Late Acute Rejection Research Articles

Demographic Factors, Medication Adherence, and Post-transplant Health Outcomes: A Longitudinal Multilevel Modeling Approach.

Few studies in pediatric solid organ transplantation have examined non-adherence to immunosuppressive medication over time and its associations with demographic factors and post-transplant outcomes including late acute rejection and hospitalizations. We examined longitudinal variation in patient Medication Level Variability Index (MLVI) adherence data from pediatric kidney, liver, and heart transplant recipients. Patient and administrative data from the United Network for Organ Sharing were linked with electronic health records and MLVI values for 332 patients. Multilevel mediation modeling indicated comparatively more variation in MLVI values between patients than within patients, longitudinally, over 10years post transplant. MLVI values significantly predicted late acute rejection and hospitalization. MLVI partially mediated patient factors and post-transplant outcomes for patient age indicating adolescents may benefit most from intervention efforts. Results demonstrate the importance of longitudinal assessment of adherence and differences among patients. Efforts to promote medication adherence should be adapted to high-risk patients to increase likelihood of adherence.

Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis

Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs. We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR. IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8+ T cells, increased granzyme B positivity of both CD8+ and CD4+ T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort. IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden.

#4769 EFFECT OF EXTREMELY LONG DIALYSIS VINTAGE ON RENAL ALLOGRAFT SURVIVAL: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Dialysis vintage is long in kidney transplant recipients (KTRs) due to the donor shortage in Turkey. We assessed the effect of pre-transplant dialysis duration (more than 10 years) on the outcomes of renal allografts. Method We retrospectively evaluated 480 KTRs who were grafted between January 2009 and October 2020 at Ankara University School of Medicine, Ibni Sina Hospital. KTRs were divided into two groups according to the duration of pre-transplant dialysis treatment: Group A, ≥10 years and Group B, <10 years. Data on demographics, comorbidities, immunologic properties and graft survivals were compared between the two groups. Results Group A included 60 patients and dialysis vintage was 288±60 months (Table 1). 420 patients in Group B had an average of 19 months period of dialysis treatment. While cadaveric transplantation was 78.3% in Group A, it was much lower in Group B (11.2%, p<0.001). Most of the patients were on hemodialysis treatment (95.0% vs. 58.3%, respectively, P = .001). Recipients’ age (P = .001), HLA mismatch number (P = .008) and PRA positivity (P = .001) were significantly higher in Group A. Although anti-human T-thymocyte globulin had been mostly chosen for induction therapy in Group A (p<0.001); almost all patients were under standard triple maintenance immunosuppression therapy. First year and late acute rejection rates were similar between two groups (p=1.000 and P = .407, respectively). Clinically important difference was demonstrated in graft loss, which was mostly seen in the ≥10 years dialysis group (Group A, 18.3% vs. Group B, 8.3%, P = .014). The 1-, and 5- years graft survival rates were 91.4%, and 81.3%, respectively, in Group A and 97.4%, and 93.4%, respectively, in Group B (P = .034 and P = .029, respectively). Patient loss was significantly higher in Group A (Group A, 28.3% vs. Group B, 14.3%, P = .018). Conclusion We demonstrated that pre-transplant dialysis duration for more than 10 years has adverse effects on post-transplant graft and patient outcomes, accompanied by high immunological risk. Updates of organ allocation system considering sensitized candidates and strategies to expand donor pool and donation rates are needed to reduce waiting times on dialysis.

Research Highlights.

Research Highlights.

Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients

BackgroundNonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. MethodsWe screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. ResultsOne hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. ConclusionsConversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. Level of evidenceLevel IV.

Complications and Long-Term Outcomes in Adult Patients Undergoing Living Donor Liver Transplantation Because of Fulminant Hepatitis

