Incidence Of Acute Cellular Rejection Research Articles

Surveillance with Dual Non-invasive Testing for Acute Cellular Rejection After Heart Transplantation: Outcomes from the Surveillance HeartCare Outcomes Registry (SHORE)

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.

Basiliximab Induction and Postoperative Steroid-free Immunosuppression With Tacrolimus in Pediatric Liver Transplantation: A Randomized Clinical Trial.

Optimizing the immunosuppressive regimen is essential to improve the long-term outcomes of pediatric liver transplant recipients. We conducted a prospective, randomized, open-label study to compare the safety and efficacy of 2 treatment approaches during pediatric liver transplantation: tacrolimus monotherapy following basiliximab induction (the study group) and a dual regimen of tacrolimus plus steroids (the control group). A total of 150 patients were enrolled, with 75 patients allocated to each group. In both groups, recipients achieved graft and recipient overall survival rates exceeding 93%, with no statistically significant differences between them. However, the study group exhibited a significantly lower incidence of acute cellular rejection (ACR), delayed occurrence of ACR, and an improved ACR-free survival rate at 2 y compared with the control group. Notably, the study group also showed a significant reduction in the incidence of de novo donor-specific antibodies at 3-mo and 2-y posttransplant. Furthermore, 6 mo after the transplant, the study group demonstrated significant improvements in weight-for-age Z score and height-for-age Z score. No notable differences were observed in postoperative complications or the incidence of liver fibrosis between the 2 groups. Basiliximab induction combine with tacrolimus (TAC) monotherapy is a safe and effective immunosuppressive regimen to reduce the episodes of ACR without influencing the development of liver fibrosis and graft and recipient survival rate after pediatric liver transplantation.

Difficulties in diagnosing and predicting possible complications in patients after heart transplantation: single-center experience in the Krasnodar region

Aim. To evaluate the early and long-term outcomes of heart transplantation (HT) at the Research Institute of the S. V. Ochapovsky Regional Clinical Hospital № 1.Material and methods. On the basis of the Research Institute of the S. V. Ochapovsky Regional Clinical Hospital № 1 from March 2010 to March 2023, 230 HTs were carried out. Among the patients, men predominated 86% (n=198), women — 14% (n=32). The mean age was 48,3±11,7 years. The reason for HT in 42,6% (n=98) was ischemic cardiomyopathy (ICM), in 40% (n=92) — dilated cardiomyopathy (DCM), while 17,4% were operated on for another cardiac pathology (n=40). All recipients underwent immunological examination, endomyocardial biopsy (EMB), 2D-speckle-tracking echocardiography (2D-STE), transthoracic echocardiography (TTE), coronary angiography (CAG), as well as a number of studies for early diagnosis of possible cancer complications.Results. Acute rejection during the first three years was detected in 77 recipients (42,5%), of which cellular rejection (grade ≥2, 3) and humoral rejection was verified in 49 and 28 recipients, respectively. During the entire follow-up period, de novo anti-human leukocyte antigen (HLA) antibodies were detected in 34 recipients in the posttransplantation period, of which 50% (n=17) and 35% (n=12) were diagnosed with humoral and cellular rejection, respectively. Of the 34 patients with anti-HLA antibodies, 11 (32%) died. All of them died due to a humoral rejection. The survival rate of patients with antibodies was lower (59%) than in patients without antibodies (66%), p=0,023. The annual survival rate of all patients after transplantation in our center was 83,1% (during the first year after transplantation, 30 and 9 patients died due to an acute rejection and infectious complications, respectively).Conclusion. Since the introduction and modification of immunosuppressive therapy regimens, tremendous progress has occurred, and the incidence of acute cellular rejection has decreased. However, the risk of humoral rejection and long-term complications remains one of the main reasons for graft failure.

