Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders

EBV-positive and EBV-negative posttransplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013–2019), and compared them to PTLD-free Transplant Controls (TC, n = 21). We measured absolute lymphocyte counts (n = 108), analyzed NK- and T cell phenotypes (n = 49 and 94), and performed EBV-specific functional assays (n = 16 and 42) by multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4⁺<300 cells/mm³, p <  .001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median = 60 cells/mm³) and a high proportion of NK cells expressing PD-1 (vs. TC, p = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .013 vs. TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis.     

Co‐localized immune protection using dexamethasone‐eluting micelles in a murine islet allograft model

The broad application of ß cell transplantation for type 1 diabetes is hindered by the requisite of lifelong systemic immunosuppression. This study examines the utility of localized islet graft drug delivery to subvert the inflammatory and adaptive immune responses. Herein, we have developed and characterized dexamethasone (Dex) eluting Food and Drug Administration‐approved micro‐Poly(lactic‐co‐glycolic acid) micelles and examined their efficacy in a fully major histocompatibility complex‐mismatch murine islet allograft model. A clinically relevant dose of 46.6 ± 2.8 μg Dex per graft was confirmed when 2 mg of micelles was implemented. Dex‐micelles + CTLA‐4‐Ig (n = 10) resulted in prolonged allograft function with 80% of the recipients demonstrating insulin independence for 60 days posttransplant compared to 40% in empty micelles + CTLA‐4‐Ig recipients (n = 10, P = .06). Recipients of this combination therapy (n = 8) demonstrated superior glucose tolerance profiles, compared to empty micelles + CTLA‐4‐Ig recipients (n = 4, P < .05), and significantly reduced localized intragraft proinflammatory cytokine expression. Histologically, increased insulin positive and FOXP3⁺ T cells were observed in Dex‐micelles + CTLA‐4‐Ig grafts compared to empty micelles + CTLA‐4‐Ig grafts (P < .01 and P < .05, respectively). Localized drug delivery via micelles elution has the potential to alter the inflammatory environment, enhances allograft survival, and may be an important adjuvant approach to improve clinical islet transplantation outcomes.     

Long‐term survival in visceral transplant recipients in the new era: A single‐center experience

There is a paucity of data on long‐term outcomes following visceral transplantation in the contemporary era. This is a single‐center retrospective analysis of all visceral allograft recipients who underwent transplant between November 2003 and December 2013 with at least 3‐year follow‐up data. Clinical data from a prospectively maintained database were used to assess outcomes including patient and graft survival. Of 174 recipients, 90 were adults and 84 were pediatric patients. Types of visceral transplants were isolated intestinal transplant (56.3%), combined liver‐intestinal transplant (25.3%), multivisceral transplant (16.1%), and modified multivisceral transplant (2.3%). Three‐, 5‐, and 10‐year overall patient survival was 69.5%, 66%, and 63%, respectively, while 3‐, 5‐, and 10‐year overall graft survival was 67%, 62%, and 61%, respectively. In multivariable analysis, significant predictors of survival included pediatric recipient (P = .001), donor/recipient weight ratio <0.9 (P = .008), no episodes of severe acute rejection (P = .021), cold ischemia time <8 hours (P = .014), and shorter hospital stay (P = .0001). In conclusion, visceral transplantation remains a good option for treatment of end‐stage intestinal failure with parenteral nutritional complications. Proper graft selection, shorter cold ischemia time, and improvement of immunosuppression regimens could significantly improve the long‐term survival.     

Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony‐stimulating factor treatment

Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony‐stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000‐1499), moderate (500‐999), or severe (<500) and as a time‐varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05‐8.41, P = .040), mild (aHR 14.508, 95% CI 1.58‐13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89‐12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93‐13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07‐0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes.     

