Rejection-free Survival Research Articles

Outcomes of kidney transplantation over a 16-year period in Korea: An analysis of the National Health Information Database.

This study investigated the outcomes of kidney transplantation (KT) over a 16-year period in Korea and identified risk factors for graft failure using a nationwide population-based cohort. We investigated the Korean National Health Insurance Service-National Health Information Database. Health insurance claims for patients who underwent KT between 2002 and 2017 were analyzed. The data from 18,331 patients who underwent their first KT were reviewed. The percentage of antithymocyte globulin (ATG) induction continuously increased from 2.0% in 2002 to 23.5% in 2017. Rituximab began to be used in 2008 and had increased to 141 patients (9.6%) in 2013. Acute rejection occurred in 17.3% of all patients in 2002 but decreased to 6.3% in 2017. The rejection-free survival rates were 78.8% at 6 months after KT, 76.1% after 1 year, 67.5% after 5 years, 61.7% after 10 years, and 56.7% after 15 years. The graft survival rates remained over 80% until 12 years after KT, and then rapidly decreased to 50.5% at 16 years after KT. In Cox's multivariate analysis, risk factors for graft failure included being male, more recent KT, KT from deceased donor, use of ATG, basiliximab, or rituximab, tacrolimus use as an initial calcineurin inhibitor, acute rejection history, and cytomegalovirus infection. ATG and rituximab use has gradually increased in Korea and more recent KT is associated with an increased risk of graft failure. Therefore, meticulous preoperative evaluation and postoperative management are necessary in the case of recent KT with high risk of graft failure.

Keratoplasty for Keratoconus in Young Patients: Demographics, Clinical Features, and Post-transplant Outcomes

To examine pretransplant findings and outcomes of corneal transplants for keratoconus in children. Retrospective cohort (national registry) study. Data on all patients aged 16 or younger (n=170) who had a first transplant for keratoconus between 2003 and 2018 in all corneal transplant centers in the UK were compared to adult patients aged 17 and older (n=7,191). The influence of demographic variables, pretransplant corneal findings, and transplant type on 2-year visual, rejection-free, and transplant survival outcomes was examined. Children had poorer pretransplant visual acuity and higher rates of corneal vascularization and ocular surface disease than adults. However, 2-year post-transplant corrected visual acuity reached 20/20 or better in 35% of children compared to 28% of adults (P=.1). Transplant rejection and failure rates were 11% (P=.79) and 3% (P=.31), respectively, for children, which were comparable to rates for adults. Endothelial rejection was reported following penetrating keratoplasty (PK) in 13% of children (10% in adults). Irreversible rejection was not recorded for any transplant in a child. Despite a lack of difference in transplant outcomes, there was a significant age effect in the Cox regression model for transplant rejection, such that for every 5-year increase in age there was a 6% reduction in the hazard of rejection. Transplant survival following anterior lamellar keratoplasty and PK in children was similar. Young keratoconus patients have excellent transplant outcomes and visual results comparable to adults. Overall, the hazard of rejection was found to decrease with advancing age. However, in this large cohort of young patients with keratoconus and poor vision, there is no evidence of outcome advantage in delaying transplant until adult years.

OPTN/SRTR 2019 Annual Data Report: Pancreas

The overall number of pancreas transplants decreased slightly, from 1027 in 2018 to 1015, in 2019, up from a nadir of 947 in 2015. However, the number of simultaneous pancreas-kidney transplants (SPKs) increased in 2019, with a corresponding drop in pancreas-after-kidney transplants (PAKs) and pancreas transplants alone (PTAs). New waitlist registrations increased to 1772 in 2019, from 1606 in 2018. This was predominately driven by SPK listings, and those with type 2 diabetes. Waiting time for SPK decreased by 2 months, to a median of 12 months in 2019, but PTA recipient mean waiting time remained substantially higher, at 24 months, in 2018. Both short- and long-term outcomes, including patient survival, kidney graft survival, and acute rejection-free graft survival, have shown consistent improvement over the last decade. Pancreas graft survival data with the uniform definition of allograft failure is being collected by the Organ Procurement and Transplant Network (OPTN) and will be included in a future report.

Definition and Analysis of Textbook Outcome: A Novel Quality Measure in Kidney Transplantation.

"Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30days (N = 155, 50%); the least common was mortality within 90days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.

