Biopsy-proven Acute Cellular Rejection Research Articles

Detrimental impact of early biopsy-proven rejection in liver transplantation.

Existing literature offers conflicting conclusions about whether early acute cellular rejection influences long-term outcomes in liver transplantation. We retrospectively collected donor and recipient data on all adult, first-time liver transplants performed at a single center between 2008 and 2020. We divided this population into two cohorts based on the presence of early biopsy-proven acute cellular rejection (EBPR) within the first 90 days post-transplant and compared outcomes between the groups. There were 896 liver transplants that met inclusion criteria with 112 cases (12.5%) of EBPR. Recipients who developed EBPR had higher biochemical Model for End-Stage Liver Disease scores (28vs. 24, p<.01), but other donor and recipient characteristics were similar. Recipients with EBPR had similar overall survival compared to patients without EBPR (p=.09) but had decreased graft survival (p<.05). EBPR was also associated with decreased time to first episode of late (>90 days post-transplant) rejection (p<.0001) and increased vulnerability to bacterial and viral infection (p<.05). In subgroup analysis of recipients with autoimmune indications for liver transplantation, EBPR had a more pronounced association with patient death (hazard ratio [HR] 3.9, p<.05) and graft loss (HR 4.0, p<.01). EBPR after liver transplant is associated with inferior graft survival, increased susceptibility to late rejections, and increased vulnerability to infection.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus

Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell+My-rept+corticosteroid) and the control group (dual-drug regimen: TacroBell+corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P = .468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P = .376). Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV.

The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children.

Background.Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT.Methods.Paired peripheral blood DNA samples were obtained before and after LT from 17 children, including 4 rejectors (Rs) and 13 nonrejectors (NRs), and assayed with MethylC capture sequencing approach covering 5 million CpGs in immune-cell–specific regulatory elements. Differentially methylated CpGs (DMCs) were identified using generalized linear regression models adjusting for sex and age and merged into differentially methylated regions (DMRs) comprising 3 or more DMCs.Results.Contrasting Rs versus NRs, we identified 2238 DMCs in post-LT and 2620 DMCs in pre-LT samples, which clustered in 216 and 282 DMRs, respectively. DMCs associated with R were enriched in enhancers and depleted in promoters. Among DMRs, the proportion of hypomethylated DMRs increased from 61/282 (22%) in pre-LT to 103/216 (48%, P < 0.0001) in post-LT samples. The highest-ranked biological processes enriched in post-LT DMCs were antigen processing and presentation via major histocompatibility complex (MHC) class I, MHC class I complex, and peptide binding (P < 7.92 × 10−17), respectively. Top-ranked DMRs mapped to genes that mediate B-cell receptor signaling (ADAP1) or regulate several immune cells (ARRB2) (P < 3.75 × 10−08). DMRs in MHC class I genes were enriched for single nucleotide polymorphisms (SNPs), which bind transcription factors, affect gene expression and splicing, or alter peptide-binding amino acid sequences.Conclusions.Dynamic methylation in distal regulatory regions reveals known transplant-relevant MHC-dependent rejection pathways and identifies novel loci for future mechanistic evaluations in pediatric transplant subcohorts.

Antithymocyte globulin versus basiliximab induction for kidney transplantation in elderly patients: matched analysis within the Korean multicentric registry.