Postoperative cognitive dysfunction and mortality following lung transplantation

Preliminary evidence suggests that postoperative cognitive dysfunction (POCD) is common after lung transplantation. The impact of POCD on clinical outcomes has yet to be studied. The association between POCD and longer‐term survival was therefore examined in a pilot study of posttransplantation survivors. Forty‐nine participants from a prior randomized clinical trial underwent a neurocognitive assessment battery pretransplantation and 6 months posttransplantation, including assessments of the domains of Executive Function (Trail Making Test, Stroop, Digit Span), Processing Speed (Ruff 2 and 7 Test, Digit Symbol Substitution Test), and Verbal Memory (Verbal Paired Associates, Logical Memory, Animal Naming, and Controlled Oral Word Association Test). During a 13‐year follow‐up, 33 (67%) participants died. Greater neurocognition was associated with longer survival (hazard ratio [HR] = 0.49 [0.25‐0.96], P = .039), and this association was strongest on tests assessing Processing Speed (HR = 0.58 [0.36‐0.95], P = .03) and Executive Function (HR = 0.52 [0.28‐0.97], P = .040). In addition, unadjusted analyses suggested an association between greater Memory performance and lower risk of CLAD (HR = 0.54 [0.29‐1.00], P = .050). Declines in Executive Function tended to be predictive of worse survival. These preliminary findings suggest that postoperative neurocognition is predictive of subsequent mortality among lung transplant recipients. Further research is needed to confirm these findings in a larger sample and to examine mechanisms responsible for this relationship.     

Impact of ureteral stricture and treatment choice on long‐term graft survival in kidney transplantation

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long‐term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long‐term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long‐term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long‐term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long‐term graft survival.     

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.     

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective,matched cohort study

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).     

Recipient HO‐1 inducibility is essential for posttransplant hepatic HO‐1 expression and graft protection: From bench‐to‐bedside

By documenting potent antioxidative and anti‐inflammatory functions, preclinical studies encourage heme oxygenase‐1 (HO‐1)‐inducing regimens in clinical orthotopic liver transplantation (OLT). We aimed to determine the importance of recipient‐derived HO‐1 in murine and human OLTs. Hepatic biopsies from 51 OLT patients were screened for HO‐1 expression (Western blots) prior to put‐in (basal) and post reperfusion (stressed) and correlated with the hepatocellular function. In parallel, livers from HO‐1 proficient mice (WT; C57/BL6), subjected to ex vivo cold storage (18 hour), were transplanted to syngeneic myeloid HO‐1 deficient (mHO‐1 KO) or FLOX (control) hosts, and sampled postreperfusion (6 hour). In human OLT, posttransplant but not pretransplant HO‐1 expression correlated negatively with ALT levels (P = .0178). High posttransplant but not pretransplant HO‐1 expression trended with improved OLT survival. Compared with controls, livers transplanted into mHO‐1 KO recipient mice had decreased HO‐1 levels, exacerbated hepatic damage/frequency of TUNEL+ cells, increased mRNA levels coding for TNFα/CXCL1/CXCL2/CXCL10, higher frequency of Ly6G+/4HN+ neutrophils; and enhanced MPO activity. Peritoneal neutrophils from mHO‐1 KO mice exhibited higher CellRox+ ratio and increased TNFα/CXCL1/CXCL2/CXCL10 expression. By demonstrating the importance of posttransplant recipient HO‐1 phenotype in hepatic macrophage/neutrophil regulation and function, this translational study identifies recipient HO‐1 inducibility as a novel biomarker of ischemic stress resistance in OLT.     

Kidney allograft biopsy findings after COVID-19

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis.     

Blood CD9+ B cell,a biomarker of bronchiolitis obliterans syndrome after lung transplantation

Bronchiolitis obliterans syndrome is the main limitation for long‐term survival after lung transplantation. Some specific B cell populations are associated with long‐term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow‐up. CD24^hiCD38^hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24^hiCD38^hi transitional B cells specifically secrete IL‐10 and express CD9. Thus, patients with a total CD9⁺ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL‐10‐secreting CD24^hiCD38^hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9‐expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long‐term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival.     

