Biopsy-negative Rejection Research Articles

Therapeutic Plasma Exchange is Associated with Increased Survival in Heart Transplant Recipients Experiencing Severe Primary Graft Dysfunction

BackgroundPrimary graft dysfunction (PGD) remains the leading cause of 30-day mortality post-heart transplantation (HTx). HTx recipients experiencing severe PGD have been found to have high levels of circulating proteins associated with PGD occurrence and post-HTx survival. Whether treating these patients with therapeutic plasma exchange (TPE) can attenuate ongoing immunological and inflammatory processes and improve post-transplant outcomes has not been well-investigated. AimWe aim to examine the impact of treatment with TPE on 30-day and 1-year clinical outcomes of patients experiencing severe PGD post-HTx. MethodsBetween 2010 and 2022, we included 42 HTx patients who developed severe PGD. All included patients were placed on veno-arterial extracorporeal membrane oxygenation. We divided these patients into those who received TPE and those who did not (by physician choice). Endpoints included 30-day and 1-year survival, as well as 1-year-freedom from Any-treated rejection (ATR), acute cellular rejection (ACR), antibody-mediated rejection (AMR), biopsy negative rejection (BNR), cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and freedom from left ventricular dysfunction (LVD) at 1-year post-HTx. ResultsCompared to patients who did not receive TPE, those managed with TPE had increased survival rates at 30 days (78.1% vs. 40%, P=0.007) and at 1-year post-HTx (56.25% vs. 30% P=0.035). However, no statistically significant differences were recorded in other outcomes of interest, including 1-year freedom from CAV, ATR, ACR, AMR, BNR, NF-MACE, or LVD. ConclusionTPE may serve as a promising therapeutic approach in HTx recipients experiencing severe PGD.

(788) - The Outcome of Biopsy Negative Rejection After Heart Transplantation: Does Severity of BNR Matter?

(788) - The Outcome of Biopsy Negative Rejection After Heart Transplantation: Does Severity of BNR Matter?

Treatment and Outcome of AL Amyloid After Heart Transplantation: Is It Viable?

<h3>Purpose</h3> In the past, light chain (AL) amyloid has been associated with poor outcomes after heart transplantation (HTx), mainly due to its complicated course. Many AL amyloid patients will require stem cell transplant following HTx. It is not known whether these patients have acceptable outcomes after HTx. <h3>Methods</h3> Between 2008 and 2020, we assessed all AL amyloid patients undergoing HTx. Patients were divided into those that required stem cell therapy and those that did not. Both groups were compared to age-matched control that did not have amyloid. Endpoints included 1-year survival, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejection (any treated rejection [ATR], acute cellular rejection [ACR], antibody-mediated rejection [AMR], biopsy-negative rejection [BNR]). <h3>Results</h3> There was no difference between AL amyloid patients with and without stem cell therapy in 1-year survival, or freedom from CAV, NF-MACE, or ATR. Compared to matched controls, post-transplant outcomes were similar. (See table.) <h3>Conclusion</h3> In the current era, therapies for AL amyloid post-heart transplant appear successful with acceptable outcome compared to non-amyloid patients. AL amyloid is not a contraindication for heart transplantation.

Are Calcineurin Inhibitor-Free Protocols Safe and Effective in the Long-Term After Heart Transplant?

<h3>Purpose</h3> Calcineurin inhibitors (CNIs) tacrolimus and cyclosporine, have improved outcomes of heart transplant (HTx) patients but unfortunately have many side effects which include nephrotoxicity, hypertension, and malignancy. CNI-free regimens may protect the kidneys but at the risk of rejection. The purpose of this study was to assess our center's experience with CNI minimization and discontinuation. <h3>Methods</h3> We assessed 34 HTx patients transplanted between 2010-2020, who transitioned to CNI-free regimens 6m-2 years post HTx and 2-5 years post HTx. Outcomes assessed were any treated rejection (ATR; including acute cellular rejection [ACR], antibody-mediated rejection [AMR], and biopsy-negative rejection [BNR]), survival, cardiac dysfunction (ejection fraction ≤40%) in the 1 year following CNI-free initiation. We also assessed the need for antihypertensive medications, HgbA1c, and estimated glomerular filtration rate (eGFR). <h3>Results</h3> Of 34 HTx recipients, 89% of patients were successfully weaned off CNI at <2 years and 94% at 2-5 years after transplant. eGFR for both groups was markedly improved at 1-year post CNI-free initiation. There was no difference between groups in anti-hypertensive medications or HgbA1c. However, CNI had to be restarted in 50% of the CNI-free in <2 years group and in 31% of the CNI-free at 2-5 years group. Return to CNI was for: rejection, medication intolerance, and death. (Table). <h3>Conclusion</h3> CNI-free regimens are safe and efficacious for select patients but may not be sustainable. Additional strategies for renal protection and immunosuppression optimization are warranted.