Topical 0.03% tacrolimus versus systemic mycophenolate mofetil as adjuncts to systemic corticosteroids for preventing graft rejection after repeat keratoplasty: one-year results of a randomized clinical trial.

To compare the efficacy of topical 0.03% tacrolimus in combination with systemic corticosteroids versus systemic mycophenolate mofetil (MMF) and corticosteroids in preventing corneal allograft rejection after repeat keratoplasty. This prospective, randomized clinical trial enrolled 63 consecutive eyes of 63 patients who underwent repeat keratoplasty after a failed penetrating keratoplasty. Group 1 (32 eyes) received MMF orally 1 g twice daily for the first 6 months and then 1 g daily for the next 6 months, and group 2 (31 eyes) received topical 0.03% tacrolimus four times a day for 12 months. All patients were treated with topical and oral corticosteroids postoperatively. The participants were observed closely for signs of graft rejection, and the rates of rejection-free graft survival were calculated and compared between the two groups at postoperative month 12. The groups were balanced in patient's age and risk factors for graft rejection (e.g., original diagnosis, number of previous grafts, and quadrants of corneal vascularization). Endothelial graft rejection occurred in 5 eyes (15.6%) of group 1 and 6 eyes (19.4%) of group 2 (P = 0.75). Irreversible endothelial graft rejection resulting in graft failure occurred in 3 eyes of each group (P = 0.99). The rate of rejection-free graft survival was 84.4% in group 1 and 80.6% in group 2 at postoperative month 12 (P = 0.74). Topical 0.03% tacrolimus was as effective as systemic MMF as adjuncts to topical and systemic corticosteroids in reducing endothelial graft rejection with 12 months follow up after repeat keratoplasty.

Hematopoietic stem cell transplant referral patterns for children with sickle cell disease vary among pediatric hematologist/oncologists' practice focus: A Sickle Cell Transplant Advocacy and Research Alliance (STAR) study.

Hematopoietic stem cell transplantation (HSCT) provides a curative therapy for children severely affected by sickle cell disease (SCD). Rejection-free survival after matched sibling donor (MSD) HSCT is very high, but adoption of HSCT as a curative SCD therapy has been slow. In this study, we assess providers' perceptions about MSD HSCT for children with variable SCD severity, and determine the influence of provider characteristics on HSCT referrals. After our Institutional Review Board deemed the study exempt, American Society of Pediatric Hematology/Oncology Clinical Forum listserv subscribers and American Society of Hematology members who self-identified as pediatric hematologists/oncologists (PHO) were emailed a survey. Analysis was performed to describe and evaluate correlations between participant demographics (including practice focus within PHO) and likelihood of HSCT referral for each scenario. Spearman's rank correlation analysis did not reveal any significant relationship between demographic characteristics except practice focus and likelihood to refer to HSCT for any scenarios. Providers focused on SCD and HSCT were more likely to refer a child who had never been admitted to the hospital or had suboptimal adherence to hydroxyurea than general PHOs. A significantly higher proportion of all respondents would refer a child with β-thalassemia major (87%) than an asymptomatic child with HbSS (47%, P<.00001) or non-HbSS variant (23%, P<.00001). PSCD and HSCT physicians are more likely to refer for MSD HSCT in almost every condition than general PHO practitioners, likely because of increased awareness of long-term effects of SCD and safety of MSD HSCT for children with SCD.

HLA matching and rabbit antithymocyte globulin as induction therapy to avoid multiple forms of rejection after a third liver transplantation

BackgroundDespite immunosuppressive drug regimens, T cell-mediated rejection, antibody-mediated rejection with donor-specific antibodies, and chronic rejection occur after liver transplantation (LTx). Rejection may significantly impact allograft survival and often a standard re-LTx is required. However, in some cases rejection recurs. Little is known on how to approach this and which aspects to consider. CaseHere we describe a case in which two successive liver grafts where lost due to T cell-mediated rejection, possible antibody-mediated rejection with de novo donor-specific antibody formation, and chronic rejection that occurred within a month. In an attempt to avoid recurrence with the third graft, we decided to administer a more rigorous immunosuppressive drug induction regimen with rabbit antithymocyte globulin, while applying HLA matching between recipient and donor. This resulted in rejection free survival for 337 days until a mild T cell-mediated rejection occurred, which could then be easily treated with high dose steroids. Graft survival is now at least 683 days without chronic rejection, antibody-mediated rejection or de novo donor-specific antibody formation. ConclusionIn conclusion, when a liver graft is lost due to multiple forms of rejection short after LTx, the combination applied in this case could be considered as a viable option to improve graft and patient survival instead of a standard re-LTx.