BackgroundThe present study investigates the complications that may occur during long-term follow-up in patients aged 18 years and older undergoing living donor liver transplantation (LDLT) in our clinic because of fulminant hepatitis. MethodsThe study included patients aged 18 years and older with a minimum survival of 6 months who underwent an LDLT between June 2000 and June 2017. The demographic data of the patients were evaluated in terms of late-term complications. ResultsOf the 240 patients who met the study criteria, 8 (3.3%) underwent LDLT for fulminant hepatitis. The indication for transplantation in patients with fulminant hepatitis was cryptogenic liver hepatitis in 4 patients, acute hepatitis B infection in 2 patients, hemochromatosis in 1 patient, and toxic hepatitis in 1 patient. Of the 240 patients, 65 (27%) undergoing LDLT underwent a liver biopsy for suspected rejection because of an elevation in liver function test results during follow-up. Histopathologic scoring was carried out according to the Banff scoring system. A diagnosis of late acute rejection was made in only 1 of the 8 patients (12.5%) who underwent LDLT for fulminant hepatitis. ConclusionPatients with fulminant hepatitis must be prepared for an LDLT, if available, while waiting for a cadaveric donor. The results of the present study suggest that LDLTs in patients with fulminant hepatitis are safe, and the outcomes are acceptable in terms of survival and complications.

T-cell infiltrate intensity is associated with delayed response to treatment in late acute cellular rejection in pediatric liver transplant recipients.

Late acute cellular rejection (ACR) is associated with donor-specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. ACR is primarily T-cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response (DR) to rejection therapy, we performed a single-center retrospective case-control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations. Pediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin-fixed paraffin embedded (FFPE) liver biopsy tissue. Liver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti-thymocyte globulin was only required in the DR group. The frequency of liver-infiltrating CD20+ and CD8+ lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma-glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR. Higher serum GGT level, presence of autoantibodies, and increased CD8+ T-cell infiltration portends DR in late ACR treatment in children.

Transitional B cell cytokines risk stratify early borderline rejection after renal transplantation

Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at risk for shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4 mos). 217/851 (25%) had BL and were compared to 387/851 without significant inflammation (NI). Serial surveillance and for-cause biopsies and seven-year follow-up were used to evaluate histological and clinical progression. To identify high-risk patients, we examined clinical/histological parameters using regression and non-linear dimensionality reduction (tSNE) and a biomarker based on peripheral blood transitional-1 B cell (T1B) IL-10/TNFα ratio. Compared to NI, early BL was associated with increased progression to late acute rejection (AR; 5-12 mos), premature interstitial fibrosis and tubular atrophy (IFTA) and decreased seven-year graft survival. However, decreased graft survival was limited to BL patients who progressed to late AR or IFTA, and was not influenced by treatment. Although tSNE clustered patients into groups based on clinical factors, the ability of these factors to risk stratify BL patients was modest. In contrast, a low T1B IL-10/TNFα ratio at 3 months identified BL patients at high risk for progression to AR (ROC AUC 0.87) and poor 7-yr graft survival (52% vs. 92%, p=0.003), while BL patients with a high ratio had similar graft survival to patients with NI (91%, p=NS). Thus, progressive early allograft inflammation manifested as BL that progresses to late AR in the first post-transplant year represents a high-risk clinical state for poor allograft outcomes. Such high-risk status can be predicted by the T1B IL-10/TNFα ratio before irreversible scarring sets in, thus allowing timely risk stratification.

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of "immunologic privilege," isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.

Association between time in therapeutic range of tacrolimus blood concentration and acute rejection within the first three months after lung transplantation

BackgroundTacrolimus is a key drug in immunosuppressive therapy following lung transplantation. The blood tacrolimus levels are likely to fluctuate in the early postoperative period, and failure to maintain the tacrolimus trough level in target ranges is a risk factor for rejection. However, there is little information about the relationship between the time in therapeutic range (TTR) of the tacrolimus trough level (tacrolimus TTR) and clinical outcomes. This study aimed to evaluate the association between tacrolimus TTR and acute rejection (AR) within the first three months after lung transplantation.MethodsThis was a retrospective study of patients who underwent lung transplantation at a single center. The target tacrolimus trough levels were 10–15 ng/mL, and tacrolimus TTR was calculated using the Rosendaal method. The cut-off value of the tacrolimus TTR was estimated by receiver operating characteristic analysis based on AR.ResultsThe study included 90 patients. AR was observed in 26 patients. In this study, ‘‘early-AR’’ was defined as any AR within 2 weeks post-transplant (n = 22) and ‘‘late-AR’’ was defined as any AR after 1-month post-transplant (n = 4). For early AR, the relationship between tacrolimus TTR and the onset of AR was examined. There were no differences in the tacrolimus TTR between the early-AR group and non-AR group (35.7 ± 22.4 vs 31.5 ± 19.9%, P = 0.416). For late-AR, the relationship with tacrolimus TTR was examined every 10 d. The tacrolimus TTR during postoperative days (POD) 21–30 and POD 31–onset was significantly lower in the late-AR group than the no-AR group (50.0 ± 7.1 vs. 71.8 ± 18.0% and 37.0 ± 26.6 vs. 68.9 ± 31.5%, P < 0.05, respectively). The cutoff value of the tacrolimus TTR during POD 21–30 was estimated as 55.0%.ConclusionsOur findings suggest that a lower tacrolimus TTR is a predictor of late AR. A tacrolimus TTR of 55% or higher is necessary to reduce the risk of AR during this period after lung transplantation.