Eculizumab for Treatment of Biopsy Negative Rejection in Heart Transplantation

Introduction Antibody mediated rejection (AMR) may be suspected in Heart Transplant (HT) patients with biopsy negative rejection (BNR). Donor specific antibodies (DSA) can support this diagnosis. Molecular phenotyping of endomyocardial biopsies (EMB) has identified rejection associated transcripts which correlate with decreased left ventricular ejection fraction (EF) but not with AMR on EMB. BNR may respond to augmented immunosuppression. Thus, there is evidence that BNR may represent rejection. The pathophysiology of AMR involves complement activation. Eculizumab, a monoclonal antibody targeting C5a treats AMR in renal transplant patients. We present two cases of eculizumab use for BNR with presumed AMR in HT patients. Case Report A 22 year old male underwent HT in 2007 for non-ischemic cardiomyopathy (NICM). His post-operative course was complicated by grade 2 AMR and mild cardiac allograft vasculopathy (CAV1) with normal graft function. In 2018 he presented with EF 20%. Coronary angiography (CA) showed CAV1. EMB and DSA were negative. Following treatment for presumed AMR with steroids, IVIG, therapeutic plasma exchange (TPE) and extracorporeal photopheresis (ECP), EF improved to 54%. Three months later he developed symptomatic graft dysfunction (EF 35%). EMB, DSA were negative. CA was stable. Cardiac magnetic resonance imaging (MRI) showed mid myocardial late gadolinium enhancement (LGE). He underwent empiric AMR treatment, with addition of eculizumab. EF normalized with sustained improvement at 18 months. He is maintained on monthly ECP and eculizumab. Our second patient is a 27 year old male with HT in 2009 for NICM. He had recurrent cellular and AMR with re-transplantation in 2013 for recalcitrant CAV. In 2017 he presented in cardiogenic shock, EF 35%. CA showed CAV1. EMB showed grade 1 CMR, negative for AMR. Class I DSA was positive, low level MFI (1053). He was treated with steroids, TPE, IVIG and thymoglobulin. EF further declined to 25%. MRI showed subendocardial inferior LGE. Eculizumab was commenced. Side effects included mild headaches. EF normalized at 6 months. He continues with biweekly ECP and eculizumab. Summary In our patients with BNR and presumed refractory AMR, eculizumab resulted in improved graft function. Research is needed into the efficacy, dosing and duration of therapy. Eculizumab is a therapeutic prospect for HT patients with presumed AMR and BNR.

Safety and Efficacy of CD3 Guided Anti-Thymocyte Globulin Dosing after Pediatric Heart Transplant

Rabbit anti-thymocyte globulin (ATG) is the most frequently used induction agent after pediatric heart transplant (pHTx). The ISHLT guidelines suggest guiding ATG dosing by absolute CD3 counts, targeting between 25 and 50 cells/mm3 until post-operative day 7 (POD7). We sought to determine if using CD3 counts to guide ATG dosing after pHTx will result in lower drug usage, cost savings, and decreased incidence of early infections, with similar rejection rates as compared to a fixed dose cohort. Retrospective review before and after implementation of an ATG dosing protocol using absolute CD3 count through POD7 was conducted. Inclusion criteria- pHTx with ATG induction at Primary Children's Hospital from August 2014-September 2019. Exclusion criteria- multi-organ transplants or re-transplants. The primary endpoint was incidence of treated rejection within 90 days of transplant before and after protocol implementation. Secondary endpoints include time to rejection, severity of rejection, average ATG dose, cost, and incidence of infection within 90 days of HTx. A total of 41 patients were included in the study, 23 in the pre-implementation period (fixed-dose cohort) and 18 in the post-period (CD3 guided cohort). Patients were predominantly male (71%) and transplanted for congenital heart disease (71%). Rates of rejection within 90 days post pHTx were similar (Table 1); largely treatment for biopsy-negative rejection. Infections in the fixed dose cohort included pneumonia, pneumatosis, and molloscum lesions. Infections in the CD3 group included bacteremia (2), pneumatosis, influenza, and sapovirus. Median cost savings were $2,581.95 per patient. No graft loss occurred in either group within 90 days of transplant. Utilizing CD3 counts to guide ATG dosing reduces cost and overall drug exposure after pHTx and may not increase risk of rejection. A large multi-centered study should be conducted to appropriately power for outcomes.

