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.     

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.     

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor–associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage‐specific deletion of TRAF6 (LysM^CreTraf6 ^fl/fl) or mTOR (LysM^CreMtor^fl/fl) did not affect acute allograft rejection. However, treatment of LysM^CreMtor^fl/fl recipients with CTLA4‐Ig induced long‐term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysM^CreTraf6 ^fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4‐Ig–treated LysM^CreTraf6 ^fl/fl mice was similar to that of CTLA4‐Ig–treated wild‐type B6 recipients. Mechanistically, we found that the graft‐infiltrating macrophages in LysM^CreMtor^fl/fl recipients expressed high levels of PD‐L1, and that PD‐L1 blockade readily induced rejection of otherwise survival grafts in the LysM^CreMtor^fl/fl recipients. Our findings demonstrate that targeting mTOR‐dependent M2 cells is critical for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD‐1/PD‐L1 coinhibitory pathway.     

Exploring predicted indirectly recognizable HLA epitopes (PIRCHE-II) in liver transplant recipients on calcineurin inhibitor-free maintenance immunosuppression. A retrospective single center study

The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients.This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses.CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3–49, p = .02; and HR: 0.88, 95% CI: 0.00–0.96, p = .007, respectively).PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results.     

Subcutaneous administration of a neutralizing IL‐1β antibody prolongs limb allograft survival

Cytokine‐expression profiles revealed IL‐1ß highly upregulated in rejecting skin of limb allografts. We investigate the effect of intragraft treatment with a neutralizing IL‐1β antibody in limb transplantation. Following allogenic hind‐limb transplantation, Lewis rats were either left untreated 1 or treated with anti‐lymphocyte serum + tacrolimus (baseline) 2 ; baseline immunosuppression + anti‐IL‐1β (1 mg/kg once/week, 6‐8 subcutaneous injections) into the transplanted 3 or contralateral 4 limb. Endpoint was rejection grade III or day 100. Graft rejection was assessed by histology, immunohistochemistry, flow cytometry phenotyping of immune cells, and monitoring cytokine expression. Anti‐IL‐1β injections into the allograft or contralateral limb resulted in a significant delay of rejection onset (controls: 58.60 ± 0.60; group 3: 75.80 ± 10.87, P = .044; group 4: 73.00 ± 6.49, P = .008) and prolongation of graft survival (controls: 64.60 ± 0.87; group 3: 86.60 ± 5.33, P = .002; group 4: 93.20 ± 3.82, P = .002), compared to controls. Although the phenotype of the graft infiltrating immune cells did not differ between groups, significantly decreased skin protein levels of IL‐1β, IL‐4, IL‐13, IP‐10, MCP‐1, and MCP‐3 in long‐term‐survivors indicate an overall decrease of chemoattraction and infiltration of immune cells as the immunosuppressive mechanism of anti‐IL‐1β. Inhibition of IL‐1β with short‐term systemic immunosuppression prolongs limb allograft survival and represents a promising target for immunosuppression in extremity transplantation.     

Discovery of non‐HLA antibodies associated with cardiac allograft rejection and development and validation of a non‐HLA antigen multiplex panel: From bench to bedside

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non‐HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody–negative, endothelial cell crossmatch–positive sera obtained from 12 cardiac allograft recipients at the time of biopsy‐proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non‐HLA antibodies associated with rejection (P < .1) including 4 newly identified non‐HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non‐HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non‐HLA antigens synergize with HLA donor‐specific antibodies and significantly increase the odds of rejection (P < .1). The non‐HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non‐HLA antibodies identifies cardiac transplant recipients at risk of rejection.     

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.     

Protocol endomyocardial biopsy beyond 6 months—It is time to move on

The optimal duration and frequency of routine surveillance endomyocardial biopsy (EMB) have been questioned in the current era of heart transplantation (HT), where the advances in immunosuppression and donor selection strategies have led to a decline in acute allograft rejection. We investigated the utility of routine EMB beyond 6 months post-HT. A single-center retrospective review was performed on 2963 EMBs from 220 HT recipients over 10 years. Each EMB was categorized into protocol or symptom-triggered biopsy and reviewed for rejection. Heart transplant recipients with ≥2 known risk factors for rejection were designated as an elevated risk group. The majority of rejections occurred within 3 months following HT. The yield of routine protocol EMBs was significantly lower than symptom-triggered EMBs, not only during the first 6 months post-HT (1.6% vs. 33.3%, P < .0001), but more so during the 6-12 months (0.1% vs 83.0%, P < .0001). A similar pattern was observed in heart transplant recipients at both elevated and standard risk for rejection. In conclusion, EMB was found to be a low-yield screening modality for rejection beyond 6 months post-HT.     

