript sets (PBTs) representing biological processes in injured or diseased tissue. Applying this annotation to microarray results revealed that changes in single molecules and PBTs reflected a large-scale coordinate disturbance, stereotyped across various diseases and injuries, without absolute specificity of individual molecules or PBTs for rejection. Nevertheless, expression of molecules and PBTs was quantitatively specific: IFNG effects for rejection; T cell and macrophage transcripts for T cell-mediated rejection; endothelial and NK transcripts for antibody-mediated rejection. Various diseases and injuries induced the same injury,repair response, undetectable by histopathology, involving epithelium, stroma and endothelium, with increased expression of developmental, cell cycle and apoptosis genes and decreased expression of differentiated epithelial features. Transcripts reflecting this injury,repair response were the best correlates of functional disturbance and risk of future graft loss. Late biopsies with atrophy-fibrosis, reflecting their cumulative burden of injury, displayed more transcripts for B cells, plasma cells and mast cells. Thus the molecular phenotype is best described in terms of three elements: specific diseases, including rejection; the injury,repair response and the cumulative burden of injury. [source] An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney TransplantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010P. F. Halloran Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury,repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell-mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury,repair response, including de-differentiation, cell cycling and apoptosis. The active injury,repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease. [source] Peritransplant Immunoadsorption for Positive Crossmatch Deceased Donor Kidney TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010G. Bartel Various desensitization protocols were shown to enable successful living donor kidney transplantation across a positive complement-dependent cytotoxicity crossmatch (CDCXM). Positive crossmatch transplantation, however, is less well established for deceased donor transplantation. We report a cohort of 68 deceased donor renal allograft recipients who, on the basis of broad sensitization (lymphocytotoxic panel reactivity ,40%), were subjected to a protocol of peritransplant immunoadsorption (IA). Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by posttransplant IA and antilymphocyte antibody therapy. Twenty-one patients had a positive CDCXM, which could be rendered negative by pretransplant apheresis. Solid phase HLA antibody detection revealed preformed donor-specific antibodies (DSA) in all 21 CDCXM-positive and in 30 CDCXM-negative recipients. At 5 years, overall graft survival, death-censored graft survival and patient survival were 63%, 76% and 87%, respectively, without any differences between CDCXM-positive, CDCXM-negative/DSA-positive and CDCXM-negative/DSA-negative recipients. Furthermore, groups did not differ regarding rates of antibody-mediated rejection (24% vs. 30% vs. 24%, p = 0.84), cellular rejection (14% vs. 23% vs. 18%, p = 0.7) or allograft function (median 5-year serum creatinine: 1.3 vs. 1.8 vs. 1.7 mg/dL, p = 0.62). Our results suggest that peritransplant IA is an effective strategy for rapid desensitization in deceased donor transplantation. [source] Case Report: Eculizumab, Bortezomib and Kidney Paired Donation Facilitate Transplantation of a Highly Sensitized Patient Without Vascular AccessAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010B. E. Lonze A 43-year-old patient with end-stage renal disease, a hypercoagulable condition and 100% panel reactive antibody was transferred to our institution with loss of hemodialysis access and thrombosis of the superior and inferior vena cava, bilateral iliac and femoral veins. A transhepatic catheter was placed but became infected. Access through a stented subclavian into a dilated azygos vein was established. Desensitization with two cycles of bortezomib was undertaken after anti-CD20 and IVIg were given. A flow-positive, cytotoxic-negative cross-match live-donor kidney at the end of an eight-way multi-institution domino chain became available, with a favorable genotype for this patient with impending total loss of a dialysis option. The patient received three pretransplant plasmapheresis treatments. Intraoperatively, the superior mesenteric vein was the only identifiable patent target for venous drainage. Eculizumab was administered postoperatively in the setting of antibody-mediated rejection and an inability to perform additional plasmapheresis. Creatinine remains normal at 6 months posttransplant and flow cross-match is negative. In this report, we describe the combined use of new agents (bortezomib and eculizumab) and modalities (nontraditional vascular access, splanchnic drainage of graft and domino paired donation) in a patient who would have died without transplantation. [source] NK Cell Transcripts and NK Cells in Kidney Biopsies from Patients with Donor-Specific Antibodies: Evidence for NK Cell Involvement in Antibody-Mediated RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010L. G. Hidalgo To explore