Quantitative myocardial tissue characterization by cardiac magnetic resonance in heart transplant patients with suspected cardiac rejection.

Distinct histopathologic changes occur in acute cellular rejection (ACR), antibody-mediated rejection (AMR), and biopsy-negative rejection (BNR). Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization can be used to quantify these changes. We assessed T1, T2, and extracellular volume fraction (ECV) by CMR in patients with subtypes of rejection. T1, T2, and ECV were quantified at the mid-ventricular level and compared between patients with and without rejection. The association between quantitative tissue characteristics and the combined outcome of death, retransplantation, heart failure hospitalization, or myocardial infarction was evaluated with a Cox-proportional hazards model. In 46 patients, mean age 53.3±13.7years, 71.7% male, at a median of 7.4years from transplant, average myocardial T1 was increased in BNR compared with no rejection (1057 vs 1012msec, P=.006). Average myocardial T2 was elevated in all types of rejection, P<.05. In a cox-proportional hazards model, higher T2 values were associated with an increase in the combined clinical outcome (adjusted HR 1.21, 95% CI 1.06-1.37, P=.004) after adjusting for left ventricular mass index. Myocardial tissue characteristics are abnormal in all subtypes of rejection, and abnormal T2 quantified by CMR provides additional prognostic value.

Non-HLA Antibodies as a Cause for Biopsy Negative Rejection: Is It Worth Testing for Them?

Purpose Biopsy negative rejection (BNR) after heart transplantation is not uncommon. BNR is diagnosed when there is an acute reduction in cardiac function along with symptoms of heart failure. As the endomyocardial biopsy shows no rejection, a search for other causes is pursued. Non-HLA antibodies may not demonstrate C4d deposition in the heart biopsy therefore remains a possible cause of this form of rejection. It is not clear if non-HLA antigens are detected during these cases. Therefore, we reviewed our experience with BNR and detection of non-HLA antibodies. Methods Between 2000 and 2017 we performed 1391 heart transplants and identified 96 cases of BNR (6.9%). Non-HLA antibodies were obtained at the time of BNR and included angiotensin type 1 receptor (AT1R), major-histocompatibility-complex (MHC) class I-related chain A (MICA) and anti-endothelial cell antibodies. All patients with BNR were treated with various anti-rejection regimens including high dose corticosteroids, immune globulin (IVIG), anti-lymphocyte globulin (ATG) and/or plasmapheresis. Results BNR was detected in 96 patients. The following non-HLA antibodies were detected: AT1R (15 patients), MICA (7 patients), and anti-endothelial cell antibodies (3 patients). This constituted 26% of BNR patients. 24% percent of patients recovered with initial anti-humoral therapy. The percent of BNR with anti-HLA antibodies was 12.0% percent. Conclusion BNR is not uncommon after heart transplantation. Non-HLA antibodies are observed in approximately 26.0% percent of patients with BNR, thus, non-HLA testing is worthwhile to initiate appropriate anti-rejection therapy.

Biopsy-Negative Rejection Late after Heart Transplantation: Impact on Long-Term Outcome

Purpose Biopsy-negative rejection (BNR) is an entity where the endomyocardial biopsy (EMB) shows no findings of rejection, but there is proven cardiac dysfunction i.e. low echocardiographic left ventricular ejection fraction or abnormal cardiac hemodynamics . BNR has been noted both early and late after heart transplantation (HTx). It has been reported that late biopsy-proven acute rejection (both cellular and antibody rejection) has been associated with worse outcome. It is not known whether late BNR is associated with long-term adverse outcomes . Methods Between 2008 and 2013, we assessed 33 HTx patients who developed BNR via the following criteria: ACR≤1R, AMR 0, cardiac dysfunction (LVEF≤40%, CI cardiac allograft vasculopathy (CAV) as defined by stenosis ≥ 30% by angiography , and non-fatal major adverse cardiac events (NF-MACE: myocardial infarction , new congestive heart failure , percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). Results Late BNR was associated with significantly reduced subsequent 5-year survival and an increase in the development of angiographic CAV compared to those with early BNR. The timing of BNR did not make a difference in the development of NF-MACE. (see Table) Conclusion Late BNR in HTx is associated with poor long-term outcome. The mechanism of this rejection is not clear but represents a heightened immune response that is being missed on EMB. More aggressive augmentation of immunosuppression and/or immunomodulation are indicated in patients presenting with late BNR.