Acute Rejection and Infectious Complications in ABO- and HLA-Incompatible Kidney Transplantations.

BackgroundPatients receiving ABO-incompatible (ABOi) or human leukocyte antigen (HLA)-incompatible (HLAi) kidney transplantation (KT) require potent immunosuppression and are thus at a higher risk of infectious complications. We evaluated the clinical outcomes of KT stratified by ABO and HLA incompatibilities and identified the factors associated with the clinical outcomes.Material/MethodsRecipients who underwent living-related KT between 2012 and 2017 were included and classified into 4 groups: ABO-compatible and HLA-compatible (ABOc/HLAc), HLA-incompatible (ABOc/HLAi), ABO-incompatible (ABOi/HLAc), and ABO-incompatible and HLA-incompatible (ABOi/HLAi). Cox proportional hazards regression analyses were carried out to evaluate the risk factors of acute rejection. Out of the 1732 patients who underwent KT, 1190, 131, 358, and 53 were in the ABOc/HLAc, ABOi/HLAc, ABOc/HLAi, and ABOi/HLAi groups, respectively.ResultsThe ABO/HLAi group showed the lowest 5-year graft survival rate (91.7%). Death-censored graft survival was not significantly different among the groups. The mortality rate from infections was significantly higher in the ABOi/HLAi group (7.5%) than the other groups. Antibody-mediated rejection-free graft survival was the lowest in the ABOi/HLAi group, with significant differences compared with the ABOi/HLAc group (P=0.02) and the ABOc/HLAi group (P=0.03). ABOi/HLAi (hazard ratio [HR], 2.63; 95% confidence interval [CI], 1.04–6.65; P<0.01) and combined infection (HR, 1.91; 95% CI, 1.45–2.51; P<0.01) were significant risk factors for acute rejection.ConclusionsPatients with both ABO and HLA incompatibilities showed inferior rates of overall patient and graft survival due to infectious complications. Infection was a prominent risk factor of acute rejection following KT after adjusting for possible confounders including ABO and HLA incompatibility.

Outcomes for Somali immigrant kidney transplant recipients in a large-volume transplant center

IntroductionKidney transplantation (KT) demands that patients navigate a complex healthcare system and adhere to lifelong therapy and surveillance. Cultural and linguistic discordance between patients and providers has been identified as a barrier to successful KT. We studied KT outcomes and disparities among a native Somali population living in Minnesota. MethodsBetween 1995 and 2015, 2,385 patients underwent KT at our institution; 22 were self-designated Somali nationals. Patient and graft survival and time to first rejection were analyzed. Utilization of interpreter services was evaluated. ResultsPatient survival for the Somali cohort at 1 year was 100% and 95.5% at 5 years; compared to 97.2% at 1 year and 89.1% at 5 years for the Caucasian cohort (p = 0.40). Graft survival for the Somali cohort at 1 year was 100% and 95.5% at 5 years; for the Caucasian cohort 94.8% and 81.6% (p = 0.35). Rejection-free survival in the Somali cohort was 100% at 1 and 5 years, for the Caucasian cohort 86.2% and 82.1 (p = 0.41). Among 22 adult Somali KT recipients, 15 (68%) patients frequently utilized interpreter services in their KT-related clinical encounters. ConclusionImmigrant Somali KT recipients, appear to have comparable KT outcomes compared to a contemporaneous Caucasian cohort.

EVIDENCE FOR GTKO/Β4GALNT2KO PIGS AS THE PREFERRED ORGAN-SOURCE FOR OLD WORLD MONKEYS AS A PRECLINICAL MODEL OF XENOTRANSPLANTATION INSTEAD OF TRIPLE-KNOCKOUT PIGS