the mechanisms of antibody-mediated rejection (ABMR) in kidney transplants, we studied the transcripts expressed in clinically indicated biopsies from patients with donor-specific antibody (DSA). Comparison of biopsies from DSA-positive versus DSA-negative patients revealed 132 differentially expressed transcripts: all were associated with class II DSA but none with class I DSA. Many transcripts were expressed in DSA-positive ABMR but were also expressed in T-cell-mediated rejection (TCMR), reflecting shared molecular features. Removal of shared transcripts created 23 DSA selective transcripts (DSASTs). Some DSASTs (6/23) showed selective high expression in NK cells, whereas others (8/23) were expressed in endothelium or in endothelium plus other cell types (7/23). Of 145 biopsies ranked by DSAST expression, the 25 with highest DSAST expression primarily consisted of ABMR (22/25, 88%), either C4d-positive or C4d-negative. By immunostaining, CD56+ and CD68+ cells in peritubular capillaries, but not CD3+ cells, were increased in ABMR compared to TCMR, compatible with a role for NK cells, as well as macrophages, as effectors in endothelial injury during ABMR. Thus, the strategy of using DSASTs in the biopsy to identify mechanism-related transcripts in biopsies from patients with clinical phenotypes indicates the selective involvement of NK cells in ABMR. [source] Thrombotic Microangiopathy After Kidney TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010M. Noris Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation that often causes graft failure. TMA may occur de novo, often triggered by immunosuppressive drugs and acute antibody-mediated rejection, or recur in patients with previous history of hemolytic uremic syndrome (HUS). Recurrent TMA is very rare in patients who had developed end-stage renal failure following HUS caused by Shiga-toxin producing E. scherichia coli, whereas disease recurrence is common in patients with atypical HUS (aHUS). The underlying genetic defect greatly impacts the risk of posttransplant recurrence in aHUS. Indeed recurrence is almost the rule in patients with mutations in genes encoding factor H or factor I, whereas patients with a mutation in membrane-cofactor-protein gene have a good transplant outcome. Prophylactic and therapeutic options for posttransplant TMA, including plasma therapy, combined kidney and liver transplantation and targeted complement inhibitors are discussed in this review. [source] Antibody-Mediated Rejection: Emergence of Animal Models to Answer Clinical QuestionsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010William M. Baldwin III Decades of experiments in small animals had tipped the balance of opinion away from antibodies as a cause of transplant rejection. However, clinical experience, especially with sensitized patients, has convinced basic immunologists of the need to develop models to investigate mechanisms underlying antibody-mediated rejection (AMR). This resurgent interest has resulted in several new rodent models to investigate antibody-mediated mechanisms of heart and renal allograft injury, but satisfactory models of chronic AMR remain more elusive. Nevertheless, these new studies have begun to reveal many insights into the molecular and pathological sequelae of antibody binding to the allograft endothelium. In addition, complement-independent and complement-dependent effects of antibodies on endothelial cells have been identified in vitro. As small animal models become better defined, it is anticipated that they will be more widely used to answer further questions concerning mechanisms of antibody-mediated tissue injury as well as to design therapeutic interventions. [source] ABO Antibody Titer and Risk of Antibody-Mediated Rejection in ABO-Incompatible Renal TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010A. A. R. Tobian Therapeutic plasma exchange (TPE) preconditioning with immunosuppressive therapy reduces ABO antibody titers, permitting engraftment of ABO-incompatible (ABO-I) kidney transplants. The posttransplant predictive role of ABO antibody titers for antibody-mediated rejection (AMR) is unknown. This retrospective study evaluated 46 individuals who received TPE to permit ABO-I kidney transplantation. ABO antibody titers were performed using donor-type indicator red cells. Seven individuals (15.2%) experienced clinical or subclinical AMR. There was no significant difference between recipient blood group, number of pretransplant TPE and baseline titer between those with and without AMR. At 1,2 weeks posttransplant the median titer was 64 (range 4 , 512) among individuals with AMR and 16 (range 2 , 256) among individuals without AMR. Total agglutination reactivity score was significantly higher among individuals with AMR (p = 0.046). The risk of AMR was significantly higher among individuals with an elevated posttransplant titer of ,64 (p = 0.006). The sensitivity of an elevated posttransplant titer was 57.1% with a specificity of 79.5%. The positive predictive value was 33.3% and the negative predictive value was 91.2%. Most individuals with AMR have an elevated titer, however, the positive predictive value of a high titer for AMR is poor. [source] Efficacy of Induction Therapy with ATG and Intravenous Immunoglobulins in Patients