Graft Failure In Transplantation Research Articles

Deficits in Pre- and Post-Transplant Functional Status, Motor Ability, Cognition, and Academic Capacity is Associated with Graft Failure in Pediatric Liver Transplantation

Deficits in Pre- and Post-Transplant Functional Status, Motor Ability, Cognition, and Academic Capacity is Associated with Graft Failure in Pediatric Liver Transplantation

Corneal Graft Rejection: Is it Reflected in Peripheral Immune Cells? Results of a Prospective Multicenter Study (VISICORT).

Allogeneic graft rejection is the leading cause of graft failure in corneal transplantation (CT) despite the immune privilege of the anterior chamber and corneal bed. The ability to identify patients at higher risk of acute rejection before or after CT could have a major impact on the clinical management of these patients. To address this important issue, a multicenter European cohort of low-risk (n = 142) and high-risk (n = 102) CT recipients was established, and the immune system was evaluated in detail in peripheral blood mononuclear cells and plasma before and 6 and 12 mo posttransplantation. Eleven patients in the low-risk group and 11 in the high-risk group experienced acute rejection. Mass spectrometry analysis of plasma showed a high similarity in composition between patients with and without acute rejection, regardless of their preexisting clinical risk. Pretransplant and longitudinal immune cell analysis of peripheral blood mononuclear cells using deconvolution of transcriptomic profiling and high-dimensional flow cytometry revealed a lack of immune-related biomarkers associated with acute rejection. Our results indicate that the immune response leading to acute rejection of CT is unlikely to be detected in the peripheral blood and suggest that analysis of compartments in close proximity to the cornea is more likely to yield clinically applicable predictive biomarkers.

Drowned Kidney and Liver Donors Demonstrate No Difference in Mortality and Graft Failure Compared With the 4 Most Common Extrinsic Causes of Donor Deaths.

The risks of mortality and graft failure in those receiving organ transplants from donors who have drowned are unclear. We compared 5-year mortality and graft survival from those receiving a drowned donor kidney or liver to those receiving organs from alternative causes of nondrowning donor death. In this retrospective analysis, we searched the United Network for Organ Sharing database between January 1, 2010, and June 30, 2022. Pediatric donors and recipients and multiple-organ transplants were excluded. Subjects were sorted into causes of death by drowning, gunshot, drug intoxication, aspiration, and blunt injury. We used analysis of variance tests for continuous variables and chi-square or Fischer exact tests for categorical variables, depending on sample size and distribution of the variables included. Survival curves and estimates for the outcomes were obtained with the Kaplan-Meier product limit method. In survival analyses of transplant outcomes, death (for recipient survival) or graft failure (for graft survival) were the endpoints. We used multivariable Cox regression to adjust for covariates. No significant differences were shown in graft failure (P = .584, P = .990, P = .878, P = .816) or mortality rates (P = .374, P = .297, P = .217, P = .210) up to 5 years after transplant for recipients of kidneys from drowned donors. The same comparisons among recipients of livers from drowned donors yielded no significant difference in graftfailure (P = .991, P = .376, P = .639, P = .937) or mortality (P = .970, P = .863, P = .966, P = .899). Transplant institutions should consider including drowned donors in their expanded criteria as we found no significant difference in graftfailure or mortality in both kidney and liver recipients.

Incidence and risk factors of graft failure in allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis in a nationwide pediatric cohort. A study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

Mucopolysaccharidosis (MPS) requires urgent treatment to prevent neurological damage. While gene therapy holds promise for effectively treating these diseases with minimal toxicity, access remains limited for most patients. Consequently, advancing allogeneic hematopoietic stem cell transplantation (HSCT) for young children is crucial. Since the 2010s, cord blood (CB) transplants with reduced-toxicity conditioning (RTC) have become the standard of care. Recent reports in France indicate a significant incidence of graft failures (GF), prompting a large-scale retrospective study from the French-speaking bone marrow transplantation society's registry, to understand GF risks, guide clinicians in selecting transplant platforms, and describe outcomes of second HSCT in young patients. This report analyses 93 children who underwent HSCT for MPS between 2000 and 2020. The GF rate was notably high (22.6% at day 100), primarily associated with the donor's HLA compatibility and the recipient's age. Well-matched CB and RTC were not found to be risk factors for GF. This study also details the procedures for second and third transplants in patients who rejected their first HSCT. In the era of RTC, CB remains a viable and expedient option for MPS transplantation.

