Rates Of Acute Cellular Rejection Research Articles

Induction immunosuppression strategies and outcomes post-lung transplant: A single center experience

PurposeCurrently 80% of lung transplant centers use induction immunosuppression. However, there is a lack of standardization of induction protocols within and across lung transplant centers. This study explores the association of two different induction immunosuppression strategies used at our center [single dose rabbit antithymocyte globulin (rATG) vs. alemtuzumab] compared to no induction with immunologic and clinical outcomes after lung transplantation. MethodsA total of 174 consecutive lung transplant recipients (LTR) between 2016 and 2019 were included in the analysis. Twenty nine LTR (16.7%) received no induction, 22 LTR (12.6%) received alemtuzumab, 123 LTR (70.6%) received a single dose of rATG; 1.5 mg/kg within 24 h of transplant for induction. All LTR had a negative flow cytometry crossmatch on the day of the transplant. All LTR were assessed for de novo HLA donor-specific antibodies (DSA) development and clinical outcomes, including the risk of acute cellular rejection (ACR), antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), and overall survival post-transplant. ResultsThe median lung allocation score (LAS) was significantly higher in LTR that did not receive Induction immunosuppression (76; range = 35.3–94.3) compared to induction with rATG (41.6; range = 31.6–91) and alemtuzumab (51; range = 33.1–88.2) (p < 0.001). De novo HLA DSA were detected in 50/174 (28.7%) LTR within 12 months post-transplant. They were detected in 13/29 (44.8%) LTR without induction immunosuppression compared to 28/123 (22.8%) and 9/22 (40.9%) LTR with rATG and alemtuzumab induction, respectively (p = 0.02). The percent freedom from ACR rates between LTR who received alemtuzumab induction was significantly higher compared to LTR who received rATG or no induction at 1 (p = 0.02), 2 (p = 0.01) and 3 (p = 0.05) years post-transplant. In addition, the overall 1-year survival rates were significantly higher in LTR who received rATG or alemtuzumab induction compared to LTR without induction immunosuppression (p = 0.02). ConclusionInduction immunosuppression strategies utilizing rATG or Alemtuzumab have unique and contrasting benefits in LTR. Combination of alemtuzumab induction and a lower dose of maintenance immunosuppression may reduce the incidence of ACR in LTR. Single-dose rATG or alemtuzumab induction immunosuppression may also improve the 1 year overall LTR survival compared to no induction.

Surveillance with dual noninvasive testing for acute cellular rejection after heart transplantation: Outcomes from the Surveillance HeartCare Outcomes Registry

BackgroundMolecular testing with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual non-invasive surveillance on clinical decision-making has not been widely investigated. MethodsWe evaluated 2077 subjects from the SHORE registry who were enrolled between 2018 and 2021 and had verified biopsy data, and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. Incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LR+) were calculated and biopsy rates over time were analyzed. ResultsThe incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive and 9.2% for dual positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive and 35.4% for dual positive results. The LR+ for ACR was 1.37, 2.91 and 3.90 for GEP positive, dd-cfDNA positive and dual positive testing, respectively. From 2018-2021, first-year biopsy rates declined from 5.9 to 5.3 biopsies/patient, and second year from 1.5 to 0.9 biopsies/patient. At two-years, survival was 94.9% and only 2.7% had graft dysfunction. ConclusionsDual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. Use of dual non-invasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction.

Low Mortality Associated with COVID-19 Infection in Lung Transplant Recipients at a Single Center