Purpose: Triple-knockout pigs (TKO, in which expression of the three known pig xenoantigens has been deleted) are likely to be an optimal source of organs for transplantation into human recipients, some of whom do not have natural antibodies against TKO pig cells. However, Old World monkeys, e.g., baboons, have natural antibodies directed to TKO cells, i.e., to a ‘fourth’ xenoantigen that appears when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to evaluate in vitro (i) anti-pig IgM/IgG binding, and (ii) complement-dependent cytotoxicity (CDC) to several kinds of pig peripheral blood mononuclear cells (PBMCs) using baboons sera. In addition, (iii) in vivo we compared the survival in baboons of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs) or (b) did not express Neu5Gc (GTKO/CMAHKO or TKO pigs) and therefore expressed the ‘fourth’ xenoantigen. Methods:In vitro, we measured (i) anti-pig IgM/IgG binding, and (ii) CDC by flow cytometry to GTKO, GTKO/β4GalNT2KO (that do not express the ‘fourth’ xenoantigen), and TKO pig PBMCs using 72 baboon sera. In vivo, life-supporting renal transplants were carried out in baboons using GTKO (n=6) or CMAHKO (TKO or GTKO/CMAHKO) (n=6) pig kidneys under an anti-CD40mAb-based regimen. Results:In vitro studies: Mean IgM antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to GTKO or TKO pig PBMCs (p<0.01). Mean IgG antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to TKO PBMCs (p<0.01). Mean CDC of GTKO/β4GalNT2KO pig PBMCs was significantly lower than of GTKO or TKO pig PBMCs (p<0.01) (Figure1). In vivo studies: One baboon in each group required early euthanasia for acute gastric dilatation, and were excluded from further analysis. GTKO pig kidneys functioned for 90-260 days (median 237 days, mean 196 days), with histopathological features of antibody-mediated rejection (AMR) being seen in only 2 of 5. The rejection-free survival of pig kidneys not expressing Neu5Gc (TKO or GTKO/CMAHKO) was significantly shorter (median 35 days; mean 57 days) (p<0.05) (Figure2). Four of 5 grafts failed from AMR within 1-61 days, and one baboon was euthanized for peripheral artery embolism at 183 days without features of rejection. Conclusions: Even though considered ideal for clinical xenotransplantation, the presence of natural antibodies to CMAHKO (TKO or GTKO/CMAHKO) pig cells in baboons complicates the survival of CMAHKO pig kidneys in baboons. Based on this vitro data, the use of GTKO/β4GalNT2KO (instead of TKO) pigs would be preferable for pig-to-baboon organ transplantation.

THE KOREAN ORGAN TRANSPLANTATION REGISTRY (KOTRY): FIRST OFFICIAL KIDNEY TRANSPLANTATION REPORT

Korean Organ Transplantation Registry Study Group. Korean Organ Transplantation Registry (KOTRY), a first prospective-deigned national transplantation registry in Korea, was launched in 2014. This is an initial report on the status of patients received kidney transplants over the past 4 years. A total of 4839 kidney transplants (KTs) from 32 transplant centers were collected from April 2014 to December 2018. Among these, 3039 patients received kidneys from living donors, and 1800 patients received kidneys from deceased donors. We analyzed baseline characteristics of recipients and donors, and short-term post-transplantation outcomes. Among 4839 KTs, 3039 patients (62.8%) received kidneys from living donors (LDs), and 1800 patients (37.2%) received kidneys from deceased donors (DDs). The average recipient age was 48 years; there were 1774 (58.4%) male recipients. The mean age of patients undergoing LD kidney transplantation was 4 years younger than that of patients undergoing DD kidney transplantation. Even though glomerulonephritis was the most common cause of end-stage renal disease (33.3%), the number of diabetic nephropathy was increasing. At the time of transplantation, 10.9% and 29.8% of KTs had cardiovascular disease and diabetes, respectively. The average donor age was 47 years; there was 2593 (53.6%) male donors. The mean age of LD was 2 years younger than that of DD. Expanded criteria donors (30.8%) were frequently used. During follow-up period, new-onset cardiac events and NODAT were identified in 9.4% and 8.4% of the recipients, respectively. The overall 1- and 4-year patient survival rates were 98.4% and 96.9%, respectively. During the follow-up period, 84 KTs died, and the most common cause of death was infection (47.6%). The overall 1- and 4-year graft survival rates were 97.1% and 93.0%, respectively, and the most common cause of graft loss was rejection (43.5%). The overall 1- and 4-year rejection-free survival rates were 81.8% and 72.2%, respectively. In multivariate analysis, older recipients, history of cardiovascular disease, an increasing number of HLA mismatch, bortezomib induction, cyclosporine use at discharge, no anti-metabolite at discharge, an increase serum creatinine at discharge, and long cold ischemic time were significantly associated with death after transplantation. And no anti-metabolite at discharge, an increase serum creatinine at discharge and long cold ischemic time were significantly associated with graft loss after transplantation. With the establishment of KOTRY, it is possible to present the first nationwide epidemiological data of Korean kidney transplantation. KOTRY will provide better understanding regarding nationwide epidemiological data for kidney transplantation in Korea. Novartis Korea, Ltd.. Research of Korea Centers for Disease Control and Prevention (2014-ER6301-00, 2014-ER6301-01, 2014-ER6301-02, 2017-ER6301-00, 2017-ER6301-01).