The Impact of Perioperative Bilirubin and Albumin Levels on Postoperative Early Complications in Adult Liver Transplantation.

Postoperative complications persist as a significant cause of graft failure in liver transplantation. Identifying circulatory markers that predict such complications holds excellent clinical value. This study aimed to investigate serological indicators that can indicate early complications in adult liver transplantation. This study included 436 patients who underwent liver transplantation at our hospital, along with corresponding monitoring protocols. The differences and interactions of circulating indicators at various time points were analyzed using repeated measures analysis of variance. Post-hoc multiple comparisons were adjusted using the Bonferroni method. Restricted cubic spline regression models assessed non-linear associations between circulating markers, complications, and mortality. This study demonstrated significant time effects for all related markers, with substantial differences in complications and mortality for direct bilirubin and albumin. The restricted cubic spline model revealed a significant positive association between direct bilirubin and complications across three postoperative phases (p postoperative phase 1 = 0.0011, p postoperative phase 2 = 0.0001, p postoperative phase 3 = 0.0020). Conversely, albumin showed a significant negative association with complications in phases 1 and 2 (p postoperative phase 1 = 0.0001, p postoperative phase 2 = 0.0009). Furthermore, direct bilirubin was significant associated with increased mortality of postoperative phase 2 and phase 3 (p postoperative phase 2 < 0.0001, p postoperative phase 3 < 0.0001), while albumin showed a significant negative association with mortality (p postoperative phase 1 = 0.0306). Direct bilirubin and albumin are potential critical factors affecting early complications after liver transplantation. Close monitoring of these markers within 24-72 postoperative hours may help predict the occurrence of complications.

Marginal zone B cells are required for optimal humoral responses to allograft

Antibody-mediated rejection (AMR) is among the leading causes of graft failure in solid organ transplantation. However, AMR treatment options are limited by an incomplete understanding of the mechanisms underlying de novo donor-specific antibody (DSA) generation. The development of pathogenic isotype-switched DSA in response to transplanted allografts is typically attributed to follicular B cells undergoing germinal center reaction whereas the contribution of other B cell subsets has not been previously addressed. The current study investigated the role of recipient marginal zone B cells (MZ B cells) in DSA responses using mouse models of heart and renal allotransplantation. MZ B cells rapidly differentiate into antibody-secreting cells in response to allotransplantation. Despite the selective depletion of follicular B cells in heart allograft recipients, MZ B cells are sufficient for T-dependent IgM and early IgG DSA production. Furthermore, the presence of intact MZ B cell subset is required to support the generation of pathogenic isotype-switched DSA in renal allograft recipients containing donor-reactive memory helper T cells. These findings are the first demonstration of the role of MZ B cells in humoral alloimmune responses following solid organ transplantation and identify MZ B cells as a potential therapeutic target for minimizing de novo DSA production and AMR in transplant recipients.

Association of UGT1A Gene Polymorphisms with BKV Infection in Renal Transplantation Recipients.

BK virus (BKV) infection is an opportunistic infectious complication and constitutes a risk factor for premature graft failure in kidney transplantation. Our research aimed to identify associations and assess the impact of single-nucleotide polymorphisms (SNPs) on metabolism-related genes in patients who have undergone kidney transplantation with BKV infection. The DNA samples of 200 eligible kidney transplant recipients from our center, meeting the inclusion criteria, have been collected and extracted. Next-generation sequencing was used to genotype SNPs on metabolism-associated genes (CYP3A4/5/7, UGT1A4/7/8/9, UGT2B7). A general linear model (GLM) was used to identify and eliminate confounding factors that may influence the outcome events. Multiple inheritance models and haplotype analyses were utilized to identify variation loci associated with infection caused by BKV and ascertain haplotypes, respectively. A total of 141 SNPs located on metabolism-related genes were identified. After Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) analysis, 21 tagger SNPs were selected for further association analysis. Based on GLM results, no confounding factor was significant in predicting the incidence of BK polyomavirus-associated infection. Then, multiple inheritance model analyses revealed that the risk of BKV infection was significantly associated with rs3732218 and rs4556969. Finally, we detect significant associations between haplotype T-A-C of block 2 (rs4556969, rs3732218, rs12468274) and infection caused by BKV (P = 0.0004). We found that genetic variants in the UGT1A gene confer BKV infection susceptibility after kidney transplantation.