Long‐term outcomes of eculizumab‐treated positive crossmatch recipients: Allograft survival,histologic findings,and natural history of the donor‐specific antibodies

We aimed to determine the long‐term outcomes of eculizumab‐treated, positive crossmatch (+XM) kidney transplant recipients compared with +XM and age‐matched negative crossmatch (?XM) controls. We performed an observational retrospective study and examined allograft survival, histologic findings, long‐term B‐cell flow cytometric XM (BFXM), and allograft‐loss–associated factors. The mean (SD) posttransplant follow‐up was 6.3 (2.5) years in the eculizumab group; 7.6 (3.5), +XM control group; 7.9 (2.5), ?XM control group. The overall and death‐censored allograft survival rates were similar in +XM groups (P = .73, P = .48) but reduced compared with ?XM control patients (P < .001, P < .001). In the eculizumab‐treated group, 57.9% (11/19) of the allografts had chronic antibody‐mediated rejection, but death‐censored allograft survival was 76.6%, 5 years; 75.4%, 7 years. Baseline IgG3 positivity and BFXM ≥300 were associated with allograft loss. C1q positivity was also associated with allograft loss but did not reach statistical significance. Donor‐specific antibodies appeared to decrease in eculizumab‐treated patients. After excluding patients with posttransplant plasmapheresis, 42.3% (9/21) had negative BFXMs; 31.8% (7/22), completely negative single‐antigen beads 1 year posttransplant. Eculizumab‐treated +XM patients had reduced allograft survival compared with ?XM controls but similar survival to +XM controls. BFXM and complement‐activating donor‐specific antibodies (by IgG3 and C1q testing) may be used for risk stratification in +XM transplantation.     

Subclinical inflammation phenotypes and long‐term outcomes after pediatric kidney transplantation

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single‐center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell–mediated rejection without clinical dysfunction) is associated with a 5‐year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.     

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation

Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.

     

Longitudinal dose and type of immunosuppression in a national cohort of Australian liver,heart, and lung transplant recipients, 1984–2006

Unconfounded comparative data on the type and dose of immunosuppressive agents among solid organ transplant recipients are sparse, as are data on longitudinal immunosuppressive therapy since transplantation. We addressed this issue in a population‐based cohort of Australian liver (n = 1895), heart (n = 1220), and lung (n = 1059) transplant recipients, 1984–2006. Data on immunosuppressive therapy were retrospectively collected at discharge, three months, and one, five, 10, and 15 yr after first transplant. We computed unadjusted and adjusted estimates for the association between the type and dose of immunosuppressive therapy and organ type. After adjustment for confounders, use of induction antibody and maintenance corticosteroids was more common in heart and lung compared to liver recipients (p < 0.001), and antibody therapy for rejection more common in liver recipients (p < 0.001). Liver recipients were more likely to receive calcineurin inhibitor monotherapy, with or without corticosteroids, compared to heart and lung recipients (p < 0.001). Liver recipients consistently received lower doses of azathioprine than heart and lung recipients (p < 0.001). These differences in immunosuppression may partly explain variations in immunosuppression‐related morbidity by transplanted organ, for example, malignancy risk. Longitudinal changes in the type and the dose of immunosuppressive therapy over time since transplantation also demonstrate the need for time‐dependent data in observational research.     

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart–Liver Transplantation

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart–liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune‐mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol‐ and indication‐specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell–mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor‐specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody‐mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0–0.02; p < 0.0001), antibody‐mediated rejection (OR 0.04, 95% CI 0–0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07–0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.     

Response to treatment and long‐term outcomes in kidney transplant recipients with acute T cell–mediated rejection

The recent recognition of complex and chronic phenotypes of T cell–mediated rejection (TCMR) has fostered the need to better evaluate the response of acute TCMR—a condition previously considered to lack relevant consequences for allograft survival—to the standard of care. In a prospective cohort of kidney recipients (n = 256) with biopsy‐proven acute TCMR receiving corticosteroids, we investigated clinical, histological, and immunological phenotypes at the time of acute TCMR diagnosis and 3 months posttreatment. Independent posttreatment determinants of allograft loss included the glomerular filtration rate (GFR) (HR = 0.94; 95% CI = 0.92‐0.96; P < .001), proteinuria (HR = 1.40; 95% CI = 1.10‐1.79; P = .007), time since transplantation (HR = 1.02; 95% CI = 1.00‐1.03; P = .016), peritubular capillaritis (HR = 2.27; 95% CI = 1.13‐4.55; P = .022), interstitial inflammation in sclerotic cortical parenchyma (i‐IF/TA) (HR = 1.87; 95% CI = 1.08‐3.25; P = .025), and donor‐specific anti‐HLA antibodies (DSAs) (HR = 2.67; 95% CI = 1.46‐4.88; P = .001). Prognostic value was improved using a composite evaluation of response to treatment versus clinical parameters only (cNRI = 0.68; 95% CI = 0.41‐0.95; P < .001). A classification tree for allograft loss identified five patterns of response to treatment based on the posttreatment GFR, i‐IF/TA, and anti‐HLA DSAs (cross‐validated accuracy = 0.80). Compared with responders (n = 155, 60.5%), nonresponders (n = 101, 39.5%) had a higher incidence of de novo DSAs, antibody‐mediated rejection, and allograft loss at 10 years (P < .001 for all comparisons). Thus, clinical, histological, and immunological assessment of response to treatment of acute TCMR revealed different profiles of the response to treatment with distinct outcomes.     

