Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial.

BACKGROUND: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes. METHODS: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR. RESULTS: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06). CONCLUSIONS: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077).

Outcomes after flow cytometry crossmatch-positive lung transplants managed with perioperative desensitization.

Our program previously reported successful outcomes following virtual crossmatch (VXM)-positive lung transplants managed with perioperative desensitization, but our ability to stratify their immunologic risk was limited without flow cytometry crossmatch (FCXM) data before 2014. The aim of this study was to determine allograft and chronic lung allograft dysfunction (CLAD)-free survival following VXM-positive/FCXM-positive lung transplants, which are performed at a minority of programs due to the high immunologic risk and lack of data on outcomes. All first-time lung transplant recipients between January 2014 and December 2019 were divided into 3 cohorts: VXM-negative (n = 764), VXM-positive/FCXM-negative (n = 64), and VXM-positive/FCXM-positive (n = 74). Allograft and CLAD-free survival were compared using Kaplan-Meier and multivariable Cox proportional hazards models. Five-year allograft survival was 53% in the VXM-negative cohort, 64% in the VXM-positive/FCXM-negative cohort, and 57% in the VXM-positive/FCXM-positive cohort (P = .7171). Five-year CLAD-free survival was 53% in the VXM-negative cohort, 60% in the VXM-positive/FCXM-negative cohort, and 63% in the VXM-positive/FCXM-positive cohort (P = .8509). This study confirms that allograft and CLAD-free survival of patients who undergo VXM-positive/FCXM-positive lung transplants with the use of our protocol does not differ from those of other lung transplant recipients. Our protocol for VXM-positive lung transplants improves access to transplant for sensitized candidates and mitigates even high immunologic risk.

Long-term outcomes of sensitized lung transplant recipients after peri-operative desensitization.

The Toronto Lung Transplant Program has been using a peri-operative desensitization regimen of plasma exchange, intravenous immune globulin, and antithymocyte globulin in order to accept donor-specific antibody (DSA)-positive lung transplants safely since 2008. There are no long-term data on the impact of this practice on allograft survival or the development of chronic lung allograft dysfunction (CLAD). We extended our prior study to include long-term follow-up of 340 patients who received lung transplants between January 1, 2008 and December 31, 2011. We compared allograft survival and CLAD-free survival among patients in three cohorts: DSA-positive, panel reactive antibody (PRA)-positive/DSA-negative, and unsensitized at the time of transplant. The median follow-up time in this extension study was 6.7 years. Among DSA-positive, PRA-positive/DSA-negative, and unsensitized patients, the median allograft survival was 8.4, 7.9, and 5.8 years, respectively (p = .5908), and the median CLAD-free survival was 6.8, 7.3, and 5.7 years, respectively (p = .5448). This follow-up study confirms that long-term allograft survival and CLAD-free survival of patients who undergo DSA-positive lung transplants with the use of our protocol do not differ from other lung transplant recipients. Use of protocols such as ours, therefore, may improve access to transplant for sensitized candidates.

Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.

Measuring alloantibodies: a matter of quantity and quality.

PURPOSE OF REVIEW: This review describes the utility and limitations of measure for assessing the presence, relative strength, and clinical impact of human leukocyte antigen (HLA) alloantibodies, as well as the other qualitative features of antibodies that are important considerations in assessing patient risk. RECENT FINDINGS: Using MFI as a measure of antibody amount is limited for a variety of reasons. Standardized serum manipulations such as ethylene-diamine-tetra-acetic acid treatment or serum dilution results in better definition of relationships between MFI and antibody titer or complement activation, toward greater alignment in defining positivity. Increased understanding of HLA epitopes has improved the ability to precisely define donor specific HLA antibody (DSA) specificities and the analysis of structural HLA Class II epitope mismatches in donor-recipient pairs may assist in the prevention of de novo DSA development. Studies of antibody isotypes and immunopathological mechanisms underlying graft injury mediated by non-HLA antibodies are expanding the assessemnt of immunological risk. SUMMARY: Careful analysis of both semiquantitative and qualitative properties of donor-specific antibodies continues to improve our ability to study the effects of DSA on clinical outcomes in solid organ transplantation.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

De novo donor-specific HLA antibodies in heart transplantation: Do transient de novo DSA confer the same risk as persistent de novo DSA?

BACKGROUND: It is estimated that 25%-35% of heart transplant recipients develop de novo donor-specific antibodies (dnDSA). One factor that appears to play a role in clinical outcomes is DSA persistence. The objective of this study was to determine the incidence of transient and persistent dnDSA in a Canadian heart transplant population and to evaluate their impact on coronary allograft vasculopathy (CAV), graft function, and mortality. METHODS: A retrospective study of consecutive adult and transitioned pediatric heart transplant recipients (2008-2015) in Toronto was performed. Clinical demographics were collected prospectively. HLA antibody testing was performed using Luminex single antigen assays. In statistical analysis, dnDSA was modeled as a time dependent covariate. RESULTS: During a median follow-up of 4.1 years, dnDSA were detected in 42 (23%) with a median time to detection of 329 days (156-740); 27 (64%) developed persistent dnDSA. Persistent dnDSA conferred an increased risk of death with a HR 4.0 (95%CI 1.4-12.1) when adjusted recipient age, CAV, and cytomegalovirus status. CONCLUSIONS: Transient dnDSA were not associated with adverse outcomes after heart transplantation. This suggests that transient dnDSA may not require enhanced immunosuppression, increased HLA antibody monitoring, or additional physiological assessment. By knowing the transient dnDSA status, clinicians may minimize both recipient morbidity and cost without increasing harm.