Neutrophil antigen antibodies affect engraftment and secondary graft failure in hematopoietic progenitor cell transplantation.

Research is limited on the role of antibodies against human neutrophil antigen (HNA) in hematopoietic progenitor cell (HPC) transplantation outcomes. A retrospective review was conducted on medical records of patients at the NIH Clinical Center enrolled in six research protocols. This case-control study included 21 patients tested for HNA antibodies from January 2010 to March 2022 who underwent HPC transplantation. In addition, 42 patients following the same research protocols were randomly selected as a control group. The cumulative incidence of time to neutrophil engraftment was significantly impacted by the patients' anti-HNA status (p = .042), with the patients with anti-HNA experiencing delayed engraftment. Secondary graft failure occurred in 4 out of 42 patients (9.52%; 95% confidence interval [CI]: 3.7-22.1) of the control group, while 5 out of 9 patients (55.5%; 95% CI: 26.7-81.1) with anti-HNA experienced secondary graft failure (p = .005). Furthermore, patients with anti-HNA had a lower proportion (p = .008 for full and p = .002 for partial chimerism) and cumulative incidence (p = .016 for full and p = .010 for partial chimerism) of achieving donor chimerism compared to the control group. The study reveals a potential link between anti-HNA and HPC transplantation outcomes not previously reported. Patients with anti-HNA had a lower proportion and cumulative incidence of achieving donor chimerism. Additionally, anti-HNA status affected the time for neutrophil engraftment, with a slower rate of neutrophil engraftment and increased risk of secondary failure in patients with anti-HNA.

Multi-omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation.

To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n=68) and validation (n=89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocytenuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.

Better kidney allograft survival despite higher-risk donor and recipient characteristics between 1995 and 2014.

Advances in organ procurement, surgical techniques, immunosuppression regimens, and prophylactic antibiotic therapies have dramatically improved kidney transplant graft failure. It is unclear how these interventions have affected longer-term graft failure. It is hypothesized that graft failure has improved over the last 20 years. Data on all first kidney transplants from 1995 to 2014 were extracted from the Australia and New Zealand Dialysis and Transplant Registry with follow-up as of 31 December 2021. Primary exposure was transplant era, classified into 5-year intervals. Primary outcome was all-cause 5-year graft failure. Secondary outcomes included all-cause 10-year graft failure and cause-specific graft failure. Kaplan-Meier curves and multivariable Cox proportional hazards regression models were used to assess trends in all-cause graft failure. Fine-Gray subdistribution hazard models verified that changes in death rates were not biasing the Cox proportional hazards regression models. Cumulative incidence functions were used to assess temporal trends in cause-specific graft failure. Across 10871 kidney transplants, there was a shift towards transplanting more recipients aged >45 years old, with more comorbidities, longer dialysis vintage, body mass index >30kg/m2, and greater human leukocyte antigen mismatches. Donor age has increased but no clear shift in donor source was observed. Compared to 1995-99 (reference), the adjusted hazard ratio for 5-year graft failure was 0.78 (95% CI 0.67-0.91), 0.70 (95% CI 0.59-0.83), and 0.60 (95% CI 0.50-0.73) for 2000-04, 2005-09, and 2010-14, respectively. Ten-year graft failure similarly reduced from 0.83 (95% CI 0.74-0.93) for 2000-04 to 0.78 (95% CI 0.68-0.89) for 2010-14, compared to 1995-99. Medium- and long-term all-cause graft failure has improved steadily since 1995-99. Significant reductions in graft failure due to rejection and vascular causes were observed at 5 years, and due to rejection, vascular causes, death, and glomerular disease at 10 years.

(619) - De Novo Donor Specific Antibodies is Associated with Death from Graft Failure in Lung Transplantation

(619) - De Novo Donor Specific Antibodies is Associated with Death from Graft Failure in Lung Transplantation

Ensemble Clustering to Generate Phenotypes of Kidney Transplant Donors and Recipients.