345.9: Keeping Up With Psychosocial Predictors of Outcomes in Solid Organ Transplantation: A User Friendly Interface To Identify, Organize and Facilitate Access to Empirical Data

Introduction: Psychosocial factors in solid organ transplantation have been identified as predictors of transplant outcomes such as morbidity, mortality and quality of life. Given the scarcity of available organs, systematic identification of psychosocial factors affecting outcomes is crucial for determining patient suitability for transplant, as well as reducing the risk of post-transplant complications via targeted interventions. Hundreds of individual studies and dozens of meta-analyses have quantified the impact of psychosocial variables on post-transplant outcomes. Sourcing this data, interpreting it, and systematically applying it within transplant settings is challenging due to the sheer amount of information available and lack of a system for organizing findings. Consequently, it is difficult to rigorously apply these findings to decision making for transplant suitability and patient care. The current study represents a step towards identifying, organizing and facilitating access to empirical data for the betterment of decision making and optimizing care. Method: The study involved a systematic review of meta-analyses and systematic reviews. Electronic searches were performed using PubMed, Medline OVID, PsycINFO and Web of Science. Inclusion criteria included systematic reviews and meta-analyses in English, adult population of transplant recipients, and inclusion of psychosocial outcomes. Results: Twenty-six studies met criteria for inclusion, 16 of them were systematic reviews and 10 meta-analyses. Studies included 193 data points (17 heart, 27 kidney, 89 liver, 19 lung and 41 multiple organs). Predictor variables included 26 behavioural (e.g., physical activity, medication adherence, sleep); 46 demographic (e.g., age, gender); 31 psychiatric (e.g., anxiety, depression); 25 social (e.g., social support, marital status); 57 substance use (e.g., alcohol dependence); 8 vocational (e.g., employment status). Outcome variables included 26 medical (e.g., late acute rejection); 27 mortality/survival; 87 substance use (e.g., high risk alcohol use); 20 psychological (e.g., PTSD, anxiety); 8 quality of life; 18 behavioural (e.g., medication adherence) and 7 miscellaneous. The data have been organized in user-friendly spreadsheets that allow the user to look for the information by organ, risk factors and outcomes. Conclusion: The goal of this study was to create a user-friendly interface to determine the impact of psychosocial predictors on post-transplant outcomes based on empirical data. As newer, appropriate studies arise they will be added to maintain an up-to-date interface. This will assist informed decision-making regarding transplant candidacy and guide interventions both pre and post-transplant to optimize outcomes.

Biliary Epithelial Senescence in Cellular Rejection Following Live Donor Liver Transplantation

As with the hepatocytes, cholangiocyte senescence can also easily be detected in damaged small bile ducts and bile ductules during liver disease affecting the biliary system and cholangiocytes. Despite cellular senescence being a feature of chronic progressive cholangiopathies in adults, only a few studies have investigated its role in liver transplant rejection. Transplant biopsies displaying features of rejection were reviewed and classified based on the type of rejection and the time since transplantation. An immunohistochemistry panel has been applied for 3 senescent cell markers (p53, p21, p16). Immunohistochemical expression analysis for the biliary senescence markers (53 biopsies) was done in the post-transplantation periods (Group 1-4) for the cases with the histologically proven diagnosis of rejection. In post-transplant group 1 (<3 months), group 2 (3-6 months), group 3 (6-12 months) and group 4 (>12 months), any 2 senescent markers' positivity was noted in 5/14 (35.7%), 8/13 (61.5%), 16/17 (94.1%) and 9/9 (100%) biopsies respectively and were comparable in all four groups (P= 0.001). A comparison of early biopsies (Group1; 3 months) and late biopsies (Group 2,3&4; >3 months) revealed significantly higher expression in late biopsies (>3 months) (P= 0.001 for any two markers). In ACR, LAR, ECR, and CR/DR any two senescent markers were positive in 14/28 (50%), 12/13 (92.3%) cases, 9/9 (100%), and 3/3cases (100%). Senescent markers (any two) were comparable in all four histological groups (P < 0.001).LAR group had increased expression (P= 0.009 for any two markers and 0.001 for all three markers) and has increased progression to CR (P= 0.019) as compared to ACR. This study on a large number of LDLT allograft biopsies demonstrates the role of biliary senescence in rejection and suggests a pathobiological role for senescence in the poor prognosis seen in late acute cellular rejection and chronic rejection.