Comprehensive outcomes after lung retransplantation: A single-center review.

INTRODUCTION: Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. METHODS: We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n = 38). We analyzed the postoperative course, graft function, renal function, microbiology, donor-specific antibodies (DSA), quality of life, and survival compared to a control cohort of primary transplant recipients matched for age and era. RESULTS: Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 92%). The postoperative course was more complex after retransplant than primary (ventilation time, 8 vs 2 days, P < .01; ICU stay 14 vs 4 days, P < 0.01), and peak lung function was lower (FEV1 2.2L vs 3L, P < .01). Quality of life scores were comparable, as were renal function, microbiology, and donor-specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (P = .39). CONCLUSIONS: Lung retransplantation is associated with a more complex postoperative course and lower peak lung function, but the long-term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure.

Donor specific HLA antibodies & allograft injury: mechanisms, methods of detection, manifestations and management.

The impact of donor specific HLA antibodies (DSA) on solid organ transplant outcomes has been recognised for over half a century. This article reviews the mechanisms of DSA formation, details the laboratory methods for detecting DSA, discusses the clinical and histological manifestations of DSA in the allograft and explores the options for management of DSA. The challenges posed by pre-existing and de novo DSA are explored with current therapeutic strategies described. A method for stratifying the risk associated with pre-existing DSA is explained and the importance of understanding immunological risk associated with transplantation to facilitate optimal personalised decision making for transplant recipients is highlighted. Future directions for further managing the risk associated with DSA are proposed.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

RATIONALE: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. OBJECTIVES: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. METHODS: We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. CONCLUSIONS: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation.

Kidney retransplantation is a risk factor for decreased allograft survival. Repeated mismatched HLA antigens between first and second transplant may be a stimulus for immune memory responses and increased risk of alloimmune damage to the second allograft. Historical data identified a role of repeated HLA mismatches in allograft loss. However, evolution of HLA testing methods and a modern transplant era necessitate re-examination of this role to more accurately risk-stratify recipients. We conducted a contemporary registry analysis of data from 13,789 patients who received a second kidney transplant from 1995 to 2011, of which 3868 had one or more repeated mismatches. Multivariable Cox proportional hazards modeling revealed no effect of repeated mismatches on all-cause or death-censored graft loss. Analysis of predefined subgroups, however, showed that any class 2 repeated mismatch increased the hazard of death-censored graft loss, particularly in patients with detectable panel-reactive antibody before second transplant (hazard ratio [HR], 1.15; 95% confidence interval [95% CI], 1.02 to 1.29). Furthermore, in those who had nephrectomy of the first allograft, class 2 repeated mismatches specifically associated with all-cause (HR, 1.30; 95% CI, 1.07 to 1.58) and death-censored graft loss (HR, 1.41; 95% CI, 1.12 to 1.78). These updated data redefine the effect of repeated mismatches in retransplantation and challenge the paradigm that repeated mismatches in isolation confer increased immunologic risk. We also defined clear recipient categories for which repeated mismatches may be of greater concern in a contemporary cohort. Additional studies are needed to determine appropriate interventions for these recipients.

Immune Sensitization and Mortality in Wait-Listed Kidney Transplant Candidates.

Cardiovascular mortality is the leading cause of death in ESRD. Whereas innate and adaptive immunity have established roles in cardiovascular disease, the role of humoral immunity is unknown. We conducted a retrospective cohort study in first-time adult kidney transplant candidates (N=161,308) using data from the Scientific Registry of Transplant Recipients and the Centers for Medicare and Medicaid Services to evaluate whether anti-human leukocyte antigen antibodies, measured as panel reactive antibodies (PRAs), are related to mortality in ESRD. Relationships between time-varying PRAs and all-cause or cardiovascular mortality were assessed using Cox proportional hazards models. The analysis was repeated in subcohorts of candidates at lower risk for significant comorbidities, activated on the waiting list after 2007, or unsensitized at activation. Competing risks analyses were also conducted. Fully adjusted models showed increased hazard ratios (HRs [95% confidence intervals]) for all-cause mortality (HR, 1.02 [95% CI, 0.99 to 1.06]; HR, 1.11 [95% CI,1.07 to 1.16]; and HR,1.21 [95% CI,1.15 to 1.27]) and cardiovascular mortality (HR, 1.05 [95% CI,1.00 to 1.10]; HR,1.11 [95% CI,1.05 to 1.18]; and HR,1.21 [95% CI,1.12 to 1.31]) in PRA 1%-19%, PRA 20%-79%, and PRA 80%-100% categories compared with PRA 0%, respectively. Associations between PRA and the study outcomes were accentuated in competing risks models and in lower-risk patients and persisted in other subcohorts. Our findings suggest that PRA is an independent predictor of mortality in wait-listed kidney transplant candidates. The mechanisms by which PRA confers an incremental mortality risk in sensitized patients, and the role of transplantation in modifying this risk, warrant further study.