BackgroundBasiliximab (BSX) and antithymocyte globulins (ATGs), are two major immunosuppressive agents commonly used as induction therapy for kidney transplant (KT) recipients. The superiority of ATG over BSX has not been well established, especially in elderly KT recipients with low immunological risk.MethodsA total of 847 elderly (≥60 years old), low-risk KT patients in the Korean Organ Transplantation Registry were propensity score-matched at a 1:2 ratio and compared according to ATG or BSX induction therapy. The primary outcome was patient and graft survival and biopsy-proven acute cellular rejection. The secondary outcome was graft function, BK virus nephropathy, infection, cancer, new-onset diabetes mellitus after transplantation (NODAT), and delayed graft function.ResultsIn total, 165 patients in the ATG group were matched with 298 patients in the BSX group with average ages of 64.3 and 64.2 years, respectively. During a follow-up of 28.5 ± 10.4 months, the cumulative probabilities of death-censored graft failure at 3 years posttransplantation were 1.3% and 1.4% in ATG and BSX groups, respectively, without a significant difference (p = 0.72). The cumulative probability of NODAT at 3 years posttransplantation was significantly higher in the BSX group (35.6% vs. 21.6%, p = 0.02). The median tacrolimus trough level was significantly lower at 6 months after KT in the ATG group (5.7 ng/mL vs. 6.4 ng/mL, p = 0.001). There were no differences in the other evaluated outcomes.ConclusionCompared with BSX, in elderly, low-risk KT patients, ATG reduced tacrolimus and steroid requirements without differences in all-cause mortality, rejection, or infection, resulting in a reduced NODAT incidence.

Liver transplantation for hepatocellular carcinoma following checkpoint inhibitor therapy with nivolumab

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11months. Two patients with <3months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38months of follow up. None of the patients who underwent LT >3months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss.

Association Between Total Cell Free DNA and SARS-CoV-2 In Kidney Transplant Patients: A Preliminary Study

BackgroundKidney transplant (KT) recipients are at high risk for developing severe COVID-19. Lowering immunosuppression levels in KT recipients with COVID-19 encourages native immune responses but can raise the risk of rejection. Donor-derived cell-free DNA (dd-cfDNA), reported as a fraction of total cfDNA, is a proven biomarker for KT rejection. Total cfDNA levels are elevated in patients with COVID-19, which may depress dd-cfDNA fractions, potentially leading to missed rejections.MethodsA retrospective analysis of 29 KT recipients hospitalized with COVID-19 between April and November 2020 examined total and dd-cfDNA levels. Blood samples were collected after onset of COVID-19, with follow-up samples collected from a subset of patients, when infection had likely subsided.ResultsAfter COVID-19 diagnosis, the median total cfDNA level was elevated (7.9 multiples of median [MoM]). A significant decrease in total cfDNA levels was observed between the first and second time points (6.2 MoM, 1.0 MoM; P <001). A significant positive association was identified between total cfDNA levels and COVID-19 severity (P = .02; R2 = .19). Two patients with biopsy-proven acute cellular rejection had dd-cfDNA fractions below the 1% cutoff for rejection (0.20% and 0.78%), with elevated total cfDNA levels of 7.9 MoM and 41.8 MoM, respectively.ConclusionsIn this preliminary study, total cfDNA levels were elevated in KT patients with COVID-19, subsiding after resolution of infection. High total cfDNA levels may confound dd-cfDNA results, leading to failure to identify rejection. Considering total cfDNA levels is important in interpretation of dd-cfDNA tests for assessment of rejection in KT patients with COVID-19 or other infection.

Abstract 11935: The Index of Microcirculatory Resistance to Predict Subsequent Acute Cellular Rejection and Cardiac Events After Heart Transplantation

Introduction: Single center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute cellular rejection. Hypothesis: To validate whether IMR measured early after transplantation can predict subsequent acute cellular rejection and long-term outcome in a large multicenter cohort. Methods: From 5 international heart transplantation cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was biopsy-proven acute cellular rejection of grade 2 or 3 within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE, the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission due to a cardiac cause) at 10 years. Results: IMR was measured at a median of 7 weeks (interquartile range: 3 to 10 weeks) post-transplantation. Patients with acute cellular rejection grade 2 or 3 at the time of IMR assessment were excluded. At 1 year, the incidence of acute cellular rejection was 14.0%. IMR was associated proportionally with the risk of acute cellular rejection (per increase of 1-unit IMR; adjusted hazard ratio [aHR], 1.04; 95% confidence interval [CI], 1.01-1.06; P=0.002). The incidence of acute cellular rejection in patients with IMR ≥ 18 was 23.8%, while the incidence of acute cellular rejection in those with IMR &lt; 18 was 5.5% (aHR, 4.09; 95% CI, 1.67-10.0; P=0.002). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-unit IMR; aHR, 1.03; 95% CI, 1.01-1.05; P=0.002). Conclusions: IMR measured early after heart transplantation is associated with subsequent acute cellular rejection at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized post-transplantation management.