A comparative histological analysis of early and late graft dysfunction in different time zones following living donor liver transplantation.

Liver biopsy plays a crucial role in evaluating allograft dysfunction. Comprehensive analysis of the histological spectrum of complications, particularly rejection, in different time zones is lacking. To evaluate the histological spectrum of rejection, in four time zones, in a large Living donor liver transplant series. Retrospective analysis of 313 biopsies for the last 10 years of living donor liver transplantation (LDLT) recipients. 123 of which had rejection as diagnosis, were redistributed in four time zones [1-early (<3), 2-intermediate (3-6), 3 and 4-late (6-12 and > 12) months] and were assessed for sixteen histological parameters. Biopsies in time zone 1 (26.5%), 2 (20.7%), 3 (24.6%), and 4 (28.1%)] were nearly equal. Multiple coexistent complications existed in 12% of the cases. Rejection diagnosed in time zone groups: 1 = 22 (17.9%), 2 = 27 (22%), 3 = 36 (29.3%), and 4 = 38 (30.9%). Portal inflammation mixed type (P < 0.000), portal vein (P = 0.001) and hepatic vein endothelialitis (P < 0.000), portal eosinophils (P = 0.001), and lymphocytic bile duct damage (P = 0.01) were most pronounced in group 1. Perivenulitis without hepatic vein endothelialitis was observed (P = 0.03) in groups 3, whereas bile duct atypia (P = 0.01) and duct loss (P < 0.000) were observed in group 4. Multiple episodes of rejection displayed significant association with central perivenulitis (P = 0.002) and bile duct loss (P < 0.001). Histological analysis in large series of LDLT recipients highlights the spectrum of complications in different time zones. Late acute and chronic rejection occurred as early as 3 months posttransplant. Central perivenulitis and bile duct atrophy were associated with repeated episodes of rejection and deterioration.

Late acute cellular rejection after switch to everolimus monotherapy at 11 months following liver transplantation

BackgroundAcute cellular rejection beyond the 6th month posttransplant is an uncommon complication after liver transplantation. The inadequate immunosuppression (IS) remains the main risk factor. We report a case of acute cellular rejection after a switch to everolimus monotherapy at 11 months following liver transplantation.Case presentationThis was a 69-year-old man who underwent liver transplantation after hepatocellular carcinoma. The initial immunosuppression was a combination of three immunosuppressive drugs (corticosteroids + tacrolimus + mycophenolate mofetil). The corticosteroid therapy was stopped at the 4th month posttransplant. Serious side effects of the immunosuppressive drugs (agranulocytosis and renal dysfunction), which occurred 4 months after transplantation, required a reduction and then a discontinuation of tacrolimus and mycophenolate mofetil. Everolimus was introduced as a replacement. The patient was consulted at 11 months after liver transplantation, 1 month after stopping the two immunosuppressive drugs, for liver function test abnormalities such as cytolysis and anicteric cholestasis. A moderate late acute cellular rejection was confirmed by a liver biopsy. A satisfactory biological evolution was observed following corticosteroid boluses and optimization of basic immunosuppressive drugs.ConclusionLate acute cellular rejection remains an uncommon complication, observed mostly in the first year after liver transplantation. The main risk factor is usually the decrease of immunosuppression.

Highest Recorded Serum Creatinine

Serum creatinine is a commonly used laboratory marker to assess kidney function; however, there has not been an established level of serum creatinine to predict mortality. After extensive literature review, we present a case of the highest recorded serum creatinine of 73.8 mg/dL in a 23-year-old male with the history of pediatric deceased donor kidney transplant (DDKT). He initially presented with uremia and signs of acute renal allograft failure after two months of immunosuppressive medication nonadherence, ultimately requiring emergent hemodialysis, which was complicated by new onset seizures. This was the patient's fourth episode of late acute rejection and emphasizes the need for education of immunosuppressant adherence and periodic monitoring of renal function in high-risk patients. Though there is no known creatinine level incompatible with life, this patient appears to have the highest known serum creatinine in a uremic patient on record.