Extracorporeal photopheresis in solid organ transplant-associated acute graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T-cell lymphoma, or mediators of chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT-GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation-associated GVHD (SOT-GVHD) is unclear. Mortality rates in SOT-GVHD rival those of transfusion-associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT-GVHD cases to date, with one surviving. STUDY DESIGN AND METHODS: Clinicolaboratory features (including HLA relationships) in a case of multivisceral transplantation were reviewed from the time of surgery to the onset and progression of SOT-GVHD. ECP, which was introduced as a less immunosuppressive and more selective intervention, was assessed for its effect on serial PBC (as measured by short-tandem-repeat analysis) and clinical outcome. RESULTS: Multivisceral SOT-GVHD manifested with erythroderma, neutropenic sepsis, and PBC increasing from 6% on Posttransplant Day (PTD) 38 to 78% by PTD 60 (at a doubling time of 6 days despite corticosteroids). ECP was administered on PTDs 62 and 67 and was associated with the first evidence of PBC decay to 67% on PTD 69. Death nevertheless ensued on the last day of salvage antithymocyte globulin (PTDs 69-73) despite further PBC reduction to 41%. CONCLUSION: Further study is needed to determine if the sooner or more frequent application of ECP might attenuate the high case fatality rates of SOT-GVHD.

Utility of HLA Antibody Testing in Kidney Transplantation.

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor-specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes.

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection.

In this study, we conducted a systematic review of the literature to re-evaluate the role of C4d in the diagnosis of acute antibody-mediated rejection of kidney allografts. Electronic databases were searched until September 2013. Eligible studies allowed derivation of diagnostic tables for the performance of C4d by immunofluorescence or immunohistochemistry with comparison to histopathological features of acute antibody-mediated rejection and/or donor-specific antibody (DSA) assays. Of 3492 unique abstracts, 29 studies encompassing 3485 indication and 868 surveillance biopsies were identified. Assessment of C4d by immunofluorescence and immunohistochemistry exhibited slight to moderate agreement with glomerulitis, peritubular capillaritis, solid-phase DSA assays, DSA with glomerulitis, and DSA with peritubular capillaritis. The sensitivity and specificity of C4d varied as a function of C4d and comparator test thresholds. Prognostically, the presence of C4d was associated with inferior allograft survival compared with DSA or histopathology alone. Thus, our findings support the presence of complement-dependent and -independent phenotypes of acute antibody-mediated rejection. Whether the presence of C4d in combination with histopathology or DSA should be considered for the diagnosis of acute antibody-mediated rejection warrants further study.

Kidney paired donation: principles, protocols and programs.

Due to the ongoing shortage of deceased-donor organs, novel strategies to augment kidney transplantation rates through expanded living donation strategies have become essential. These include desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer donor options, single-center or small KPD programs may be less successful in transplanting the more sensitized patients; the optimal solution for the difficult-to-match patient is access to more potential donors and large multicenter or national registries are essential. Multicenter KPD programs have become common in the last decade, and now represent one of the most promising opportunities to improve transplant rates. To maximize donor-recipient matching, and minimize immunologic risk, these multicenter KPD programs use sophisticated algorithms to identify optimal match potential, with simultaneous two-, three- or more complex multiway exchanges. The article focuses on the recent progresses in KPD and it also reviews some of the differences and commonalities across four different national KPD programs.

Better understanding of transplant glomerulopathy secondary to chronic antibody-mediated rejection.

Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.

C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients.

Antibody-mediated rejection (AMR) occurs in 10-20% of patients after heart transplantation. C4d immunostaining is one parameter used in its diagnosis. This study aimed to determine whether C4d staining has prognostic significance for mortality, coronary allograft vasculopathy (CAV), cell-mediated rejection (CMR), and graft dysfunction in patients post-transplantation. Consecutive patients receiving an endomyocardial biopsy between 2007 and 2008 were selected. Left ventricular function, angiography, episodes of AMR/CMR, and death were noted. C4d was graded from 0 to 3 (immunostaining). Cox proportional models (recurrent events analysis) were used to evaluate C4d staining with mortality, graft dysfunction, CAV (≥grade 2), and episodes of ≥2R-CMR. We analyzed 2525 biopsy specimens (n = 217). During a follow-up of 4.5 ± 2 years, 35 died, 49 had graft dysfunction, seven had ≥grade 2 CAV, and 95 episodes of CMR occurred. A one-grade increase in C4d staining was associated with an increase in mortality (HR 1.57; 95% CI 1.0-2.5), a higher risk of CAV (HR 2.4, 95% CI 1.04-5.4), and a trend toward graft dysfunction (HR 1.42; 95% CI 1.0-2.09). C4d was not associated with CMR. C4d immunostaining was a significant predictor of CAV and death but not subsequent episodes of CMR. There was also a trend toward increased graft failure.