Towards donor lung recovery—gene expression changes during ex vivo lung perfusion of human lungs

We and others have demonstrated that acellular normothermic ex vivo lung perfusion of high‐risk donor lungs can result in posttransplant outcomes equivalent to that of contemporaneous lung transplantation using standard donor lungs. However, the mechanism of this effect remains unclear. Given the restoration of cellular metabolic activity during normothermic perfusion, one possibility is that of lung healing via natural innate recovery mechanisms. We explored this by examining the gene expression changes occurring in human lungs during ex vivo lung perfusion. Human lungs clinically rejected for transplantation were perfused for 12 hours of EVLP with biopsies taken at the start, at 1 hour, at 3 hours, and then every 3 hours thereafter to 12 hours. Temporal changes were identified in 2585 genes using the Short Time‐series Expression Miner and used for pathway analysis. Despite increases in endothelial markers of inflammation, circulating leukocyte cell‐specific gene expression fell over 12 hours of ex vivo lung perfusion (EVLP), suggesting an interrupted inflammation response secondary to washout of circulating leukocytes. Analysis of these gene changes suggests lung recovery follows specific stages: cellular death, cellular preservation, cellular reorganization, and cellular invasion. EVLP may improve posttransplant lung function by washout of leukocytes and facilitating innate mechanisms of repair.     

Short-term therapy with anti-ICAM-1 monoclonal antibody induced long-term liver allograft survival in nonhuman primates

Tolerance induction remains challenging following liver transplantation and the long-term use of immunosuppressants, especially calcineurin inhibitors, leads to serious complications. We aimed to test an alternative immunosuppressant, a chimeric anti-ICAM-1 monoclonal antibody, MD-3, for improving the outcomes of liver transplantation. We used a rhesus macaque liver transplantation model and monkeys were divided into three groups: no immunosuppression (n = 2), conventional immunosuppression (n = 4), and MD-3 (n = 5). Without immunosuppression, liver allografts failed within a week by acute rejection. Sixteen-week-long conventional immunosuppression that consisted of prednisolone, tacrolimus, and an mTOR inhibitor prolonged liver allograft survival; however, recipients died of acute T cell–mediated rejection (day 52), chronic rejection (days 62 and 66), or adverse effects of mTOR inhibitor (day 32). In contrast, 12-week-long MD-3 therapy with transient conventional immunosuppression in the MD-3 group significantly prolonged the survival of liver allograft recipients (5, 96, 216, 412, 730 days; p = .0483). MD-3 effectively suppressed intragraft inflammatory cell infiltration, anti-donor T cell responses, and donor-specific antibody with intact anti-cytomegalovirus antibody responses. However, this regimen ended in chronic rejection. In conclusion, short-term therapy with MD-3 markedly improved liver allograft survival to 2 years without maintenance of immunosuppressant. MD-3 is therefore a promising immune-modulating agent for liver transplantation.     

Outcomes of kidney retransplantation after graft loss as a result of BK virus nephropathy in the era of newer immunosuppressant agents

We conducted this study using the updated 2005‐2016 Organ Procurement and Transplantation Network database to assess clinical outcomes of retransplant after allograft loss as a result of BK virus–associated nephropathy (BKVAN). Three hundred forty‐one patients had first graft failure as a result of BKVAN, whereas 13 260 had first graft failure as a result of other causes. At median follow‐up time of 4.70 years after the second kidney transplant, death‐censored graft survival at 5 years for the second renal allograft was 90.6% for the BK group and 83.9% for the non‐BK group. In adjusted analysis, there was no difference in death‐censored graft survival (P = .11), acute rejection (P = .49), and patient survival (P = .13) between the 2 groups. When we further compared death‐censored graft survival among the specific causes for first graft failure, the BK group had better graft survival than patients who had prior allograft failure as a result of acute rejection (P < .001) or disease recurrence (P = .003), but survival was similar to those with chronic allograft nephropathy (P = .06) and other causes (P = .05). The better allograft survival in the BK group over acute rejection and disease recurrence remained after adjusting for potential confounders. History of allograft loss as a result of BKVAN should not be a contraindication to retransplant among candidates who are otherwise acceptable.     