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation.

Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04-1.34], P=0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6-65.7], P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P<0.001; net reclassification index 1.05, P<0.001; integrated discrimination index 0.20, P<0.001). Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02798731.

MO995DO THE TIMELINE AND SPECTRUM OF INFECTIONS CHANGE AFTER ANTI-REJECTION THERAPY IN KIDNEY TRANSPLANT RECIPIENTS?

Abstract Background and Aims The infections in kidney transplant recipients has been well defined. The timeline of infections and type of infection among patients who received anti-rejection therapy for acute rejection when compared to the patients who did not develop an acute rejection. Method Renal transplant recipients with post-transplant median follow up of four years from July 2009-June 2018 were included in a retrospective cohort study at a tertiary care hospital. Demographic characteristics, biopsy proven rejections, infections and graft and patient outcome were collected from transplant records and the hospital clinical workstation. Early and late acute rejections were defined as less than and more than 3 months respectively. The rates of various infections, type and time to develop an infection in the acute rejection group were compared with the patients who did not develop any rejection. Results A total of 794 patients underwent kidney transplant during the study with mean age of 35.5±12 years and 78% being male. Two hundred and eight four patients (35.8 %) had one or more biopsy proven rejections during the median follow up of 48 months (IQR 28,77). 213 patients (75%) developed early acute rejection (less than 3 months) while the remainder developed late acute rejection. The median time to develop the first acute rejection was 12 days (IQR 6,93.3). Majority of the patients (176, 62%) developed biopsy proven acute cellular rejection, 77 patients (27.1%) acute antibody mediated rejection and rest (10.9%) either mixed or borderline rejection who were treated. The proportion of BKV infection and infective diarrhea were more in rejection group when compared to no rejection group which was statistically significant (refer Table 1). At follow up, the patients who developed rejection had more graft loss (p value 0.010) but no increase in mortality. The predictors of infection among the patients who received anti-rejection therapy were identified. The median time to develop any infection in both groups were also compared. The spectrum of infections and outcome following early and late rejections were compared. Subgroup analysis was done to look at the eGFR, proteinuria trend, graft outcomes in patients with no rejection, rejection without any infection at follow up and rejection with any infection at follow up. The effect of type of anti-rejection therapy on spectrum of infections was also studied. Conclusion This is one of the few studies which looked at the effect of anti-rejection therapy in kidney transplant recipients. Anti-rejection treatment received post kidney transplant resulted in increased rates of BKV infection and infective diarrhea. Patients with acute rejection had more graft loss during follow up with no significant effect on mortality.

Comparison of De Novo Donor Specific and Non-Specific Antibodies on the Outcome after Heart Transplantation