2714. Invasive Fungal Disease in Lung Transplant Recipients: Incidence, Risk Factors, and Outcomes

Abstract Background Invasive fungal disease (IFD) is common after lung transplant and is associated with increased morbidity and mortality. Antifungal prophylaxis is a common preventative strategy against IFD in lung transplant recipients (LTRs). We assessed the incidence of IFD in the first 3-years post-transplant, diagnosed by EORTC/MSG criteria, risk factors for developing IFD, and outcomes of LTRs stratified by development of IFD at a single center that does not use universal antifungal prophylaxis post-lung transplant. Table 1 Preoperative and perioperative characteristics and clinical outcomes of lung transplant recipients stratified by invasive fungal disease (IFD) status Methods A single-center, retrospective study of lung transplant recipients between January 2017 and December 2019 was performed with 3-year follow-up. Donor and recipient preoperative characteristics, microbiologic and radiographic data, perioperative characteristics, and 1- and 3-year outcomes were adjudicated and analyzed. Results In this 3-year study period, 168 patients underwent lung transplant. 26 (15%) developed IFD; 23 (14%) were proven or probable, and 3 (1%) were possible [Table 1]. 21 (81%) had evidence of pulmonary infection and 17 (65%) were mold infections with Aspergillus being the predominant pathogen. 4 (15%) were Candida. 81% (21/26) of patients who developed IFD were recipients of bilateral lung transplants compared to 95% (135/142) of patients who did not develop IFD (p = 0.022). Other donor/recipient characteristics and 12-month outcomes between patients who did vs did not develop IFD were similar. 21% of patients (4/19) who developed IFD had developed antibody-mediated rejection (AMR) by three years post-transplant compared to only 4% of patients without IFD (5/112) (p = 0.025). The incidence of acute cellular rejection, chronic allograft rejection, and overall survival at three years were similar. Conclusion Despite the lack of universal antifungal prophylaxis in the first 90 days post-transplant, we observed a low incidence of IFD in LTRs at our center in this 3-year cohort. Other than receipt of a single vs bilateral lung transplant, there were no significant differences in preoperative or perioperative recipient characteristics. Other than an increased proportion of patients who had AMR, patients who developed IFD had similar overall outcomes to those who did not have IFD, including overall survival at 1, 2, and 3 years. Disclosures Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Astellas: Grant/Research Support|Boehringer Ingelheim: Advisor/Consultant|Fujifilm: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support

Rabbit Antithymocyte Globulin for Treatment of Corticosteroid Refractory Acute Cellular Rejection After Lung Transplantation.

Chronic lung allograft dysfunction (CLAD) remains a major cause of death after the first year posttransplant, with acute cellular rejection (ACR) being a major risk factor for CLAD. We evaluated the use of rabbit antithymocyte globulin (rATG) for corticosteroid refractory ACR in lung transplant recipients. We retrospectively identified 112 adult lung transplant recipients who received rATG for refractory ACR after lung transplantation. The primary endpoint was the incidence of ACR on follow-up transbronchial biopsy. Secondary endpoints included freedom from ACR within 1 y post-rATG, CLAD progression at 1 y post-rATG, and all-cause mortality at 1 y post-rATG. A complete resolution of ACR was observed in 60.2% of patients, an improvement but not complete resolution in 22.1%, and no response on follow-up biopsy in 17.8%. Mean A grade 1 y post-rATG was 0.51 in complete responders, 1.01 in partial responders, and 2.19 in nonresponders ( P < 0.001). Complete responders had significantly less new or worsening CLAD at 1 y than partial responders (17% versus 40%; P = 0.02). All-cause mortality rate was 14.9% in complete responders, 40% in partial responders, and 30% in nonresponders ( P < 0.01). rATG appears to be an effective treatment of refractory ACR in lung transplant recipients. Failure to respond to rATG carries an increased risk of early CLAD and death.

Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p<.001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p=.004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4%vs. UP 34.4%, p<.001). Incidence of detectable CAV was similar at 1 year (PET 8.2%vs. UP 9.5%, p=.698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7%vs. UP 43.6%, p=.036). The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Incidence of Acute Cellular Rejection After Granulocyte Colony-Stimulating Factor in Lung Transplant Recipients.

BackgroundNeutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P = .070). In multivariable analysis, filgrastim use was not associated with ACR at 6months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P = .049) and 6-month ACR score was higher in the filgrastim group (.49 vs .33, P = .047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs.

Primary Graft Dysfunction Is Associated With Development of Early Cardiac Allograft Vasculopathy, but Not Other Immune-mediated Complications, After Heart Transplantation.

We investigated associations between primary graft dysfunction (PGD) and development of acute cellular rejection (ACR), de novo donor-specific antibodies (DSAs), and cardiac allograft vasculopathy (CAV) after heart transplantation (HT). A total of 381 consecutive adult HT patients from January 2015 to July 2020 at a single center were retrospectively analyzed. The primary outcome was incidence of treated ACR (International Society for Heart and Lung Transplantation grade 2R or 3R) and de novo DSA (mean fluorescence intensity >500) within 1 y post-HT. Secondary outcomes included median gene expression profiling score and donor-derived cell-free DNA level within 1 y and incidence of cardiac allograft vasculopathy (CAV) within 3 y post-HT. When adjusted for death as a competing risk, the estimated cumulative incidence of ACR (PGD 0.13 versus no PGD 0.21; P = 0.28), median gene expression profiling score (30 [interquartile range, 25-32] versus 30 [interquartile range, 25-33]; P = 0.34), and median donor-derived cell-free DNA levels was similar in patients with and without PGD. After adjusting for death as a competing risk, estimated cumulative incidence of de novo DSA within 1 y post-HT in patients with PGD was similar to those without PGD (0.29 versus 0.26; P = 0.10) with a similar DSA profile based on HLA loci. There was increased incidence of CAV in patients with PGD compared with patients without PGD (52.6% versus 24.8%; P = 0.01) within the first 3 y post-HT. During the first year after HT, patients with PGD had a similar incidence of ACR and development of de novo DSA, but a higher incidence of CAV when compared with patients without PGD.

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?

Center volume effect on acute cellular rejection and outcomes in pediatric lung transplant recipients

Acute cellular rejection (ACR) is common after lung transplant (LTx). We sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. The United Network for Organ Sharing (UNOS) Registry was queried for patients <18-years-of-age who underwent LTx 1987-2020. Cohorts were children who survived the first-year post transplant and were treated for ACR within that first year (ACR group) and those not treated for ACR (non-ACR). LTx center volume was defined as: high volume center (HVC) (>5LTxs/year), medium volume center (MVC) (>1≤5 LTxs/year), and low volume center (LVC) (≤1LTxs/year). 1320 patients were enrolled into the study; 269 (20.4%) did not experience ACR. The ACR cohort was older (median 14 [11-16] vs 13 [7-16] years, p<0.001), female (65.3% vs 57.3%, p=0.016), cystic fibrosis diagnosis (62.3% vs 45.5%, p<0.001), and higher lung allocation score (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). The ACR cohort trended (p=0.06) towards lower survival at 5-year (37% vs 47%) and 10-year (25% vs 34%) post-LTx. Among children at HVCs, ACR occurred in 17% of recipients (n=98/574), compared to 18.5% (n=73/395) at MVCs and 27% (n=100/369) at LVCs. Children treated for ACR at HVCs had higher survival than LVCs at 5-years (52% vs 29%) and 10-years (36% vs 15%) (p<0.001) but similar survival to MVCs at 5-years (52% vs 43%) and 10-years (36% vs 24%) (p=0.081). No survival differences were detected in MVCs vs LVCs (p=0.14). ACR treated within the first post-LTx year influence survival of children. ACR incidence was lowest at higher volume centers whereas post-ACR treatment survival outcomes were also superior.

Conversion to belatacept after lung transplantation: Report of 10 cases.

Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.

Basiliximab induction versus no induction in adult heart transplantation.

Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12months following heart transplant in patients who received BAS or no induction. This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90days post-transplant, incidence of antibody-mediated rejection (AMR) at 90days and 1year, incidence of infection, and all-cause mortality at 1year. A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p<.002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p<.001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p=.20). BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.

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.

One-year immunologic outcomes of lung transplantation utilizing hepatitis C-viremic donors.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n=21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n=21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4%vs. 85.7%, P=.17) or rejection requiring treatment (33.3%vs. 57.1%, P=.12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD± .37], P=.67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P=.09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P=.14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

CD26-inhibition correlates with the absence of chronic lung allograft dysfunction and decreases fibroblast activity in vitro

Abstract Objective Chronic lung allograft dysfunction (CLAD) limits the survival after lung transplantation (Tx). CLAD is characterized by progressive fibrosis of small airways and lung parenchyma. No effective therapy is available that reverses or prevents CLAD. CD26 is a molecule with enzymatic activity also playing a key role in the progression of fibrotic diseases. Here, we analyzed the inhibitory effect of CD26 on fibroblast activity in vitro and the role of CD26-inhibition on allograft rejection in lung transplant patients. Methods Profibrogenic mRNA and protein levels were analyzed in vitro on the CD26-expressing fibroblast cell line Wi-38 using RT-qPCR and Western blot. CD26 was inhibited by Vildagliptin. Migration and proliferation activity of activated fibroblasts were analyzed by Incucyte® and Celltiter-Glo®. Characteristics of patients undergoing lung Tx between 2004 and 2021 were reviewed. Lung biopsies were analyzed by immunohistochemistry (IHC) for CD26. Results In vitro, the expression of profibrogenic genes (αSMA, FAPα, IGFBP7, Collagen 3 and Fibronectin) was significantly reduced in activated lung fibroblasts by Vildagliptin treatment. Also, migration and proliferation activity were attenuated by Vildagliptin. In 221 patients analyzed, CLAD was absent in 34 patients treated with the CD26-inhibitor Sitagliptin vs. an incidence of 18% in patients without Sitagliptin intake (p=0.02). Five-year survival in patients on Sitagliptin was significantly improved vs. patients without CD26-inhibitor intake (80% vs. 58%, p=0.006). Likewise, the incidence of acute cellular rejection (ACR) was significantly reduced in patients on Sitagliptin (7% vs. 35%, p=0.01). IHC of patient lung biopsies showed expression of CD26 in perifibrotic areas of CLAD lesions. Additional clinical data from University Hospital Zurich and from University Hospital Padua confirmed the finding that Sitagliptin intake correlated with the absence of acute and chronic allograft rejection. Conclusion CD26-inhibition attenuates key pro-fibrotic mediators and fibroblast activity in vitro. Impressively, patients on CD26-inhibitor did not show any CLAD. Moreover, ACR was significantly reduced. Gliptins which are in routine clinical use for the treatment of type II diabetes therefore seem to have great potential to be repurposed for a novel clinical application against lung allograft rejection.

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.

High Volume Centers Have Lower Incidence of Acute Cellular Rejection in Pediatric Lung Transplant Recipients and Better Survival After Treatment

Purpose Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. Methods The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). Results 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). Conclusion ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR. Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR.

Acute Cellular Rejection at Long-Term Follow-Up After Heart Transplantation: A Single Center Experience in Japan