with Low-Level Donor-Specific HLA-AntibodiesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010K. Bächler Low-level donor-specific HLA-antibodies (HLA-DSA) (i.e. detectable by single-antigen flow beads, but negative by complement-dependent cytotoxicity crossmatch) represent a risk factor for early allograft rejection. The short-term efficacy of an induction regimen consisting of polyclonal anti-T-lymphocyte globulin (ATG) and intravenous immunoglobulins (IvIg) in patients with low-level HLA-DSA is unknown. In this study, we compared 67 patients with low-level HLA-DSA not having received ATG/IvIg induction (historic control) with 37 patients, who received ATG/IvIg induction. The two groups were equal regarding retransplants, HLA-matches, number and class of HLA-DSA. The overall incidence of clinical/subclinical antibody-mediated rejection (AMR) was lower in the ATG/IvIg than in the historic control group (38% vs. 55%; p = 0.03). This was driven by a significantly lower rate of clinical AMR (11% vs. 46%; p = 0.0002). Clinical T-cell-mediated rejection (TCR) was significantly lower in the ATG/IvIg than in the historic control group (0% vs. 50%; p < 0.0001). Within the first year, allograft loss due to AMR occurred in 7.5% in the historic control and in 0% in the ATG/IvIg group. We conclude that in patients with low-level HLA-DSA, ATG/IvIg induction significantly reduces TCR and the severity of AMR, but the high rate of subclinical AMR suggests an insufficient control of the humoral immune response. [source] Histopathology and Immunophenotype of the Spleen During Acute Antibody-Mediated RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010B. Kaplan Splenectomy has been reported to have a beneficial effect in treating Acute antibody-mediated rejection (ABMR). This reason for this often rapid and profound beneficial effect is not readily apparent from what is known about normal splenic immunoarchitecture. While the spleen is rich in mature B cells, it has not been noted to be a repository for direct antibody-secreting cells. We present a case of a Native American female who received a renal transplant and developed a severe episode of ABMR. The patient was initially refractory to both plasmapheresis and IVIG. The patient underwent an emergent splenectomy with almost immediate improvement in her renal function and a rapid drop in her DR51 antibodies. Immunohistochemical stains of the spleen demonstrated abundant clusters of CD138+ plasma cells (>10% CD138 cells as opposed to 1% CD138 cells as seen in traumatic controls). Though this is a single case, these findings offer a rationale for the rapid ameliorative effect of splenectomy in cases of antibody rejection. It is possible that the spleen during times of excessive antigenic stress may rapidly turn over B cells to active antibody-secreting cells or serve as a reservoir for these cells produced at other sites. [source] Complement Independent Antibody-Mediated Endarteritis and Transplant Arteriopathy in MiceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010T. Hirohashi Complement fixation, as evidenced by C4d in the microvasculature, is a widely accepted criterion of antibody-mediated rejection. Complement fixation has been shown to be essential in acute antibody-mediated rejection, but its role in chronic rejection has not been addressed. Previous studies showed that passive transfer of complement fixing monoclonal IgG2a anti-H-2Kk into B6.RAG1,/, KO recipients of B10.BR hearts led to progressive chronic transplant arteriopathy (CTA) over 14,28 days, accompanied by C4d deposition. The present studies were designed to test whether complement was required for these lesions. We report that a noncomplement fixing donor-specific alloantibody (DSA, monoclonal IgG1 anti-H-2Kk) injected into B6.RAG1 -/- KO recipients of B10.BR hearts also promotes CTA, without C4d deposition. Furthermore, a passive transfer of DSA (monoclonal IgG2a anti-H-2Kk) initiated endarteritis followed by CTA in B6.RAG1,/- mice genetically deficient in the third component of complement (RAG1,/,C3,/,). These studies indicate that antibody to class I MHC antigens can trigger chronic arterial lesions in vivo without complement participation, in contrast to acute antibody-mediated rejection. This pathway may be relevant to C4d-negative chronic rejection sometimes observed in patients with DSA, and argues that lack of C4d deposition does not exclude antibody-mediated chronic rejection. [source] Baseline Donor-Specific Antibody Levels and Outcomes in Positive Crossmatch Kidney TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010J. M. Gloor Renal transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (,XM) transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and ,XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of ,XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates. [source] Equivalent Outcomes for Pediatric Heart Transplantation Recipients: ABO-Blood Group Incompatible versus ABO-CompatibleAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. I. Dipchand ABO-blood group incompatible infant heart transplantation has had excellent short-term outcomes. Uncertainties about long-term outcomes have been a barrier to the adoption of this strategy worldwide. We report a nonrandomized