Heightened Immune Response in Heart Transplant Patients Surviving Severe Primary Graft Dysfunction

Purpose Primary graft dysfunction (PGD) now has a standard nomenclature as per the International Society for Heart and Lung Transplantation. Severe PGD is defined as significant graft dysfunction within 24 hours of heart transplantation (HTx) requiring mechanical circulatory support. The cause of severe PGD is not clear but may be due to donor, recipient, and peri-operative factors. The long-term outcome of these patients (especially rejection episodes) is not clear. Methods Between 2010 and 2017, we identified 25 heart transplant patients who developed severe PGD supported by extracorporeal membrane oxygenation (ECMO). This group was compared to 670 patients who did not have PGD. Endpoints for both groups included 1-year survival, and 1-year freedom from cardiac allograft vasculopathy (CAV) as defined by stenosis ≥ 30% by angiography, NF-MACE (myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), any-treated rejection (ATR), acute cellular rejection (ACR), antibody-mediated rejection (AMR), and biopsy-negative rejection (BNR). This study also assessed whether severe PGD led to increased donor-specific antibody (DSA) development within the first-year post-transplant. Results The severe PGD group had significantly lower first-year survival compared to patients without PGD. The PGD group also had lower freedom from NF-MACE, ATR, AMR, and BNR compared to the control. The development of DSA was numerically lower in the severe PGD group, but this was not statistically significant. Conclusion Severe PGD requiring ECMO support leads to poor outcome after HTx. The lower freedom from ATR, AMR and BNR suggests a heightened immune response in these patients. Further study into the mechanism of PGD is needed to avoid and treat this high-mortality complication.

Intravenous Methamphetamine Does Not Appear to Be a Contraindication for Heart Donation in Heart Transplantation

Purpose Intravenous methamphetamine (IV meth) use in potential heart donors has been of concern due to the possibility of methamphetamine cardiomyopathy and transmission of infections. There is also concern regarding the development of primary graft dysfunction (PGD) and cardiac allograft vasculopathy (CAV) due to possible endothelial cell dysfunction. Therefore, we reviewed our HTx data to identify those donors who primarily used IV meth in the past 6 months prior to organ donation. Methods Between 2010-2017 we identified 32 heart donors who were actively using IV meth. We compared this to 329 donors who had no history of drug use during the same time period. Endpoints included 1-year survival, 1-year freedom from CAV (as defined by stenosis ≥ 30% by angiography), non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), Any-Treated Rejection (ATR), Acute-Celular Rejection (ACR), Antibody-Mediated Rejection (AMR), and Biopsy-Negative Rejection (BNR). The incidence of PGD was also assessed. Results There was no significant difference in endpoints between IV meth use in donors and those donors without meth use (see table). The incidence of PGD was also not different between the groups. Other drugs that were being abused (in combination) included heroin at 46.8% and cocaine at 9.4%. The addition of these drugs did not change outcome. Conclusion The use of donors using IV meth does not appear to be a contraindication for HTx. Longer term follow up will be necessary to confirm these findings.

Utility of Routine versus Triggered Evaluations of Rejection Greater Than Two Years Following Heart Transplant