<h3>Purpose</h3> Acute cellular rejection (ACR) is a major cause of death within 1-3 years after heart transplantation (HTx). However, recipients are usually asymptomatic in the early stages of ACR, and it is difficult to obtain specific findings of ACR using non-invasive tests. Therefore, regular endomyocardial biopsy plays an important role in monitoring for ACR. Although mortality from ACR decreases in the long term after HTx, there is no strong evidence of screening methods such as the appropriate frequency of biopsies. We retrospectively analyzed the outcome of ACR in our institution. <h3>Methods</h3> We enrolled 136 patients who underwent HTx at our hospital from May 1999 to April 2020. 7 Recipients under the age of 18 at the time of HTx were excluded. The current myocardial biopsy schedule is 1,2,3,5,7,11 weeks, 4.5,6,9 months, twice a year from 1 to 2 years, and once a year until 10 years after HTx. After that, it is once every two years. Tacrolimus (cyclosporine before 2005), mycophenolate mofetil, and prednisolone were used as first immunosuppressive therapies. Basiliximab was administered in patients with impaired renal function, elderly patients, and anti-donor antibody-positive patients. <h3>Results</h3> 129 HTx recipients (74% male, age at transplantation 41.8 ± 12.9 years) were analyzed. Grade 2R or higher grade of ACR were observed in 19 times in 13 patients during a mean follow-up period of 7.4 ± 5.0 years. Only one case with Grade 2R (3.5 years after HTx) combined with antibody-mediated rejection developed heart failure. All recipients with ACR recovered with steroid pulse therapy, and no deaths due to ACR were observed. The frequency of ACR of Grade 2R or higher in less than 1 year, 1-3 years, 3-5 years, 5-10 years, and 10 years or more after HTx was 4.0, 2.1, 2.2, 0.7, and 0 %/patients/years, respectively. The incidence of ACR was significantly higher in 15 patients who took cyclosporine as the first calcineurin inhibitor after HTx than in 114 patients who took tacrolimus (40% vs 6.1%, p <0.05). Late recurrence of ACR after HTx was seen in a patient with poor medication adherence and in a patient after immunosuppressive drug changes. <h3>Conclusion</h3> The frequency of developing ACR decreased over the years after HTx. Careful observation is still required in cases with a high risk of recurrence, such as inadequate medication adherence even long after HTx.

Rabbit Anti-Thymocyte Globulin for Treatment of Corticosteroid Refractory Acute Cellular Rejection After Lung Transplantation

<h3>Purpose</h3> Chronic Lung Allograft Dysfunction (CLAD) is the major cause of graft failure and death after the first-year post-transplant. Acute Cellular Rejection (ACR) of grade A2 or higher is a major risk factor for CLAD. Rabbit anti-thymocyte globulin (rATG) is often used when ACR is nonresponsive to pulse-dose corticosteroids. Data is lacking regarding the impact of rATG on steroid refractory ACR (rACR) after lung transplantation. The objective of this retrospective study was to evaluate the use of rATG for rACR in lung transplant recipients and define its success in improving or resolving ACR. <h3>Methods</h3> Adult patients were included if they had received a single or double lung transplant as identified by ICD 9 and 10 procedure codes between January 2010 and August 2019 and had received rATG after the date of transplantation through September 2020. rATG treatment was identified using medication charge data. Patients were included if rATG was administered for ACR. The primary endpoint was the incidence of ACR on follow-up transbronchial biopsy. ACR was classified by complete resolution, improvement but not complete resolution, or no response in A grade. Secondary endpoints included freedom from ACR at one-year post-rATG, CLAD incidence or progression at one-year post-rATG, and all-cause mortality at one-year post-rATG. <h3>Results</h3> 112 patients were included in the primary outcome analysis. 60.2% of patients had a complete resolution, 22.1% had an improvement but not complete resolution, and 17.8% had no response on follow-up biopsy. Mean A grade one-year post-rATG was 0.51 in complete responders, 1.01 in partial responders, and 2.19 in non-responders (p < 0.001). There was no statistical difference in new or worsening CLAD depending on response to rATG (17% vs 40% vs 30%; p = 0.09). All-cause mortality was significantly lower in patients who had a complete histologic response to rATG (14.9% vs 40% in partial responders, and 30% in non-responders (p < 0.01). <h3>Conclusion</h3> rATG appears to be an effective treatment of rACR in lung transplant recipients. Response to rATG appears to be sustained at one-year post-rATG. Patients that do not respond to rATG for rACR may have an increased risk of mortality.