HLA‐DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA‐DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA‐DR/DQ whole antigen mismatch, HLA‐DR/DQ single molecule eplet mismatch improved the correlation with de novo donor‐specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection (P = .0006), HLA‐DR/DQ de novo donor‐specific antibody development (P < .0001), antibody‐mediated rejection (P < .0001), as well as all‐cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA‐DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.     

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.     

Outcomes of immunosuppression minimization and withdrawal early after liver transplantation

The Immune Tolerance Network ITN030ST A‐WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1‐ to 2‐years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8‐step reduction algorithm with ≥8 weeks per level. Fifty‐two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.     

Significance of HLA-matching and anti-HLA antibodies in heart transplant patients receiving induction therapy?

ObjectivesThough Human Leukocyte Antigen (HLA) matching benefits are demonstrated in renal transplantation, evidence in heart transplantation is lacking, and its clinical feasibility is uncertain. Post-transplantation anti-HLA antibodies are being increasingly studied in organ transplantation, with diverging conclusions between transplantated organs.MethodsWe analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, acute rejection and chronic allograft vasculopathy in 309 patients receiving induction therapy and triple-drug immunosuppression.ResultsThe average number of HLA-A/B/DR mismatches between donor and recipient was 4.9 ± 1. The majority of mismatches was for Class I HLA-A/B with an average of 3.3, then for Class I HLA-DR with an average of 1.6. Overall, the HLA-A/-B/-DR mismatches had no influence on the cardiac allograft survival (p = 0.28). However, HLA-DR mismatches were negatively correlated to severe cellular and/or humoral allograft rejection (p = 0.04). Our analysis found anti-HLA antibodies in 27% of recipients, de novo anti-HLA antibodies in 16% of recipients, and donor-specific anti-HLA (DSA) antibodies in 8% of recipients. Furthermore, de novo DSA had no influence on the 5-year survival (78% with DSA vs. 92% without DSA; p = 0.49), which may be masked by the limited number of recipients in analysis By univariable analysis, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on severe cellular and/or humoral rejection or on chronic allograft vasculopathy.ConclusionsHLA-DR mismatch was negatively correlated to severe cellular and/or humoral allograft rejection but had no influence on cardiac allograft survival. In this study, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on cellular and/or humoral rejection or on chronic allograft vasculopathy. The results of this study add to the controversy on the impact of allo-antibodies in heart transplant recipients receiving induction therapy and contemporary immunosuppression.     

Incidence and risk factors for new‐onset diabetes in living‐donor liver transplant recipients

With the increased number of long‐term survivors after liver transplantation, new‐onset diabetes after transplantation (NODAT) is becoming more significant in patient follow‐up. However, the incidence of new‐onset diabetes after living‐donor liver transplantation (LDLT) has not been well elucidated. The aim of this study was to evaluate the incidence and risk factors for NODAT in adult LDLT recipients at a single center in Japan. A retrospective study was performed on 161 adult patients without diabetes who had been followed up for ≥three months after LDLT. NODAT was defined according to the 2003 American Diabetes Association/World Health Organization guidelines. The recipient‐, donor‐, operation‐, and immunosuppression‐associated risk factors for NODAT were assessed. Overall, the incidence of NODAT was 13.7% (22/161) with a mean follow‐up of 49.8 months. In a multivariate analysis, the identified risk factors for NODAT were donor liver‐to‐spleen (L‐S) ratio (hazard ratio [HR] = 0.022, 95% confidence interval [CI] = 0.001–0.500, p = 0.017), and steroid pulse therapy for acute rejection (HR = 3.320, 95% CI = 1.365–8.075, p = 0.008). In conclusion, donor L‐S ratio and steroid pulse therapy for acute rejection were independent predictors for NODAT in LDLT recipients. These findings can help in screening for NODAT and applying early interventions.     

Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study

Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000–2014. Pretransplant RRT modality ≥60 days as grouped into “no RRT” (n = 136), “haemodialysis (HD)” (n = 1847), “peritoneal dialysis (PD)” (n = 159), and “HD + PD” (n = 135) was evaluated. Kaplan–Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5–56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR = 0.707 (0.469–1.064)], and rejection was less frequent [HR = 0.700 (0.508–0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in “PD” versus “HD” groups. Living donation benefit for allograft function was most pronounced in groups “no RRT” and “PD”. Functional allograft decline (eGFR slope) was lowest for “PD”. Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).