Late Rejection Research Articles

P.259: Late antibody-mediated rejection with inferior allograft prognosis compared with early rejection: A single-center study.

P.259: Late antibody-mediated rejection with inferior allograft prognosis compared with early rejection: A single-center study.

Single machine scheduling with the total weighted late work and rejection cost

AbstractWe study a single machine scheduling problem with the total weighted late work and the total rejection cost. The late work of a job is the part of this job executed after its due date, and the rejection cost of a job is the fee of rejecting to process it. We consider a Pareto scheduling and two restricted scheduling problems. The Pareto scheduling problem aims to find all non‐dominated values of the total weighted late work and the total rejection cost. The restricted scheduling problems are dedicated to minimizing the total weighted late work with the total rejection cost not greater than a given threshold, and minimizing the total rejection cost with the total weighted late work not greater than a given threshold, respectively. For the Pareto scheduling problem, we prove that it is binary NP‐hard by providing a pseudo‐polynomial time algorithm, and give a fully polynomial time approximation scheme (FPTAS). For the restricted scheduling problems, we prove that there are no FPTASes unless , which answers an open problem. Moreover, we develop relaxed FPTASes for these two restricted scheduling problems.

Implementation of a multicomponent medication adherence promotion system is associated with a decrease in late T-cell-mediated rejection.

Poor immunosuppression adherence in pediatric recipients of liver transplant (LT) contributes to late T-cell-mediated rejection (TCMR) in ~90% of cases and increases the risk of mortality. A medication adherence promotion system (MAPS) was found to reduce late rejection in pediatric recipients of kidney transplants. Using quality improvement methodology, we adapted and implemented the MAPS in our LT clinic. Our primary outcome was population-level rates of late TCMR, measured as a monthly incident rate. Three-hundred fourteen patients undergoing LT are currently cared for at our institution. One-hundred sixty-two (52%) are females with a median age of 16 years and a median age at LT of 2 years. Preimplementation, monthly rejection rates were 0.84 rejections per 100 patient-months. After iterative implementation of MAPS over 2.3 years, monthly rejection rates decreased to 0.46 rejections per 100 patient-months, a 45% decrease in late TCMR. Implementation of MAPS was associated with a sustained 45% decrease in TCMR at a single center, suggesting that quality improvement tools may help improve clinical outcomes. MAPS may be an important tool to ensure long-term allograft health. Future studies should rigorously test MAPS across a multicenter sample.

A Decade-Long Cohort Analysis of Human Cytomegalovirus (HCMV)-Induced Early and Late Renal Rejection in Post-Transplant Patients in the Eastern Indian Population.

Background: HCMV causes severe clinical complications in transplant recipients and may lead to graft rejection. Successful renal transplantation heavily relies on the early prevention and diagnosis of CMV infections, followed by prompt prophylactic treatment before transplantation. Despite the majority of renal rejection cases with acute HCMV infections being asymptomatic and occurring one to two years later, the objective of this research was to comprehend the effect of late HCMV infection on renal rejection by examining specific clinical parameters in the Eastern Indian cohort. Method: In this study, 240 patients were studied for five years following transplantation, and their data were collected from the local metropolitan hospital in Eastern India. Both HCMV-positive and -negative post-transplant patients were investigated using the clinical parameters and viral loads for latent infection. Results: Within the studied population, 79 post-transplant patients were found to be HCMV positive. Among them, 13 (16.45%) patients suffered from renal rejection within less than 2 yrs. of transplantation (early rejection) and 22 (27.84%) patients suffered from renal rejection after 2 yrs. from the operation date (late rejection). Assessment of clinical parameters with respect to HCMV infection revealed that in early rejection cases, fever (p-0.035) and urinary tract infection (p-0.017) were prominent, but in late rejection, hematuria (p-0.032), diabetes (p-0.005), and creatinine level changes (p < 0.001) were significant along with urinary tract infection (p-0.047). Conclusions: This study provides valuable insights into monitoring latent CMV infections and highlights the understanding of reducing renal rejection rates and the need for further research in this field.

Pathology of explanted pediatric hearts: An 11-year study. Population characteristics and implications for outcomes.

As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia.

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90d), and 47.5% late rejection (>90d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

(1163) - Late Antibody Mediated Rejection (AMR) Treatment: A Work in Progress!

(1163) - Late Antibody Mediated Rejection (AMR) Treatment: A Work in Progress!

Serum IL-6 predicts risk of kidney transplant failure independently of immunological risk