Purpose Studies have shown that donor specific antibodies (DSA) have great impact on the clinical course and overall survival of patients after heart transplantation (HTx). De-novo non-DSA (NSA) were associated with graft loss after kidney transplantation, but it remains unclear to what extent NSA play a role in rejection, graft function and overall mortality after HTx. The aim of this study was to analyze and compare the outcome of patients with DSA and NSA after HTx. Methods Surveillance endomyocardial biopsies (EMB) were taken after 1, 3, 6 months and yearly for 5 years after HTX, and cardiac allograft vasculopathy (CAV) was evaluated via coronary angiography. Serum HLA-class I and II antibodies were collected for analysis of donor specifity twice yearly. The antibody mean fluorescence intensity (MFI) cut-off values were set at >1000. Study data was collected retrospectively from internal medical records. End points of the study were death of any cause, primary graft failure (PGF), biopsy proven acute cellular rejection (BPACR) ≥2R according to ISHLT, antibody mediated rejection (AMR) and CAV. Complete data was obtained only from patients with a survival of 12 months or greater. Results 69 patients with a follow-up time of min. 18 months to max. 6 years after HTx were divided into two groups (G1: no DSA or NSA present, n=41, G2: DSA and / or NSA present, n=27). G2 was further divided into two subgroups, patients with both DSA + NSA (n=9) and only NSA(n=26) status.All-cause mortality was n=21 (30.9%), with significant difference amongst the groups (G1: n=17 (41.5%), G2: n=4(18.4%)). This trend was also seen amongst cardiovascular mortality (G1: n=7 (17.1%), G2: n=0). No statistically significant difference was seen regarding CAV (G1: n=3 (7.3%), G2: n=2 (7.4%)), BPACR (G1: n=19 (27.9%) or G2: n=9 (22%)). Surprisingly, AMR was seen in patients in G1 n=3 (4.4%), but not in G2 (n=0), however, without statistically relevant difference. Conclusion Our study shows that DSA and NSA had no negative impact on the outcome up to 6 years after HTx. This might be due to a closer monitoring of the patients after detection of DSA and NSA, and, consequently, an adequate and early adjustment of immunosuppressive therapy including specific DSA treatments to preserve graft function.

LONG-TERM RESULTS OF EVEROLIMUS ON RENAL FUNCTION AND REJECTION AFTER HEART TRANSPLANTATION IN A REAL-LIFE SCENARIO

Introduction: Clinical study results are still controversial about the start of everolimus (ERL) with and without calcineurin inhibitor (CNI) after heart transplantation (HTx). Thus, we analyzed long-term data of the effect of ERL on renal function and the incidence of biopsy proven acute cellular rejection (BPACR) apart from clinical studies in a real-life scenario. Methods: 105 patients, who received HTx between 2005 and 2015, were divided into three groups (Gs) according to the time of ERL start; G1≤ 3 months (mo) after HTx (n=46), G2 4-12 mo after HTx (n=33) or G3 >12 mo after HTx (n=26). Additionally, we analyzed patients either with CNI withdrawal ≤3mo (sub-group, SG1, n=25) after ERL start, or with concomitant CNI therapy >12mo (SG2, n=71) after ERL start. Renal function was calculated using the MDRD formula for the glomerular filtration rate (GFR) in relation of baseline value before ERL, and at 12 and 60mo after ERL start (ΔGFR mL/min). Iincidence of BPACR (≥2R) was compared between the study groups at 12 and 60mo after HTx. Results: At 12mo after ERL start ΔGFR was a significant better in patients of G2 compared to patients of G3 (G2: +3.98 vs G3: -4.98, p=0.04). Furthermore, CNI withdrawal did not further improved renal function compared to concomitant CNI therapy at this early time point. However, patients of G1 had a higher ΔGFR at 60mo after ERL start compared to patients of either G2 or 3 (G1: +1.59, G2: -12.71, G3: -6.26, p1vs2=0.035 and p1vs3=0.27). In all three Gs, patients with early CNI withdrawal had a higher ΔGFR than patients with concomitant CNI therapy at 60mo (SG1: G1: +5.53; G2: +0.36; G3: -22.26, p1vs3=0.01, p1vs2=0.02; SG2: G1 -0.83, G2: -22.12, G3: -6.73, p1vs3=0.045; p1vs2=0.02). Incidence of BPACR at 12mo after HTx was not different between the study groups (G1: 15.2%, G2: 19.1%, G3: 19.2%, p=0.72). However, CNI-free patients of G1 had a higher incidence of BPACR than patients with concomitant CNI therapy of G1 at 12mo (SG1: 33,3% vs SG 2: 6,9%, p=0.03) and at 60mo (SG1: 22% vs. SG2: 0%, p=0.049). All BPACR were without hemodynamic compromise. Conclusion: We showed that an early ERL therapy within 3mo of HTx had a long-term beneficial effect on renal function in a real-life scenario. Early CNI withdrawal enhanced the nephroprotective effect further. While the incidence of BPACR was increased by early CNI-withdrawal, graft function, however, was not severely impaired.