Lung Transplant Recipients (LTR) are particularly vulnerable to severe infection, hospitalization, and death due to community acquired respiratory viruses. As a result, the global SARS-Cov-2 pandemic poses a higher risk to this population. We aim to study the lung function, severity of infection and mortality among LTR at a single center. A retrospective chart review was performed on all LTR at the University of San Diego, California Medical Center between June 2020 and September 2022. Spirometry was performed at 1-2 months and then again 3 months after infection. Patients were closely monitored for the development of acute cellular rejection (ACR). 72 LTR were infected with COVID-19. 37.5% required hospital admission, of which 25.9% required management in the intensive care unit (ICU). 73.6% LTR had received at least one vaccination dose prior to infection. Post-infection, the median drop in FEV1 was 140 mL and FVC was 25 mL within 1-2 months. At 3 months post-infection the median reduction in FVC was slightly larger at 75 ml, while median decline in FEV1 decreased to 55 ml. Overall, the rates of ACR and mortality in this population were both 4.2%. Additionally, monoclonal antibody (mAb) therapy reduced hospitalization (20.9% vs 62%) and mortality (0% vs 10.3%), Our study found low rates of ACR and mortality in LTR with confirmed COVID-19, despite the statistically significant decline in FEV1, and trends with FVC. The use of vaccinations and mAb therapy decreased rates of hospitalizations, with mAb therapy reducing mortality as well.

Liver Inclusion Appears to Be Protective Against Graft Loss-Due-to Chronic But Not Acute Rejection Following Intestinal Transplantation.

In intestinal transplantation, while other centers have shown that liver-including allografts have significantly more favorable graft survival and graft loss-due-to chronic rejection (CHR) rates, our center has consistently shown that modified multivisceral (MMV) and full multivisceral (MV) allografts have significantly more favorable acute cellular rejection (ACR) and severe ACR rates compared with isolated intestine (I) and liver-intestine (LI) allografts. In the attempt to resolve this apparent discrepancy, we performed stepwise Cox multivariable analyses of the hazard rates of developing graft loss-due-to acute rejection (AR) vs. CHR among 350 consecutive intestinal transplants at our center with long-term follow-up (median: 13.5years post-transplant). Observed percentages developing graft loss-due-to AR and CHR were 14.3% (50/350) and 6.6% (23/350), respectively. Only one baseline variable was selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to AR: Transplant Type MMV or MV (p < 0.000001). Conversely, two baseline variables were selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to CHR: Received Donor Liver (LI or MV) (p = 0.002) and Received Induction (p = 0.007). In summary, while MMV/MV transplants (who receive extensive native lymphoid tissue removal) offered protection against graft loss-due-to AR, liver-containing grafts appeared to offer protection against graft loss-due-to CHR, supporting the results of other studies.

246.6: Long-term Rejection Free Renal Allograft Survival With Fc-Modified Anti-CD154 Antibody Monotherapy in Nonhuman Primates

Belatacept is currently an only FDA approved costimulatory blockade (CB) used as an alternative to calcineurin inhibitors in kidney transplantation. However, it has been associated with higher rates of acute cellular rejection (ACR) and more effective CB has been sought. Blockade of the CD154/CD40 pathway with anti-CD154 antibody (aCD154) has been shown to be more effective in inhibiting alloimmune responses than CTLA4Ig. Unfortunately, clinical application of aCD154 has been abandoned due to its thrombophilic property which appears to be mediated by FcγRIIA receptor–dependent platelet activation. To address this problem, an Fc-modified aCD154 (TNX-1500), in which Fc was engineered to decrease binding to Fcγ RII, has been developed. In the current study, we have evaluated TNX-1500 for its efficacy to prevent kidney allograft rejection in NHPs. Twelve cynomolgus macaques received MHC mismatched kidney allografts with either TNX-1500 monotherapy (20mg/kg weekly) (Group A) or combined with daily mycophenolate mofetil (MMF) (TNX-1500 weekly for 6 weeks followed by every 2 weeks) (Group B). The results were compared with our historic results of no immunosuppression (No IS, n=5) or conventional immunosuppression (I.S.) with tacrolimus (Tac), MMF and methylprednisolone (Pred). (Conventional IS, n=20). Without any prophylaxis, no thromboembolic complication was observed in all nine recipients of TNX-1500. Renal allograft survival at 6 month was 80% in Group A (n=6). Histopathology at 6 months of 5/6 recipients showed no evidence of rejection (g0,i0,t0,v0,ptc0,cg0,ci0,ct0,cv0, C4d0). One recipient lost on day 28 with ACR2b. Six recipients have so far have been tested in Group B. Two recipients developed rejection on day 36 and 48 while they were still treated with weekly TNX-1500. Another recipient had to be euthanized on day 111 post-transplant due to complications from MMF. The three other recipients in this group are currently in progress with normal kidney function at days >180, >84 and >42. Renal allograft survival at four months in Conventional I.S. was 52% (p=0.33 vs. Group A) and all five recipients without I.S. rejected their kidney allografts by day 11 (p=0.0018 vs. Group A). Excellent renal allograft survival was achieved with TNX-1500 monotherapy without thromboembolic complications. Combination with MMF resulted in inferior allograft survival.Financial support from NIH Grants 1R21AI163806-01, 5T32AI007529-22 & Tonix Pharmaceuticals.