S2603 Belatacept Rescue for Late Onset Acute Antibody-Mediated Rejection in a Liver Transplant Recipient

S2603 Belatacept Rescue for Late Onset Acute Antibody-Mediated Rejection in a Liver Transplant Recipient

The impact of chronic Epstein-Barr virus infection on the liver graft of pediatric liver transplant recipients: A retrospective observational study.

Chronic high Epstein-Barr virus loads (CHEBV) are commonly observed in pediatric liver transplant patients. However, it is unclear how CHEBV impacts the liver graft. The aim of this study was to clarify the clinical and pathological impacts of CHEBV on the liver graft. From 2012 to 2020, we retrospectively investigated 46 pediatric liver transplant patients (under 16 years) who survived ≥6 months. The patients were divided into two groups: CHEBV group (EBV DNA >10000 IU/ml of whole blood for ≥6 months) and nonchronic high EBV (NCHEBV) group (patients who did not meet CHEBV criteria). Tacrolimus was reduced to <3.0 ng/ml in patients with EBV DNA >5000IU/ml. Blood biochemistry data and pathological findings, obtained at the time of protocol and episodic biopsies, were compared between the two groups. Out of 46 patients, 28 CHEBV and 18 NCHEBV patients were enrolled. The blood biochemical examination did not show a significant difference between the two groups. In addition, no significant differences between the two groups were found in the pathological findings, including frequency of late acute rejection and the progression of fibrosis at the time of both protocol and episodic biopsies. Appropriate adjustment of immunosuppression for CHEBV management may have contributed to the prevention of the progression of fibrosis. CHEBV had little adverse effect on the liver graft. Graft fibrosis might have been avoided through optimal dose modification of tacrolimus. Further long-term monitoring is necessary because CHEBV may affect the pediatric liver graft in the long term.

LIVER TRANSPLANTATION: TACROLIMUS BLOOD LEVELS VARIATION AND SURVIVAL, REJECTION AND DEATH OUTCOMES.

Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.

Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation.

An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.

A Medication Adherence Promotion System to Reduce Late Kidney Allograft Rejection: A Quality Improvement Study

Adolescent and young adult kidney transplant recipients have a high risk of rejection related to suboptimal adherence. Multicomponent interventions improve adherence in controlled trials, but clinical implementation is lacking. We describe an initiative to reduce allograft rejection using evidence-based adherence promotion strategies. Interrupted time series. Kidney transplant recipients cared for at Cincinnati Children's Hospital≥ 1 year after transplant and taking≥1 immunosuppressive medication(s) from 2014 through2017. The following interventions, collectively called MAPS (Medication Adherence Promotion System), were implemented over 14 months: (1) adherence promotion training for clinical staff, 2) electronic health record-supported adherence risk screening, (3) systematic assessment of medication adherence barriers, (4) designation of specific staff to address adherence barriers, (5) shared decision-making with the patients to overcome adherence barriers, (6) follow-up evaluation to assess progress, and (7) optional electronic medication monitoring. Primary Outcome: Late acute rejection. Process measures were conducted to assess barriers, identify barriers, and perform interventions. The secondary outcomes/balancing measures were de novo donor-specific antibodies (DSA), biopsy rate, and rejections per biopsy. Time series analysis using statistical process control evaluated patient-days between acute rejections as well as monthly rejections per 100 patient-months before and after implementation. To control for known rejection risk factors including changes in treatment and case mix, multivariable analyses were performed. The monthly rejection rate fell from 1.61 rejections per 100 patient-months in the 26 months before implementation to 0.88 rejections per 100 patient-months in the 22 months after implementation. In the multivariable analysis, MAPS was associated with a 50% reduction in rejection incidence (incidence rate ratio, 0.50 [95% CI, 0.27-0.91]; P= 0.02). DSA and time since transplant (per each additional year) were also associated with rejection incidence (incidence rate ratio, 2.27 [P= 0.02] and 0.87 [P= 0.02], respectively). Single-center study, and potential confounding by unmeasured variables. Clinical implementation of evidence-based adherence-promotion strategies was associated with a 50% reduction in acute rejection incidence over 2 years.