Use of Mycophenolate Mofetil Suspension as Part of Induction Therapy After Living-Donor Liver Transplant

The aim of this study was to evaluate recipient safety, tolerability, and pharmacokinetics of mycophenolate mofetil suspension compared with mycophenolate mofetil capsules as part of induction therapy after living-donor liver transplant. Between July 2017 and April 2019, we retrospectively enrolled 20 adult primary living-donor liver transplant recipients. Recipients were divided into 3 groups: group 1 received mycophenolate mofetil suspension of 3000 mg (n = 6), group 2 received 3000 mg mycophenolate mofetil via opened capsules (n = 8), and group 3 received mycophenolate mofetil suspension of 2000 mg (n = 6). Administration was started on postoperative day 1, with tacrolimus administered on postoperative day 2 or day 3. The values of area under the plasma concentration time curve for 0 to 12 hours were significantly higher in the 3000 mg/day mycophenolate mofetil suspension group than in the 2000 mg/day mycophenolate mofetil suspension group (P = .024) and in the 3000mg/day mycophenolate mofetil capsule group (P = .013). Significant positive correlations were shown between blood concentration at 8 hours after administration and the plasma concentration time curve for 0 to 12 hours (r2 = 0.96; P < .001) in patients in the suspension group. No patients required mycophenolate mofetil reduction because of leukopenia and diarrhea. Only 1 biopsy-proven acute cellular rejection was recognized in the mycophenolate mofetil suspension group (at 2000 mg/day). There were no significant differences in frequency of opportunistic infections among the 3 groups. Mycophenolate mofetil suspension is useful as part of immunosuppressive induction therapy after living-donor liver transplant because its concentration increases greater than that of mycophenolate mofetil capsules and because of the low risk of rejection and adverse events.

Long-Term Results of Everolimus on Renal Function and Rejection after Heart Transplantation in a Real-Life Scenario

Clinical study results are still controversial about the start of everolimus (ERL) with and without calcineurin inhibitor (CNI) after heart transplantation (HTx). Thus, we analyzed long-term data of the effect of ERL on renal function and the incidence of biopsy proven acute cellular rejection (BPACR) apart from clinical studies in a real-life scenario. 105 patients, who received HTx between 2005 and 2015, were divided into three groups (Gs) according to the time of ERL start; G1≤ 3 months (mo) after HTx (n=46), G2 4-12 mo after HTx (n=33) or G3 >12 mo after HTx (n=26). Additionally, we analyzed patients either with CNI withdrawal ≤3mo (sub-group, SG1, n=25) after ERL start, or with concomitant CNI therapy >12mo (SG2, n=71) after ERL start. Renal function was calculated using the MDRD formula for the glomerular filtration rate (GFR) in relation of baseline value before ERL, and at 12 and 60mo after ERL start (ΔGFR mL/min). Iincidence of BPACR (≥2R) was compared between the study groups at 12 and 60mo after HTx. At 12mo after ERL start ΔGFR was a significant better in patients of G2 compared to patients of G3 (G2: +3.98 vs G3: -4.98, p=0.04). Furthermore, CNI withdrawal did not further improved renal function compared to concomitant CNI therapy at this early time point. However, patients of G1 had a higher ΔGFR at 60mo after ERL start compared to patients of either G2 or 3 (G1: +1.59, G2: -12.71, G3: -6.26, p1vs2=0.035 and p1vs3=0.27). In all three Gs, patients with early CNI withdrawal had a higher ΔGFR than patients with concomitant CNI therapy at 60mo (SG1: G1: +5.53; G2: +0.36; G3: -22.26, p1vs3=0.01, p1vs2=0.02; SG2: G1 -0.83, G2: -22.12, G3: -6.73, p1vs3=0.045; p1vs2=0.02)Incidence of BPACR at 12mo after HTx was not different between the study groups (G1: 15.2%, G2: 19.1%, G3: 19.2%, p=0.72). However, CNI-free patients of G1 had a higher incidence of BPACR than patients with concomitant CNI therapy of G1 at 12mo (SG1: 33,3% vs SG 2: 6,9%, p=0.03) and at 60mo (SG1: 22% vs. SG2: 0%, p=0.049). All BPACR were without hemodynamic compromise. We showed that an early ERL therapy within 3mo of HTx had a long-term beneficial effect on renal function in a real-life scenario. Early CNI withdrawal enhanced the nephroprotective effect further. While the incidence of BPACR was increased by early CNI-withdrawal, graft function, however, was not severely impaired.