Evaluating the Incidence and Risk Factors for Acute Cellular Rejection in a Steroid Sparing Liver Transplant Center.

Corticosteroids has been the mainstay of immunosuppression (IMS) following liver transplant (LT). With the advent of more potent IMS, complete steroid withdrawal has become possible after LT. However, there is limited data regarding the incidence and risk factors for acute cellular rejection (ACR) in LT recipients on steroid sparing regimens. To identify the incidence and risk factors of ACR in LT recipients at an urban LT center utilizing a steroid-sparing IMS regimen. This was a single center retrospective study evaluating incidence of ACR in adults (>18 years) who received a LT between 01/01/2008 and 6/30/2019 at a steroid-sparing liver transplant center. Data between patients who had ACR and patients who did not were compared and risk factors were identified by multivariate logistic linear regression. A total of 266 patients were included in this analysis, of which 18.4% experienced ACR within the first year of LT. Median time to first ACR was 134 (interquartile range [IQR]: 34-246) days. Black race (odds ratio [OR]: 4.39, P < 0.001), continued need for prednisone (OR: 2.80, P = 0.015) and cytomegalovirus (CMV) viremia (OR: 6.27, P < 0.001)) were independent risk factors for ACR. Tacrolimus use was associated with less ACR (OR: 0.33, P = 0.013). Steroid sparing regimens for IMS post-LT were not associated with an increased incidence of ACR when compared to reported ACR rates in literature. Potential risk factors for ACR include Black race, the use of prednisone maintenance IMS therapy, and CMV viremia.

Temporal shifts in safety and efficacy profile of mycophenolate mofetil 2 g versus 3 g daily early after heart transplantation.

Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS. We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing. A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p=0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p=0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p=0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients. MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

Incidence of acute rejection and patient survival in combined heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p<0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p=0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p=0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5years (CHLT 82.1% vs. HA 80.9% [p=0.73]; CHLT 82.1% vs. HA 80.9% [p=0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

Anti-HLA DQ Antibodies Are Associated with Chronic Lung Allograft Dysfunction in a Pediatric Lung Transplant Population

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) limits long term survival after lung transplantation. Antibody mediated rejection (AMR) has been associated with earlier CLAD development, but studies are limited in children. Clinical AMR can exist on a spectrum from subclinical to definite AMR based on the presence of anti-HLA donor specific antibodies (DSA), allograft dysfunction, and histopathologic findings, with DSA development first to appear. This study aims to describe the relationship of elevated DSA with clinical outcomes in a single center pediatric lung transplant population. <h3>Methods</h3> This was a single center, retrospective study. Pediatric bilateral lung transplant recipients were included from 2002-2020 if they had longitudinal HLA and lung function data for at least 6 months after transplantation. Preliminary analyses with chi-squared or Fisher's exact test for categorical variables and ANOVA or Kruskal-Wallis for continuous variables were used. DSA were detected with single-antigen bead arrays, and elevated DSA was defined as a mean fluorescence intensity level above 500. <h3>Results</h3> 34 patients were included: 19 with elevated DSA and 15 without. Most patients had subclinical AMR (n=10) without allograft dysfunction and two patients had definite AMR, based on the 2018 Banff consensus statement. The proportion of patients who developed CLAD was significantly higher in the elevated DSA group and had an earlier onset of CLAD. Average graft longevity and rates of acute cellular rejection, while not significant, trended towards shorter survival and higher rates of rejection in the elevated DSA group. All persistently elevated DSA were directed against HLA Class II DQ (6 of 14 patients) epitopes. Survival analysis and the significance of different HLA antigens remains ongoing. <h3>Conclusion</h3> The development of persistently elevated HLA Class II DQ DSA is associated with CLAD and likely decreased survival in the pediatric lung transplant population.