Interleukin-6 (IL-6) is an important immune mediator and a target for novel antibody therapies. In this study, we aimed to determine whether serum IL-6 levels are associated with immunological risk, allograft rejection and outcomes in kidney transplant (Ktx) patients. We retrospectively analyzed the data of 104 patients who underwent Ktx at our center between 2011 and 2015. The patients were divided into high- and low-risk groups (n = 52 per group) based on panel reactive antibody (PRA) percentage ≥ 35%, the existence of pre-Ktx donor-specific antibodies (DSA), or a previous transplant. IL-6 concentrations were measured before and at 3 months, 12 months, and 3 years after Ktx. Serum IL-6 levels tended to be higher in high-risk patients than in low-risk patients prior to Ktx and at 12 months after Ktx; however, the difference did not reach statistical significance (pre-Ktx, high-risk: 1.995 ± 2.79 pg/ml vs. low-risk: 1.43 ± 1.76 pg/ml, p = 0.051; 12 mo. high-risk: 1.16 ± 1.87 pg/ml vs. low-risk: 0.78 ± 1.13 pg/ml, p = 0.067). IL-6 levels were correlated with the types (no rejection, T cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), or both) and time (<1 year vs. >1 year after Ktx) of rejection, as well as patient and graft survival. Patients with both TCMR and ABMR had significantly higher IL-6 levels at 3 months (14.1 ± 25.2 pg/ml) than patients with ABMR (3.4 ± 4.8 pg/ml, p = 0.017), with TCMR (1.7 ± 1.3 pg/ml, p < 0.001), and without rejection (1.7 ± 1.4 pg/ml, p < 0.001). Three years after Ktx, patients with AMBR had significantly higher IL-6 levels (5.30 ± 7.66 pg/ml) than patients with TCMR (1.81 ± 1.61 pg/ml, p = 0.009) and patients without rejection (1.19 ± 0.95 pg/ml; p = 0.001). Moreover, three years after Ktx IL-6 levels were significantly higher in patients with late rejections (3.5 ± 5.4 pg/ml) than those without rejections (1.2 ± 1.0 pg/ml) (p = 0.006). The risk of death-censored graft failure was significantly increased in patients with elevated IL-6 levels at 12 months (IL-6 level > 1.396 pg/ml, HR 4.61, p = 0.007) and 3 years (IL-6 level > 1.976 pg/ml, HR 6.75, p = 0.003), but elevated IL-6 levels were not associated with a higher risk of death. Overall, our study highlights IL-6 as a risk factor for allograft failure and confirms that IL-6 levels are higher in patients developing ABMR compared to TCMR alone or no rejection.

Medication adherence in kidney transplant recipients: A cross-sectional study from a nursing clinical practice perspective

Medication non-adherence is implicated as one of the major causes of early and late kidney transplant rejection. The present study aimed to evaluate medication adherence in kidney transplant recipients. The study design was cross-sectional and descriptive. The sample was 144 kidney transplant patients, and sampling was by convenience. The researchers collected data using a three-part questionnaire, including demographic characteristics, clinical features, and simplified medication adherence questionnaire (SMAQ). Findings suggest that medication adherence in participants was at the desired level (94.4%; 95% CI: 89.8-97.3; P&lt;0.001) and the number of hospitalizations was a predictor of medication adherence in kidney transplant recipients (95% CI: 0.236-1.009; OR:0.488; P=0.053). The mean serum levels of Tacrolimus, Sirolimus, Cyclosporine, and Everolimus in kidney transplant recipients were 8.22 (SD=4.75), 59.66 (SD=82.71), 138.25 (SD=74.99), and 5.7, respectively. Glomerular filtration rate and serum levels of Tacrolimus and Cyclosporine were higher in patients with appropriate medication adherence than those with poor medication adherence (P&gt;0.05). With the increasing number of hospitalizations, medication adherence in these patients decreased. Overall, the medication adherence in kidney transplant recipients at the Kidney Transplantation Referral Center was at the desired level. Therefore, medicating related training programs are a promising approach to improve the quality of life in kidney transplant recipients and potentially reduce the incidence of transplant rejections among kidney transplant patients.

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.

Emphasizing long-term isoagglutinin monitoring after ABO-incompatible kidney transplant: lessons from a case series on late antibody-mediated rejection

Emphasizing long-term isoagglutinin monitoring after ABO-incompatible kidney transplant: lessons from a case series on late antibody-mediated rejection

Clinical significance of late onset antibody-mediated rejection without donor-specific anti-human leukocyte antigen antibodies in kidney transplantation

Clinical significance of late onset antibody-mediated rejection without donor-specific anti-human leukocyte antigen antibodies in kidney transplantation

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, &amp;lt;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&amp;lt;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&amp;lt;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.

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?

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.

Racial and socioeconomic disparities in pediatric heart transplant outcomes in the era of anti-thymocyte globulin induction.

Black race is associated with worse outcomes across solid organ transplantation. Augmenting immunosuppression through antithymocyte globulin (ATG) induction may mitigate organ rejection and graft loss. We investigated whether racial and socioeconomic outcome disparities persist in children receiving ATG induction. Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children who underwent heart transplant with ATG induction between 2000 and 2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant). We explored the association of these outcomes with race and socioeconomic disparity, assessed using a neighborhood deprivation index [NDI] score at 1-year post-transplant (high NDI score implies more socioeconomic disadvantage). The study cohort included 1,719 ATG-induced pediatric heart transplant recipients (22% Black, 78% White). There was no difference in first year treated rejection (Black 24.5%, White 28.1%, p=0.2). During 10 year follow up, the risk of treated rejection was similar; however, Black recipients were at higher risk of HC rejection (p=0.009) and graft loss (p=0.02). Black recipients had a higher mean NDI score (p < 0.001). Graft loss conditional on 1-year survival was associated with high NDI score in both White and Black recipients (p < 0.0001). In a multivariable Cox model, both high NDI score (HR 1.97, 95% CI 1.23-3.17) and Black race (HR 2.22, 95% CI 1.40-3.53) were associated with graft loss. Black race and socioeconomic disadvantage remain associated with late HC rejection and graft loss in children with ATG induction. These disparities represent important opportunities to improve long term transplant outcomes.