Evaluation of the Efficacy and Safety of Dual Induction versus Induction Monotherapy in Orthotopic Heart Transplant Recipients

The goal of induction therapy with rabbit anti-thymocyte globulin (rATG) and basiliximab in cardiac transplant is to minimize incidence of biopsy-proven acute cellular rejection (BPAR). However, rATG has been associated with increased risk for hematologic and infectious complications. At Mayo Clinic, dual induction, consisting of rATG cumulative doses less than 6 mg/kg and basiliximab, has been utilized in recipients experiencing complications from rATG. The impact of dual induction in cardiac transplant recipients is unknown. The goal of this study was to evaluate the clinical outcomes associated with dual induction. This Institutional Review Board approved study was a retrospective review of cardiac transplant recipients who received induction therapy with rATG and/or basiliximab at Mayo Clinic in Florida between January 1, 2013 and December 31, 2017. The primary endpoint was time to first incidence of BPAR within 12 months following cardiac transplant. Secondary outcomes included time to first incidence of infectious complication, antibody-mediated rejection, and death within 12 months post-cardiac transplant. Additional secondary outcomes included time to first incidence of hematologic complication within 90 days post-cardiac transplant, time to first incidence of cytokine release syndrome and calcineurin inhibitor initiation within 14 days post-cardiac transplant. 102 cardiac transplant recipients were included. BPAR occurred in 79% patients receiving rATG induction, 90% patients receiving basiliximab induction, and 83% patients receiving dual induction. Basiliximab (HR, 1.85; 95% CI 1.06 to 3.23)and dual induction (HR, 1.81; 95% CI 1.04 to 3.15) were associated with higher risks of BPAR compared to rATG. Dual induction demonstrated an increased risk of infection, compared to both rATG (HR, 2.02; 95% CI 1.05 to 3.90) and basiliximab (HR, 3.46; 95% CI 1.31 - 9.1). Basiliximab was associated with a reduced risk of hematologic complication, compared to rATG (HR, 0.44; 95% CI 0.22 - 0.91), but an increased risk of mortality (HR, 4.32; 95% CI 1.2 to 16.1). Use of dual induction was associated with an increased risk of BPAR and infection post-transplant. Use of basiliximab demonstrated reduced risk of hematologic complications but increased risk of BPAR and mortality following transplant.

Polyfunctional CD8+ T Cells are Associated with Biopsy Proven Acute Cellular Rejection in Pediatric Heart Transplant Patients