Impact of donation after circulatory death donor allografts on outcomes following liver transplantation for fulminant hepatic failure in the United States

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients.     

Comparing outcomes of third and fourth kidney transplantation in older and younger patients

Performing third or fourth kidney transplantation (3KT and 4KT) in older patients is rare due to surgical and immunologic challenges. We aimed to analyze and compare the outcomes of younger (18–64 years) and older (≥65 years) recipients of 3KT and 4KT. Between 1990 and 2016, we identified 5816 recipients of 3KTs (153 were older) and 886 recipients of 4KTs (18 were older). The incidences of delayed graft function (24.3% vs. 24.8%, p = .89), primary non-function (3.2% vs. 1.3%, p = .21), 1-year acute rejection (18.6% vs. 14.8%, p = .24), and 5-year death censored graft failure (DCGF) (24.8% vs. 17.9%, p = .06) were not different between younger and older recipients of 3KT. However, 5-year mortality was higher in older recipients (14.0% vs. 33.8%, p < .001) which remained significant after adjustment (aHR = 3.21, 95% CI: 2.59–3.99). Similar patterns were noted in the 4KT cohort. When compared with waitlisted patients, 3KT and 4KT are associated with a lower risk of mortality; aHR = 0.37, 95% CI: 0.33–0.41 and aHR = 0.31, 95% CI: 0.24–0.41, respectively. This survival benefit did not differ by recipient age (younger vs. older, p for interaction = 3KT: .49 and 4KT: .58). In the largest cohort described to date, we report that there is a survival benefit of 3KT and 4KT even among older patients. Although a highly selected cohort, our results support improving access to 3KT and 4KT.     

Belgian multicenter experience with intestinal transplantation

Intestinal transplantation (ITx) has evolved from an experimental procedure toward a clinical reality but remains a challenging procedure. The aim of this survey was to analyze the multicenter Belgian ITx experience. From 1999 to 2014, 24 ITx in 23 patients were performed in Belgium, divided over five centers. Median recipient age was 38 years (8 months–57 years); male/female ratio was 13/10; six were children; and 17 adults. Intestinal failure was related to intestinal ischemia (n = 5), volvulus (n = 5), splanchnic thrombosis (n = 4), Crohn (n = 2), pseudo‐obstruction (n = 2), microvillus inclusion (n = 2), Churg‐Strauss (n = 1), necrotizing enterocolitis (n = 1), intestinal atresia (n = 1), and chronic rejection (n = 1). Graft type was isolated ITx (n = 9), combined liver‐ITx (n = 11) and multivisceralTx (n = 4). One was a living donor‐related transplantation and five patients received simultaneously a kidney graft. Early acute rejection occurred in 8; late acute rejection in 4; and chronic rejection in 2. Two patients developed a post‐transplant lymphoproliferative disease. Nine patients have died. Among 14 survivors at last follow‐up, 11 have been transplanted for more than 1 year. None of the latter has developed renal failure, and all were nutritionally independent with a Karnofsky score > 90%. One‐/five‐year patient and graft survivals were 71.1%, 62.8%, 58.7% and 53.1%, respectively. Based on this experience, ITx has come of age in Belgium as a lifesaving and potentially quality of life restoring therapy.     

Effect of recipient gender and donor‐specific antibodies on antibody‐mediated rejection after heart transplantation

Gender‐difference regarding antibody‐mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor‐specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single‐institution 6‐year cohort (2010‐2015), time to AMR was assessed, comparing men with women by survival analysis with a 1‐year death‐censored follow‐up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA‐, size‐ and sex‐mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1 year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard‐ratio [adj. HR] = 1.78 [1.06‐2.99]), P = .03) and the presence of pfDSA (adj. HR = 3.20 [1.80‐5.70], P < .001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR = 2.2 (P = .026) and MFI of pfDSA (per 1 MFI‐increase) adj. HR = 1.0002 (P < .0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender‐related difference in the severity of pfDSA.