Phenotype of immunosuppression reduction after kidney transplantation.

Immunosuppressive regimens are delivered without direct measure of the net state of immunosuppression. Besides therapeutic drug monitoring, adjustments in immunosuppressive medications are largely event-driven. We studied the clinical phenotype of immunosuppression reduction (ISR) among kidney transplant recipients from 2005 to 2012. Patients were grouped into: no ISR, ISR for infection, or ISR for intolerance. Outcome measures were rejection, rejection-free survival, and IFTA-free survival. 1114 adult kidney transplant recipients were included: 57% had no ISR, 16% had ISR for infection, and 27% had ISR for intolerance. ISR for infection was mainly on MMF, while ISR for intolerance was mainly on FK. ISR was associated with higher rates of acute rejection. The Kaplan-Meier analysis showed increased prevalence of rejection among patients with ISR due to infection (P=.003) or intolerance (P=.05). The risk of interstitial fibrosis and tubular atrophy was increased in patients with ISR due to infection (P=.001) or intolerance (P=.018). Immunosuppression reduction is associated with increased prevalence of rejection. The clinical phenotype of ISR is dominated by IFTA remote from theonset of ISR. Solely focusing on acute rejection may underestimate effects of ISR on long-term graft function and survival.

Treatment of borderline infiltrates with minimal inflammation in kidney transplant recipients has no effect on allograft or patient outcomes

In 2005, the Banff committee expanded the "borderline changes" category to include lesions with minimal (<10%) inflammation: "i0" borderline infiltrates. Clinical significance and optimal treatment of i0 borderline infiltrates are not known. Data suggest that i0 borderline infiltrates may have a more favorable prognosis than borderline infiltrates with higher grades of interstitial inflammation. In this single-center, retrospective, observational study, we assessed 90 renal transplant recipients with i0 borderline infiltrates on biopsies indicated for graft dysfunction. We studied the impact of treatment with corticosteroids on allograft function, allograft survival, and patient survival. We found no differences between treated and untreated groups with respect to eGFR at 4weeks and 6months after biopsy. Follow-up biopsies, available in 67% of patients, were negative for rejection in almost half of all cases, regardless of treatment status. The frequencies of persistent borderline infiltrates (38%) and higher-grade T cell-mediated rejection (1A or greater, 14%) on follow-up biopsies were similar between the two groups. There were no differences in rejection-free allograft survival, death-censored graft failure, or patient mortality among treated vs non-treated i0 borderline patients. Our findings suggest that the natural history of i0 borderline infiltrates, in relatively low immunologic risk patients, is not affected by corticosteroid treatment.

Ex-vivo treatment of allografts using adipose-derived stem cells induced prolonged rejection-free survival in an allogenic hind-limb transplantation model.

Vascularized composite tissue allotransplantation (VCA) has increasingly been adopted for the reconstruction of tissues following severe injury. However, the side effects of the post-operative use of immunosuppressants may outweigh the benefits of VCA. In order to overcome this obstacle, ex-vivo pretreatment of allografts combined with mesenchymal stem cell-based therapy may help induce immunotolerance in composite tissue allotransplantation. A hind-limb allotransplantation model of Brown-Norway to Lewis rats was established, and the allografts were infused with adipose-derived stem cells (ADSCs) and hypoxia primed ADSCs, which were injected through the vascular system along with short-term immunosuppressant treatment. The rejection-free survival of the allografts was monitored, and the histopathological examination of allografts was performed. The peripheral T lymphocytes and cytokines were analyzed using flow cytometry and ELISA, while Tregs infiltration in allotissue was detected using immunohistochemical staining (IHC). This study found that the ex-vivo treatment of allografts using ADSCs prolonged the survival of the allografts, compared with the medium control, suppressed the proliferation and infiltration of T lymphocytes and improved the secretion of immunomodulatory cytokines, such as IL-10, as well as induced regulatory T cells (Tregs) expression in the allografts. The ex-vivo pretreatment of allografts using ADSCs may function as an important adjunctive therapy for the induction of immunotolerance in VCA.