Polyfunctional T cells (PTC) have the ability to secrete ≥2 cytokines per cell when stimulated and increased presence of PTC is associated with favorable outcomes in patients undergoing chimeric antigen receptor (CAR) T cell therapy for cancer. In pediatric heart transplant recipients (PHT), the development of PTC may represent increased exposure to donor specific antigens with the potential to induce greater allograft damage through elevated cytokine production; however, the ability of circulating PTC to predict acute cellular rejection (ACR) in PHT is unknown. The goal of this pilot study was to determine the frequency of circulating PTC and secreted cytokine profiles of T lymphocytes in PHT with varying degrees of ACR, with the hypothesis that an elevation in circulating PTC is associated with ACR. Peripheral blood mononuclear cells were collected from PHT concurrently with clinically indicated cardiac biopsy. Single-cell expression profiles of 32 cytokines (Isoplexis Isocode Chip) were quantified in CD4+ and CD8+ T cells from each patient. Samples were stratified by ISHLT biopsy grade for ACR. The polyfunctional strength index (PSI) was calculated as the %PTC multiplied by the intensities of each secreted cytokine. PSI of CD8+ T cells in PHT with ACR 1R (n=4) and 2R (n=2) was increased compared to ACR 0 (n=3; Figure 1). PSI in CD4+ T cells in PHT with ACR was also increased, but less than in CD8+ T cells. Cytokines that drove an increased PSI were granzyme B, macrophage inflammatory protein (MIP)-1a, MIP-1b and sCD137 in CD8+ T cells and MIP-1a, MIP-1b and tumor necrosis factor (TNF)-α in CD4+ T cells. Correspondingly, stimulated cytokine production (CD8+ > CD4+) was increased in PHT with ACR vs no ACR. PHT with ACR had distinct circulating T lymphocyte profiles, specifically with increased polyfunctionality of circulating CD8+ T cells. Quantification of CD8+ PTC may represent a novel biomarker of ACR in PHT and warrants further investigation.

Evaluation of Induction Strategies in Heart Transplant at a Single Center

Immunosuppression induction is commonly utilized in heart transplant (HT) to prevent acute rejection and/or delay calcineurin inhibitor (CNI) initiation. However, guidance on whether to use induction and preferred agent(s) are not well defined. This is reflected by high practice variability across centers. According to ISHLT registry data, 54% of adult HT cases utilized induction, 31% with an IL-2R antagonist and 23% with a T-cell depleting agent. Our center has primarily utilized 3 strategies based on rejection risk and need to delay CNI: IL-2R antagonist (basiliximab), T-cell depleting (anti-thymocyte globulin, rabbit (rATG)), or no induction. Our study's objective was to compare these strategies' safety and effectiveness. A retrospective chart review was conducted at a large academic medical center, including HT cases performed between January 2015 and April 2019. Patients were stratified by induction strategy used at the time of transplant. The primary outcomes were rate of biopsy-proven acute cellular rejection (ACR) grade 2R or higher, treated antibody mediated rejection (AMR), and any infection within one year of transplantation. From January 2015 to April 2019, 145 total HTs were included in our study (123 heart, 20 heart-kidney, and 2 heart-liver). rATG was the most common induction strategy used (36%), followed by no induction (35%), and basiliximab (26%). Four patients (3%) received 1 dose of basiliximab but were switched to rATG. ACR rates were not statistically different among induction groups: 22% with no induction, 11% with basiliximab, 17% with rATG, and 0% with combination (p = 0.51). AMR rates were also not statistically different: 6% with no induction, 5% with basiliximab, 4% with rATG, and 0% with combination (p = 0.93). There was no difference detected in donor-specific antibody (DSA) formation at 1 year (p = 0.81). The percentages of patients with any infection were: 53% with no induction, 55% with basiliximab, 62% with rATG, and 75% with combination (p = 0.90). Incidences of ACR, AMR, DSA formation, and infection were not statistically different among induction strategies at one year post-transplant. It may be beneficial to individualize induction strategies based on recipient factors at the time of transplantation. Long term outcomes in this patient cohort are yet to be determined.

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n=115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness)BL-3Y was not significantly different between groups (P=0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.025, P=0.83). The number of 1R was not a significant predictor of ∆MITBL-3Y (P=0.58), and no significant interaction with treatment was found (P=0.98). The burden of mild ACR was not associated with CAV development.