Short and Intermediate Term Effects of COVID-19 Infection on Lung Transplant Recipients

PurposeThe characteristics and outcomes, including acute cellular rejection (ACR), of lung transplant recipients (LTR) post COVID-19 infection are incompletely studied. We sought to show whether or not COVID-19 infection in LTR is associated with ACR.MethodsThis single center, retrospective study of LTR examined data among those who contracted COVID-19 between June 2020 and May 2021. Patient demographics, immunosuppression regimen, and hospital course related to COVID-19 infection were recorded. Subsequent spirometry, imaging, and biopsy results were documented.ResultsWe identified 16 LTR who tested positive for COVID by PCR testing. Acute radiographic changes were detected in half (8) of the cohort, 3 patients eventually required ICU admission, 1 which required venovenous extracorporeal membrane oxygenation. The median drop in FEV1 and FVC after COVID-19 infection was -375 (-1140 to +120) and -260mL (-1790 to +410), respectively. ACR was diagnosed in 2 patients at 6 weeks post COVID-19 infection. Both of the patients who were diagnosed with ACR required hospitalization, and one required ICU admission. There was 1 death at >6 months after infection due to progressive chronic lung allograft dysfunction and renal failure.ConclusionThis analysis characterizes short and intermediate term outcomes of LTR after COVID-19 infection. Specifically, the association between such infection and both rates of ACR and allograft function is uniquely described. ACR was observed in 12.5% of patients 6 weeks post COVID-19 infection. There was a notable reduction in lung function, which was mostly accounted for by the 3 patients in our cohort who required ICU admission. This study has several limitations. The sample size is small and involves a single center. It is also retrospective in nature, and there were a large number of asymptomatic patients included. Further analyses, to further assess the incidence of ACR in LTR are warranted to determine the associated factors and optimize management in this at risk patient population.

Effect of Redosing Basiliximab in the Setting of Blood Loss in Heart Transplant Recipients on Infection and Rejection

<h3>Purpose</h3> A prior study examining the pharmacodynamics of basiliximab in liver transplant recipients revealed significant medication clearance with blood loss. Dose escalation studies have shown total doses of 40-60 mg are effective and well-tolerated. We sought to examine infection risk when giving a total basiliximab dose of 40 mg vs 60 mg in our heart transplant (OHT) population in the setting of blood loss and requirement of massive transfusion protocol (MTP). <h3>Methods</h3> A single-center retrospective cohort study was performed examining adult OHT patients who received basiliximab induction therapy between June 1, 2010 and October 31, 2019. Cases and controls were matched 1:1. Patients were excluded if they were determined to be immunocompromised prior to transplant. The primary endpoint was incidence of infection. Secondary endpoints included the incidence of cell-mediated or antibody-mediated rejection, as well as the incidence of graft loss within 12 months. <h3>Results</h3> Forty-eight patients who underwent OHT were included, 24 patients in each group (40 mg and 60 mg total dose). Baseline characteristics were similar except for a higher number of LVAD patients in the 60 mg group (16.7% vs 45.8%, p=0.03). A total of 12 patients in the 40 mg group and 18 patients in the 60 mg group experienced at least one infection within 12 months after OHT, although this difference did not meet statistical significance (50% vs 75%, p=0.07). The types of infections were similar between the groups. A stepwise logistic regression showed blood loss and presence of LVAD at the time of transplant were predictors of infection occurrence. Delayed chest closure occurred more frequently in the basiliximab 60 mg group (p=0.002). Acute cellular rejection rates did not differ between groups (p=0.62). Antibody-mediated rejection occurred less frequently in the 40 mg vs 60 mg group (16.7% vs 50%, p=0.03). Two patients experienced graft loss in each group. <h3>Conclusion</h3> In our single-center retrospective study, the administration of an additional dose of basiliximab in the setting of MTP during OHT did not demonstrate a statistically significant increase in the risk of infection nor reduce the risk of rejection. The presence of LVAD at time of transplant was associated with an increased risk of infection and careful consideration should be given to these patients when selecting their induction regimen.