Purpose Routine surveillance endomyocardial biopsies (EMBx) are recommended for 6-12 months after orthotopic heart transplantation (OHT) though may be replaced by gene expression profiling (Allomap) in low-risk patients after 6-months. There are limited data on the utility of routine studies after the second post-transplant year. Methods We retrospectively identified adult patients who underwent OHT from 2007-2015 and who survived ≥760 days post-OHT. Clinical characteristics and outcomes were obtained on chart review. All Allomaps and EMBx during years 2-5 were extracted from the medical record, and their clinical context reviewed to determine if they were performed routinely or were triggered by a change in clinical status defined by symptoms, imaging, or biomarkers. Significant rejection was defined as ≥2R acute cellular rejection (ACR), any antibody-mediated rejection (AMR), or treated biopsy-negative rejection. Studies within one year of a significant rejection episode were considered triggered. Patients were categorized based on whether the treating cardiologist intended to continue routine studies after the second post-OHT year. Logistic regression was used to evaluate factors predictive of surveillance strategy. Results 217 patients met the above criteria, totaling 1,368 patient-years. 1020 studies were performed after day 760 of which 835 (81.9%) were routine (201 EMBx, 634 Allomaps). Of the routine EMbx, two (1%) demonstrated rejection—one 2R ACR and one pAMR2; both patients had BNP elevations. The remaining studies were negative for significant rejection. Routinely ordered Allomaps triggered 36 EMBx (5.7%), of which 1 (0.2%) demonstrated rejection requiring treatment. 53 patients followed a “no routine surveillance” strategy and 159 a “routine surveillance” strategy. There were no differences in heart failure hospitalization, revascularization, or death between the groups. On multivariable logistic regression, treating cardiologist was the only predictor of surveillance strategy (p Conclusion Although acute rejection is rare after the second post-OHT year, routine studies were performed commonly at our institution. Treating cardiologist but not clinical risk factors predicted choice of surveillance strategy. These data do not justify routine evaluations for rejection after two years.

Heart Transplant Patients with Histologic Normal and Molecular Microscope Abnormal Biopsies: An Exploratory Analysis

Purpose In heart transplant (HTx) recipients who undergo endomyocardial biopsy (EMB), a molecular microscope (MMDx) system has been developed to assess both T cell-mediated (TCMR) and antibody-mediated (ABMR) rejection through the use of intragraft mRNA transcripts. Outcomes of patients who undergo an EMB interpreted as normal by histology and abnormal by MMDx is unknown. Methods We retrospectively reviewed cases from 2008 through 2016 of patients who underwent a “for-cause” (clinically indicated) EMB after transplant from our single center. Of 75 cases reviewed who had MMDx system performed, 10 patients had pathology normal (ACR 1R/AMR 0 or less) and abnormal MMDx results (defined as TCMR > 50% or ABMR > 50%). We describe their treatment, development of donor-specific antibody (DSA), and outcomes within 3 months of EMB. Results 10 patients had “for-cause” EMBs demonstrated normal pathology and abnormal MMDx (3 with TCMR / 7 with ABMR). 6 of these 10 patients were treated for biopsy-negative rejection with reduced LVEF (known as BNR) with therapies ranging from pulse steroids, antithymocyte globulin and/or intravenous immunoglobulins with a mean LVEF 40.8% at time of EMB (Figure). 4 of these 6 patients treated for BNR died within 3 months and 3 of 6 patients were found to have de novo DSA. Of the 4 remaining patients (not treated for BNR due to normal LVEF), all showed ABMR by MMDx with a mean LVEF 62.2%, and 1 patient developed DSA and no patients died within the 3 months follow-up. Overall, 7/10 study patients demonstrated adverse outcomes (BNR, DSA and/or death). Conclusion A majority of HTx patients who undergo a for-cause EMB interpreted as normal by histology and abnormal by MMDx experience adverse outcomes (BNR, DSA and/or death). The use of MMDx may help risk stratify symptomatic patients with normal pathology by histology and may help to direct treatment for these patients. Further studies with larger cohorts and longer follow-up are warranted.

Biopsy-Negative Rejection: a Rare but Difficult Issue in Heart Transplantation

Biopsy-negative rejection is a condition defined by a cardiac dysfunction with a left ventricular ejection fraction (LVEF) ≤ 45% with normal histology and with the absence of other causes of cardiac allograft damage. The purpose of this review is to determine the incidence of biopsy-negative rejection, the therapeutics, and the outcome in the light of new techniques of evaluation or detection of acute rejection in heart-transplanted patients. Although rare, many physicians have once experienced this difficult situation. Even though it is considered the gold standard for the diagnosis of rejection, pathology is of limited help in biopsy-negative rejection by definition. Showed advances made in the field of transplant medicine, such as cardiovascular magnetic resonance imaging, noninvasive biomarkers, and molecular assessment using transcriptomic analysis of the cardiac allograft tissue on endomyocardial biopsies. Biopsy-negative rejection marks the limit of histology; new techniques developed to improve the follow-up of heart transplant recipients could be of future help in the understanding of biopsy-negative rejection and maybe dethrone the biopsy for the diagnostic of acute rejection.