Cytomegalovirus infection and allograft rejection among pediatric heart transplant recipients in the era of valganciclovir prophylaxis.

CMV infection remains a significant cause of morbidity among pediatric HTx recipients We explored the implications of CMV infection on post-transplant outcomes among CMV risk-stratified pediatric HTx recipients receiving VGC prophylaxis. Children who underwent HTx between January 2010 and October 2016 were stratified according to CMV risk at time of transplant and evaluated for evidence of post-transplant CMV infection, rejection, CAV, and graft loss. Among 97 children, 41 (42%) were considered HR or IR risk for CMV infection and received VGC prophylaxis. CMV DNAemia was observed in 34% of children, including 71% HR, 40% IR, and 18% LR individuals. Median time to CMV DNAemia following VGC prophylaxis was 32D among HR vs 277D in IR subjects (P=.042). No differencein overall graft loss was noted among groups, but CMV HR children had decreased rejection-free survival (3.5years) compared to IR (6years, P=.015) and LR children (8years, P=.0003). CMV was noted on EMB in 13% of children but was not associated with increased CAV, rejection or graft loss. High-risk CMV status was associated with decreased time to CMV infection despite VGC prophylaxis, compared to IR, and decreased rejection-free survival times compared to both IR and LR recipients. Detection of CMV on EMB was not associated with increased rejection, CAV or graft loss. Additional studies are needed to explore the impact of CMV infection on rejection-free survival in HTx recipients.

Textbook Outcomes in Liver Transplantation.

Textbook outcome (TO) is an emerging concept within multiple surgical domains, which represents a novel effort to define a standardized, composite quality benchmark based on multiple postoperative endpoints that represent the ideal "textbook" hospitalization. We sought to define TO for liver transplantation (LT) using a cohort from a high procedural volume center. Patients who underwent LT at our institution between 2014 and 2017 were eligible for the study. The definition of TO was determined by clinician consensus at our institution to include freedom from: mortality within 90days, primary allograft non-function, early allograft dysfunction (EAD), rejection within 30days, readmission with 30days, readmission to the ICU during index hospitalization, hospital length of stay > 75th percentile of all liver transplant patients, red blood cell (RBC) transfusion requirement greater than the 75th percentile for all liver transplant patients, Clavien-Dindo Grade III complication (re-intervention), and major intraoperative complication. Two hundred and thirty-one liver transplants with complete data were performed within the study period. Of those, 71 (31%) achieved a TO. Overall, the most likely event to lead to failure to achieve TO was readmission within 30days (n = 57, 37%) or reoperation (n = 49, 32%). Overall and rejection-free survival did not differ significantly between the 2 groups. Interestingly, patients who achieved TO incurred approximately $60,000 less in total charges than those who did not. When we limit this to charges specifically attributable to the transplant episode, the difference was approximately $50,000 and remained significantly less for those that achieved TO. Here, we present the first definition of TO in LT. Though not associated with long-term outcomes, TO in LT is associated with a significantly lower charges and costs of the initial hospitalization. A multi-institutional study to validate this definition of TO is warranted.

Immunologic Complications and Graft Survival in Crohn's Disease and NOD2 Mutant Non-Crohn's Disease Adult Recipients Following Intestine Transplantation.

Background.Despite improved outcomes in the modern era of targeted immunotherapy, intestinal failure and chronic parenteral nutrition remains a significant burden for patients with Crohn’s disease (CD) worldwide. Transplantation is a key component of management when a patient with CD suffers from life-threatening complications of parenteral nutrition. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is a risk factor for both development of CD and intestinal allograft rejection.Methods.A retrospective review of a prospectively maintained database of intestinal transplants at a single center from 2003 to 2015 was conducted. Eleven adult patients with CD were identified and were compared with 103 adult control recipients. A sub-analysis was performed comparing the 11 CD recipients to the 13 NOD2 mutant non-CD recipients.Results.Patient and allograft characteristics were similar between the CD and control recipients. Although overall rejection-free survival was not significantly different, patients with CD suffered from more frequent, earlier, and more severe rejection compared with control patients. The onset, severity, and frequency of rejection was comparable between patients with CD and NOD2 mutant non-CD patients. There was a trend toward lower 5-year allograft survival for CD compared with control recipients (33% versus 63.3%; P = 0.19) and NOD2 mutant non-CD recipients (33% versus 57.14%; P = 0.41).Conclusions.Patients with CD remain a challenging population in intestine transplantation, and NOD2 mutant non-CD patients appear to have a similar immunologic phenotype. These high-risk recipients may require specialized immunosuppression protocols and management at experienced transplant centers.

TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo

Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.

Enteric Conversion of Bladder-drained Pancreas as a Predictor of Outcomes in Almost 600 Recipients at a Single Center.

Background.Complications associated with bladder-drained pancreata necessitating enteric conversion are common. Data on the outcomes after enteric conversion are conflicting. We studied the association between enteric conversion and the pancreas graft rejection, loss, and mortality.Methods.At our center, 1117 pancreas transplants were performed between 2000 and 2016. We analyzed 593 recipients with bladder-drained pancreata, of which 523 received solitary transplants and 70 received simultaneous pancreas-kidney transplants. Kaplan-Meier function was used to estimate time to conversion by transplant type. Cox proportional hazards models were utilized to evaluate patient survival, death-censored graft survival, and acute rejection-free survival while treating conversion as a time-dependent covariate. Subsequently, we examined the association between timing of conversion and the same outcomes in the conversion cohort.Results.At 10 y posttransplant, 48.8% of the solitary pancreas recipients and 44.3% of simultaneous pancreas-kidney transplant recipients had undergone enteric conversion. The enteric conversion was associated with 85% increased risk of acute rejection (hazard ratio [HR] = 1.85; 95% confidence interval [CI] = 1.37-2.49; P < 0.001). However, the conversion was not associated with graft loss or mortality. In the conversion cohort, a longer interval from engraftment to conversion was associated with an 18% lower rejection rate (HR = 0.82; 95% CI = 0.708-0.960; P = 0.013) and a 22% better graft survival (HR = 0.78; 95% CI = 0.646-0.946; P = 0.01).Conclusions.Enteric conversion was associated with increased risk of rejection, but not increased risks of graft loss or mortality. The decision to convert should consider the increased rejection risk. A longer interval from engraftment to conversion appears favorable.

Post-Heart Transplant Diabetes Mellitus: Incidence, Prevalence and Outcomes

De novo diabetes mellitus (DM) is a common complication of solid organ transplantation. However, studies about post-transplant DM (PTDM) following heart transplantation (HT) are scarce. This study aims to compare baseline characteristics and clinical outcomes between patients who developed PTDM and those who did not as well as investigate the incidence and prevalence of PTDM following HT. 148 consecutive patients undergoing HT between 4/2014 and 12/2018 were enrolled to this retrospective study. PTDM diagnosis was made based on a HbA1c ≥6.5%, fasting blood glucose ≥ 126mg/dL or use of insulin or oral hypoglycemic agents. Of the 148 patients, 57 (39%) had no DM, 37 (25%) had DM prior to HT, and 54 (36%) developed PTDM. Among the patients without DM at the time of HT, cumulative incidence of PTDM was 37% at discharge, 46% at 6 months, and 48% at 1 year post-HT. The prevalence of PTDM at 6 months post-HT was 44% and decreased to 36%, 26%, and 17% at 1, 2, and 3 years, respectively (Figure 1A). PTDM patients had a significantly higher pre-HT HbA1c compared to those without DM (5.8 (5.6, 6.0) vs 5.5 (5.3, 5.9)%; p=0.017). There was no difference in the dose of immunosuppressive medications between the groups. PTDM patients had a higher rate of infection requiring hospitalization compared to patients with no DM post-HT (80% vs 61%; p=0.036). Infection free survival was significantly lower in the PTDM group at 2 years (16% vs 35%; p=0.046) (Figure 1B). Overall survival (96% vs 96% at 2 years; p=0.986), rejection-free survival (46% vs 51% at 2 years; p=0.410), rate of cardiac allograft vasculopathy (33% vs 22%; p=0.267), kidney function and number of hospitalizations were similar between the PTDM and no DM groups. The incidence of PTDM after HT was high but prevalence decreased after 6 months. Patients with PTDM had increased pre-HT HbA1c and higher post-HT rates of infection compared to patients without DM. Further studies are needed to determine the clinical impact of PTDM.