Evaluation of Mycophenolate Dose Reductions within the First Year After Lung Transplantation and Outcomes

<h3>Purpose</h3> Mycophenolate mofetil (MMF) significantly decreases acute rejection after lung transplant, however, adverse side effects commonly lead to dose reductions (DR) or temporary discontinuations (tDC). The primary aim of this study is to characterize the impact on ACR (acute cellular rejection) rates and to secondarily characterize the incidence and reasons for DR or tDC. <h3>Methods</h3> A single center retrospective chart review was conducted on patients who received a lung transplant between 7/20/16-2/10/19. Patients who died within index hospitalization or did not discharge on MMF were excluded. Severe leukopenia was defined as WBC<3.0 and all mycophenolic acid doses were converted to MMF equivalents. <h3>Results</h3> A total of 106 patients were included (11 patients excluded for death at index hospital admission or were not discharged on MMF). Seventy-eight (73.5%) patients had MMF dose reductions within the first year with a reduction to the lowest average daily dose of 605mg (±241), and leukopenia was the leading indication (76%) (Table 1). Age greater than 65 was significantly associated with higher incidence of severe leukopenia (27/55, 49%) (p=0.043) leading to DR or tDC. <h3>Conclusion</h3> While there is high incidence of MMF DR or tDC within the first year post transplant, there was no associations with ACR or development of DSAs. Older age was associated with more severe leukopenia and may warrant lower target doses without increasing ACR episodes.

Impact of Liver Biopsy Size on Histopathologic Evaluation of Liver Allograft Rejection.

Allograft liver biopsy is the gold standard in assessing transplant recipients for graft dysfunction. The impact of biopsy sample size on the diagnosis of acute cellular rejection (ACR) has not been studied. To assess the relationship of biopsy sample length with the diagnosis and determine optimal biopsy sample size in the transplant setting. We retrospectively reviewed 68 core biopsies from patients with a history of liver transplant. Each biopsy sample was read, on 5 different occasions with differing lengths, to assess for ACR per Banff criteria. Categorical agreement was calculated from rejection severity. The length of biopsy sample strongly correlated with the number of portal tracts. ACR rates increased from 73.5% to 79.4% with increase in length from 1 cm to 2 cm, and moderate rejection increased from 27.9% to 33.82%. At 1.0 and 1.5 cm, no cases of severe rejection were detected; at 2.0 cm, 1 case was detected; and at 3.0 cm, 2 cases were detected. The major error rate was reduced to less than 10% with a length of 2.0 cm, at which length the average number of complete and partial portal triads was 10 and 13, respectively. The likelihood of diagnosing ACR and rejection grade increased substantially with increase in biopsy sample length. This study suggests that a minimum length of 2 cm, 10 complete portal triads, or 13 partial/complete portal triads should be obtained for confident exclusion and grading of ACR.