2299 Resolution of Acute Cellular Rejection Using Irradiating Packed Red Blood Cells for Exchange Transfusion in a Patient With Sickle Cell Disease and a History of Orthotopic Liver Transplantation

INTRODUCTION: Liver transplantation in patients with Sickle Cell Disease (SCD) is fairly unique; a review article from 2013 noted only 15 reported cases within the literature. This case highlights a patient with SCD who underwent orthotopic liver transplantation. His course was complicated by iron overload due to recurrent exchange transfusions, as well as biopsy-proven acute cellular rejection (ACR), that was inadequately treated with corticosteroids, with no recurrence of rejection once the patient was switched to irradiated red cell exchange transfusions. CASE DESCRIPTION/METHODS: A 32-year-old male with HbSS disease, who had also undergone orthotopic liver transplantation at the age of 26 due to complications of Caroli’s disease presented with persistent abnormal liver tests over the course of several weeks. Graft function was normal during post-transplant until monthly exchange transfusions were initiated to manage his sickle cell crises. During this period he had two episodes of ACR and was noted to have persistent liver test abnormalities despite adequate therapeutic levels of tacrolimus. The patient was switched to receiving irradiated packed red blood cells for his subsequent exchange transfusions, which led to improvement of his liver tests and resolution of his acute cellular rejection. DISCUSSION: Only a limited number of patients with sickle cell disease have undergone liver transplantation, and this is the first case of using irradiated packed red cells for transfusion to help resolve acute cellular rejection. Although it is not thoroughly understood how blood transfusions could induce acute cellular rejection, it may be related to passenger donor leukocytes within the donor blood products triggering an immune response within the transplanted liver. Given our patient’s exposure to higher volumes of transfusions, there may have been enough donor lymphocytes to trigger this response. The use of irradiated blood products is common place in patients that have received hematopoietic stem cell transplants. Current recommendations do not standardize use of irradiated red cells for solid organ transplant (SOT) recipients. Our patient presents an unusual indication for use of irradiated red cells in a SOT patient.

P1.33: Is there a role for ultrasound in the evaluation of graft small bowel?

Introduction: Intestinal graft recipients are subjected to often significant doses of radiation. MRI studies may not be feasible acutely. Endoscopic examination of the intestine is usually limited to small sections of the graft. Ultrasound (US) is an established technique in the evaluation of disease extent in patients with small bowel Crohn’s. We have utilised US for several years to evaluate the graft small bowel and have retrospectively reviewed our findings. Methods: This is a retrospective review of small bowel US studies performed post operatively for our cohort of 97 patients receiving an intestine-containing graft between 2007 and 2019. Imaging interpretation was made on the basis of grey-scale images and Doppler imaging. US images were reviewed with subsequent clinical, imaging, endoscopy and histology findings Results: 97 patients received an intestine-containing transplant between 2007 and 2019. There were 45 US studies undertaken in 27 patients. The majority of studies (23 studies in 9 patients) were undertaken in those with biopsy-proven acute cellular rejection (ACR). Imaging findings of mural thickening, loss of mural stratification, reduced peristalsis and mesenteric hypervascularity were observed in 7 patients with ACR. 2 patients with a history of ACR had normal US appearances at follow up, which correlated with endoscopic findings of recovery. Of the US performed for ACR, concurrent endoscopy (within 1 week) occurred in 11 US studies. 8 endoscopies demonstrated features related to rejection confirmed at histology. 3 demonstrated recovery. 5 patients underwent US immediately post surgery with normal findings consistent with concurrent CT or endoscopy findings. 17 US studies were undertaken for 12 patients for a range of clinical indications: 5 studies were normal, 4 consistent with clinical / imaging findings. 1 patient had drug related ulceration at endoscopy. 11 studies in 6 patients demonstrated minimal mural thickening but no further features to suggest rejection, 4 were followed with endoscopy with no features of rejection. The remainder were followed clinically and radiologically. 1 US demonstrated features suggesting rejection but normal endoscopic findings. An internal hernia was found at surgery. Conclusion: Small bowel US is a useful technique in establishing normal appearances of the bowel. When interpreted in conjunction with clinical and endoscopic findings in patients with ACR it may have a potential role in surveillance.