272 - Single-Center Outcomes of Biopsy-Negative Rejection in Heart Transplantation

Allograft rejection, defined as acute cellular rejection (ACR) or antibody-mediated rejection (AMR), carries significant morbidity and mortality after heart transplantation. Allograft dysfunction, characterized by left ventricular ejection fraction (EF) ≤ 45%, in the absence of ACR or AMR is termed biopsy-negative rejection (BNR). To date, little data exist regarding the outcomes of such patients, as BNR in the era of better-defined AMR criteria is rare. Treatment consensus is also lacking. We sought to describe our experience with BNR in a single center. Between 1992 and 2016 at the University of Maryland Medical Center, 6 patients were identified as having BNR. Mean time interval between transplant and date of BNR diagnosis was 76 ± 95 days. One was a heart-lung recipient, and 1 was a re-transplant patient. Standard immunosuppressant drugs included mycophenolate mofetil, prednisone and a calcineurin inhibitor. No one was treated for rejection before BNR, or had severe coronary allograft vasculopathy by coronary angiography with intravascular ultrasound. All had normal hemodynamics by right heart catheterization at the time of BNR diagnosis. One patient developed de novo donor-specific antibodies (DSA) prior to BNR onset. This patient received a prednisone burst with subsequent EF recovery. The heart-lung recipient did not receive BNR treatment out of concern for increased infection. His EF remained depressed (20–30%) after 6 months. One patient was also not treated at the time of BNR, only to develop grade 2R ACR 2 months later. He was then treated with a methylprednisolone burst with EF recovery. Two patients received a prednisone burst; one recovered and maintained EF > 45% (the re-transplant patient), the other's EF stayed low at 30–40%. The 6th patient had recurrent BNR in the span of 3 months, both episodes treated with methylprednisolone burst. After the 2nd episode, he had de novo DSA which prompted treatment with plasmapheresis and thymoglobulin. His EF normalized after each episode of treatment. Increased glucose uptake by PET and cardiac MRI are emerging as tools to detect rejection, so they were done for these patients but were unrevealing and did not contribute towards determining treatment. In conclusion, BNR was diagnosed within one year post transplant in all six patients. Four out of 5 patients treated for BNR recovered their heart functions. The most common treatment was steroid burst. Given the paucity of data concerning BNR, there needs to be a multi-centered study focused on non-invasive diagnostic modalities, treatments and outcomes to better serve this special heart transplant population.

Abstract 13688: Patients With Autoimmune Disease: Not a Contraindication for Heart Transplantation

Introduction: Autoimmune diseases such as lupus, scleroderma, sarcoidosis, and psoriasis are associated with an increased immune response through autoantibody formation.There has been concern that this up-regulation of the immune system may increase the risk of rejection after heart transplantation. Therefore, we evaluated our patients with autoimmune diseases who subsequently underwent heart transplantation at our institution. Methods: Between 2009 and 2013 we assessed 26 patients who had a concomitant history of autoimmune disease prior to heart transplantation. Autoimmune diseases included psoriasis (5), Grave’s disease (5), sarcoidosis (5), CREST syndrome (2), Hashimoto thyroiditis (1), dermatomyositis (1), ulcerative colitis (1), systemic lupus erythematosus (1), multiple sclerosis (1), antiphospholipid syndrome (1), polymyalgia rheumatic (1), celiac disease (1), and ANCA vasculitis (1). These patients were compared to a control group of patients who did not have pre-transplant autoimmune disease (n=363). Results: Patients with pre-transplant autoimmune disease did not have any significant difference in 1- year survival, 1-year actuarial freedom from any treated rejection, 1-year actuarial freedom from treated cellular rejection, 1- year actuarial freedom from treated antibody- mediated rejection, and 1-year actuarial freedom from biopsy negative rejection (see table). Conclusions: Pre-transplant autoimmune diseases do not appear to affect post-transplant outcomes. Therefore, preexisting autoimmune disease is not a contraindication to proceed with heart transplant.