Clinical outcomes of heart transplantation using hepatitis c-viremic donors: A systematic review with meta-analysis

Heart transplantation (HTx) from hepatitis C virus (HCV)-viremic donors to nonviremic recipients decreases mortality and costs. Consequently, many transplant centers have reported their results using this strategy. Hence, there is a need for an outcome analysis. We performed a systematic review with meta-analysis. In August 2020, we searched PubMed and EMBASE for publications containing data of nonviremic recipients who underwent HTx from HCV-viremic donors once direct-acting antiviral (DAA) therapy had become available (≥2014). We identified 398 publications, 13 of which met inclusion criteria, and analyzed the outcomes of 195 recipients. The HCV-transmission rate was >97% but, the cure rate was 100% with DAA therapy. The 6 and 12-month survival were 95.6% and 92.9%, respectively. Of 10 deaths reported, none were associated with HCV infection. The acute cellular rejection (ACR) rate was 31.1%. The overall DAA failure rate was 1.1%, defined as the need to alter the initial DAA therapy due to failure to cure HCV. However, the DAA failure rate was 0% when the DAA therapy was started within the first 2 weeks post-HTx. No statistically significant differences in HCV cure rates, survivals, ACR rates, and DAA failure rates were observed when outcomes were stratified by therapeutic approach type (i.e., a prophylactic approach in which DAA was given to the recipient before confirming HCV-transmission vs a reactive approach, in which DAA was given to the recipient only after an HCV-transmission was confirmed). Excellent clinical outcomes have been observed in nonviremic recipients of HTx from HCV-viremic donors since DAA had become available.

Current state of clinical trials regarding liver transplant rejection

BackgroundLiver transplant (LT) is the second most common transplant intervention. The rate of acute cellular rejection (ACR) is 15–25% after LT, while being higher in chronic rejection (CR). Clinical trials had a major role in getting more potent and selective immunosuppressive medications. Our study plays an important role by evaluating and tracking clinical trials related to liver transplant rejection, focusing on interventional therapeutic trials. MethodsOn October 28, we searched Clinicaltrials.gov for interventional clinical trials related to liver transplant rejection. A total of 27 clinical trials included in this study. Characteristics on each trial were collected, and availability of linked publications was searched using Medline/PubMed and Embase/Scopus. Content of publications was reviewed and main findings were summarized. ResultsMajority of trials were completed (15 out of 27). Eleven trials had between 11 and 50 participants, and 10 had above 100. The study duration was between 1 and 4 years for the majority of trials (16 trials), with an average of 3.77 years. Most of the trials were done in Europe/UK/Russia (n = 12). The results were provided in 9 trials but published in 4, showing the possible tolerogenic efficacy of MSC in liver transplantation, increased success of immunosuppression (IS) withdrawal after sirolimus addition, efficacy of Alemtuzumab, normal graft function and stability within 1 year of immunosuppression withdrawal. ConclusionThis study revealed a low number of trials, lack of variety in location and low publishing rates. The focus of trials was mainly towards side effects and safety of immunosuppressants, and their withdrawal. These trials reached results that must be built on to reach definitive guidelines and treatment strategies. This highlights the need for better management of human and financial resources, in order to reach new and more effective therapeutic strategies, leading to the decrease in rate of LTR.

A comparison of efficiency and safety between dual and triple immunosuppressive regimens in pediatric living donor liver transplantation at King Chulalongkorn Memorial Hospital

• The dual regimen in pediatric living donor liver transplantation had comparable acute cellular rejection rates with triple regimen. • The dual regimen group had higher ebstein-barr virus reactivation rates than in triple regimen group. • Side effects of calcineurin inhibitors were comparable in both regimens. • Discontinuation of antimetabolite drug was more than two-thirds of patients in triple regimen group.

Evaluating the conversion to extended-release tacrolimus from immediate-release tacrolimus in liver transplant recipients.