comparison of clinical outcomes over 10 years of the largest cohort of ABO-incompatible recipients. ABO-incompatible (n = 35) and ABO-compatible (n = 45) infant heart transplantation recipients (,14 months old, 1996,2006) showed no important differences in pretransplantation characteristics. There was no difference in incidence of and time to moderate acute cellular rejection. Despite either the presence (seven patients) or development (eight patients) of donor-specific antibodies against blood group antigens, in only two ABO-incompatible patients were these antibodies implicated in antibody-mediated rejection (which occurred early posttransplantation, was easily managed and did not recur in follow-up). Occurrence of graft vasculopathy (11%), malignancy (11%) and freedom from severe renal dysfunction were identical in both groups. Survival was identical (74% at 7 years posttransplantation). ABO-blood group incompatible heart transplantation has excellent outcomes that are indistinguishable from those of the ABO-compatible population and there is no clinical justification for withholding this lifesaving strategy from all infants listed for heart transplantation. Further studies into observed differing responses in the development of donor-specific isohemagglutinins and the implications for graft accommodation are warranted. [source] De Novo HLA Sensitization and Antibody Mediated Rejection Following Pregnancy in a Heart Transplant RecipientAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010P. J. O'Boyle Here we report a case wherein both donor-specific and third-party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody-mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier. [source] Effect of Antibodies on EndotheliumAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009X. Zhang Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms. New research has shown that antibodies can also contribute to the process of transplant rejection by stimulating proinflammatory and proproliferation signals. Antibody ligation leads to several functional alterations in EC including Weibel Palade body exocytosis, leukocyte recruitment, growth factor expression and cell proliferation. In contrast, under certain circumstances, antibodies may induce prosurvival signals and graft accommodation. The signaling events regulating accommodation vs. rejection appear to be influenced by the specificity and concentration of the anti-HLA antibody and the degree of molecular aggregation. Knowledge of the HLA and non-HLA antibody-mediated signaling pathways has the potential to identify new therapeutic targets to promote accommodation and prevent acute and chronic antibody-mediated rejection. [source] Antibody-Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant FailureAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009G. Einecke We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria. [source] Outcome of Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with Preformed Donor-Specific AntibodiesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009A. Loupy This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 ± 13.9 vs. 61.9 ± 19.2 mL/min/1.73 m2 respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR. [source] BAFF Is Increased in Renal Transplant Patients Following Treatment with AlemtuzumabAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009D. Bloom Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19+ B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2,7-fold in CD14+ cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19+ cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients. [source] Successful Renal Transplantation in a Patient with Atypical Hemolytic Uremic Syndrome Carrying Mutations in Both Factor I and MCPAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009J. M. Cruzado Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) carrying mutations in the soluble complement regulators factor H (CFH) or factor I (CFI) is associated with elevated risk of disease recurrence and almost certain graft loss. In contrast, recurrence is unusual in patients with mutations in the membrane-associated complement regulator membrane cofactor protein (MCP) (CD46). Therefore, a panel of experts recently recommended the combined liver,kidney transplantation to minimize aHUS recurrence in patients with mutations in CFH or CFI. There was, however, very limited information regarding transplantation in patients carrying mutations in both soluble and membrane-associated complement regulators to support a recommendation. Here, we report the case of an aHUS patient with a heterozygous mutation in both CFI and MCP who received an isolated kidney transplant expressing normal MCP levels. Critically, the patient suffered from a severe antibody-mediated rejection that was successfully treated with plasmapheresis and IvIgG. Most important, despite the complement activation in the allograft, there was no evidence of thrombotic microangiopathy, suggesting that the normal MCP levels in the grafted kidney were sufficient to prevent the aHUS recurrence. Our results suggest that isolated kidney transplantation may be a good first option for care in aHUS patients carrying CFI/MCP combined heterozygous mutations. [source] | ||||||||||