Rejection in heart transplantation: more antibodies than just DSA

Aim The aim of our study was to determine the frequency of antibodies to non-HLA antigens for heart recipients diagnosed with rejection (AMR, ACR, BNR-T). Antibodies to non-HLA antigens have been implicated in the antibody mediated rejection (AMR) and acute cellular rejection (ACR) processes independent of and synergistic with de novo donor HLA specific antibody (DSA). In heart transplantation, recipients are often treated for biopsy negative rejection (BNR-T). Methods Posttransplant sera from 21 heart recipients biopsied for cause were tested for DSA and for antibodies to: Precursor Endothelial Cell Antibody (IgM), Precursor Endothelial Cell Antibody (IgG), AT1R, Tubulin B, Perlican, PRKRIP1, EDNRA, FLRT2, and Vimentin 33. Results 19 of 21 recipients were diagnosed with one of these 3 forms of rejection: 3 = AMR, 2 = ACR, 14-BNR-T. Of these, 6 (32%) had DSA while 15 (79%) had AT1R-ab. Other non-HLA antibodies detected at the time of rejection included: (13.7%) Precursor Endothelial Cell Antibody (IgM), (30.2%) Precursor Endothelial Cell Antibody (IgG), (15.8%) AT1R, (6.3%) Tubulin B, (14.7%) Perlican, (5.3%) PRKRIP1, (12.6%) EDNRA, (14.7%) FLRT2, and (7.4%) Vimentin 33. Conclusions Our previous studies showed an increased negative impact of freedom for AMR and/or ACR when antibodies to both DSA and AT1R were present (p = 0.001). These studies are consistent with the detection of multiple antibodies to non-HLA antigens during the rejection process. Monitoring for these antibodies may provide increased insight into the rejection process in the absence of de novo DSA, especially regarding BNR-T. Download : Download full-size image

The Natural History of Biopsy-Negative Rejection after Heart Transplantation

Purpose. The most recent International Society for Heart and Lung Transplantation (ISHLT) biopsy scale classifies cellular and antibody-mediated rejections. However, there are cases with acute decline in left ventricular ejection fraction (LVEF ≤ 45%) but no evidence of rejection on biopsy. Characteristics and treatment response of this biopsy negative rejection (BNR) have yet to be elucidated. Methods. Between 2002 and 2012, we found 12 cases of BNR in 11 heart transplant patients as previously defined. One of the 11 patients was treated a second time for BNR. Characteristics and response to treatment were noted. Results. 12 cases (of 11 patients) were reviewed and 11 occurred during the first year after transplant. 8 cases without heart failure symptoms were treated with an oral corticosteroids bolus and taper or intravenous immunoglobulin. Four cases with heart failure symptoms were treated with thymoglobulin, intravenous immunoglobulin, and intravenous methylprednisolone followed by an oral corticosteroids bolus and taper. Overall, 7 cases resulted in return to normal left ventricular function within a mean of 14 ± 10 days from the initial biopsy. Conclusion. BNR includes cardiac dysfunction and can be a severe form of rejection. Characteristics of these cases of rejection are described with most cases responding to appropriate therapy.

683 The Natural History of Biopsy Negative Rejection after Heart Transplantation

683 The Natural History of Biopsy Negative Rejection after Heart Transplantation

531 Monoclonal Gammopathy of Undetermined Significance (MGUS) Does Not Predict Cardiac Amyloid Type

negative rejection and to assess for a possible new rejection category. Methods and Materials: We evaluated 892 pts transplanted from 1994 to 2009 and identified 19 with cardiac dysfunction and negative biopsy for cellular rejection and AMR. A 2:1 control group of heart transplant pts without AMR and matched for age, sex, time from transplant, served as controls. The following outcomes were assessed: subsequent 3-year survival, freedom from cardiac allograft vasculopathy (CAV, stenosis 30%), and freedom from non-fatal major adverse cardiac events (NFMACE: myocardial infarction, heart failure, percutaneous coronary intervention, defibrillator, stroke, or new peripheral vascular disease). Results: Biopsy-negative rejection occurred on average 43 38 months post transplant. Treatment included high dose corticosteroids, anti-thymocyte globulin, and/or intravenous immune globulin. Mean LVEF was 26 8% and improved to 48 8% in all patients alive (13/19 pts) at 1 year (4 pts died and 2 were retransplanted). Subsequent 3-year survival was significantly lower in the biopsy-negative group compared to controls (47% vs. 92%, p 0.001). The biopsy-negative group also demonstrated significantly lower subsequent freedom from CAV (63% vs. 87%, p 0.032) and lower freedom from NF-MACE (74% vs. 97%, p 0.005). Conclusions: Biopsy negative rejection with cardiac dysfunction has poor outcome and represents a possible new category for rejection. Isolation of biomarkers and search for underlying mechanism may further characterize this form of rejection. A new category of biopsy negative rejection should be considered for the ISHLT biopsy grading scale.