A new formulation of once daily extended-release tacrolimus (LCP-tac, Envarsus XR) was approved for use in the USA for kidney transplant recipients in 2015. There are limited data regarding real-world observations with conversion to LCP-tac in liver transplant recipients. We performed a retrospective analysis of liver transplant recipients treated with LCP-tac. Data collection included (1) reasons for switching to LCP-tac; (2) conversion ratio used; (3) kidney function at time of conversion and 3 months after; (4) outcomes of conversion [acute cellular rejection rates and cytomegalovirus (CMV) viremia] within 3 months of conversion. Average conversion ratio used to achieve therapeutic drug level without further dose adjustment was 1:0.73 (SD 0.11). Median time after transplant was 508 days (IQR 736). Common reasons patients were switched to LCP-tac were from fluctuations in tacrolimus levels (44%) and adverse effect of tremor (32%). Among patients who were switched due to tremors 88% noted significant improvement. There was no difference in serum creatinine (P = 0.55) or glomerular filtration rate (P = 0.64) from baseline to 3 months postconversion. There were no episodes of acute cellular rejections or CMV viremia postconversion. This observational study demonstrated that conversion of immediate-release tacrolimus to LCP-tac in liver transplant recipients was well tolerated and effective.

Outcome of Urgent Desensitization in Sensitized Heart Transplant Recipients

<h3>Purpose</h3> Desensitization therapy through reducing preformed antibody to increase the chances of a negative cross-match or permit safe transplantation across positive crossmatch. There was no consensus regarding desensitization protocol in cardiac patients, and the outcome of desensitization in sensitized recipient was still under debate. <h3>Methods</h3> Consecutive 25 sensitized heart transplant recipients received peri-operative desensitization in our institution from 2012 to 2019. One-year survival and graft rejection rate were analyzed and compared between sensitized recipients and non-sensitized recipients in our institution. <h3>Results</h3> One-year survival after transplant was 76% in sensitized recipients. Infection was the major cause of death. Incidence of rejection in the first year after transplant was 8% for antibody-mediated rejection and 16% for acute cellular rejection. Compared with the outcome in non-sensitized recipients, no significant difference in 1-year survival or rejection rate (sensitized vs. non-sensitized, survival 76 vs. 84.6%, P = 0.32; antibody-mediated rejection rate 8 vs. 3.1%, P = 0.41; acute cellular rejection rate 16 vs. 6.2% P = 0.20) could be demonstrated. <h3>Conclusion</h3> Acceptable early outcomes in patient's survival and graft rejection could be anticipated in sensitized heart transplant recipients under a perioperative algorithm using complement-dependent cytotoxicity (CDC) crossmatch - or panel reactive antibody (PRA) - directed urgent immunomodulation strategies, while infection remains the major concern.

Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis

BackgroundThe Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. MethodsA retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. ResultsTwenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. ConclusionThe use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

Faster Time-to-Therapeutic Tacrolimus Level is Associated with Lower Risk of Cellular Rejection Early after Heart Transplantation

Faster time-to-therapeutic tacrolimus (TTT) levels is associated with lower rates of acute cellular rejection (ACR) in kidney and liver transplantation. Limited data have evaluated this relationship in heart transplant (HT) recipients. Single-center retrospective chart review of patients who received HT from January 1, 2014 to June 30, 2016. Multi-organ transplant recipients, re-transplants, and those who received induction therapy with either basiliximab or thymoglobulin were excluded. A therapeutic tacrolimus concentration was defined as a trough level between 8-15 ng/mL for two consecutive days. The primary outcome was the rates of 30-day ACR in patients who were < and ≥ the median TTT level. Serum creatinine values were also collected for the first 10 post-op days. From a database of 88 HT patients we evaluated 55 patients who did not receive induction therapy (median age=56 (49-65), 73% white, 71% had a VAD prior to HT). The median TTT level was 9 days; patients < the median (n=25) had similar characteristics as those ≥ the median (n=30). Rates of ACR were significantly lower in the < median group (8 v. 43%, p=0.005) (Figure), while serum creatinine values were similar between groups (p>0.05 for each day). Patients without ACR (n=40) had a median TTT level of 8 (6-9.5) days, compared to 10 (9-12) days in the ACR group (n=15) (p=0.01). A multivariate regression model found TTT ≥9 days to be significantly associated with early ACR after adjusting for age, gender, and VAD pre-HT (OR 9.84, 95% CI [1.86-52.90], p=0.007). Quickly achieving a TTT level reduces the risk of ACR early after HT without adversely affecting renal function.