In this paper we investigate the generation of phenotypes for kidney transplant donors and recipients to assist with decision making around organ allocation. We present an ensemble clustering approach for multi-type data (numerical and categorical) using two different clustering approaches-i.e., model based and vector quantization based clustering. These clustering approaches were applied to a large, US national deceased donor kidney transplant recipient database to characterize members of each cluster (in an unsupervised fashion) and to determine whether the subsequent risk of graft failure differed for each cluster. We generated three distinct clusters of recipients, which were subsequently used to generate phenotypes. Each cluster phenotype had recipients with varying clinical features, and the risk of kidney transplant graft failure and mortality differed across clusters. Importantly, the clustering results by both approaches demonstrated a significant overlap. Utilization of two distinct clustering approaches may be a novel way to validate unsupervised clustering techniques and clustering can be used for organ allocation decision making on the basis of differential outcomes.

Time-Varying Determinants of Graft Failure in Pediatric Kidney Transplantation in Europe.

Little is known about the time-varying determinants of kidney graft failure in children. We performed a retrospective study of primary pediatric kidney transplant recipients (younger than 18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor, and transplant risk factors. Primary outcome was death-censored graft failure. We report on 4528 kidney transplantations, of which 68% with deceased and 32% with living donor. One thousand six hundred and thirty-eight recipients experienced graft failure, and 168 died with a functioning graft. Between 2011 and 2020, the 5-year graft failure risk was 10% for deceased donor and 4% for living donor kidney transplant recipients. Risk of graft failure decreased five-fold from 1990 to 2020. The association between living donor transplantation and the lower risk of graft failure was strongest in the first month post-transplant (adjusted hazard ratio, 0.58; 95% confidence interval, 0.46 to 0.73) and remained statistically significant until 12 years post-transplant. Risk factors for graft failure in the first 2 years were deceased donor younger than 12 years or older than 46 years, potentially recurrent kidney disease, and panel-reactive antibody >0%. Other determinants of graft failure included dialysis before transplantation (until 5 years post-transplant), human leukocyte antigen mismatch 2-4 (0-15 years post-transplant), human leukocyte antigen mismatch 5-6 (2-12 years post-transplant), and hemodialysis (8-14 years post-transplant). Recipients older than 11 years at transplantation had a higher risk of graft failure 1-8 years post-transplant compared with other age groups, whereas young recipients had a lower risk throughout follow-up. Analysis of the combined effect of post-transplant time and recipient age showed a higher rate of graft failure during the first 5 years post-transplant in adolescents compared with young transplant recipients. In contrast to deceased donor younger than 12 years, deceased donor older than 46 years was consistently associated with a higher graft failure risk. We report a long-term inverse association between living donor kidney transplantation and the risk of graft failure. The determinants of graft failure varied with time. There was a significant cumulative effect of adolescence and time post-transplant. The ideal donor age window was dependent on time post-transplant.

Donor-Derived Cell-Free DNA at 1 Month after Kidney Transplantation Relates to HLA Class II Eplet Mismatch Load.

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.

P.41: Modification of venous outflow to avoid thrombotic graft failure in pancreas transplantation

P.41: Modification of venous outflow to avoid thrombotic graft failure in pancreas transplantation

Research Highlights.

Research Highlights.

Errate: Modification of Venous Outflow to Avoid Thrombotic Graft Failure in Pancreas Transplantation.

The authors asked for an errata to correct the affiliation information. The corrected affiliations are as follows:Je Ho Ryu1,2, Jae Ryong Shim1, Tae Beom Lee1, Kwang Ho Yang1, Taeun Kim3, Seo Rin Kim4, Byung Hyun Choi1,21 Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, South Korea2 Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea3 Department of Radiology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, South Korea4 Department of Internal medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, South KoreaThe change of affiliation does not affect the content or findings of the publication in any way. It is solely an update to the -authors' institutional affiliations.Reference:Je Ho Ryu, Jae Ryong Shim, Tae Beom Lee, Kwangho Yang, Taeun Kim, Seo Rin Kim, Byunghyun Choi. Modification of Venous Outflow to Avoid Thrombotic Graft Failure in Pancreas Transplantation. Ann Transplant. 2022; 27: e937514. DOI: 10.12659/AOT.937514.

561 - Incidence and Outcome of Secondary Graft Failure in Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Single Center Study

561 - Incidence and Outcome of Secondary Graft Failure in Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Single Center Study

Low socio-economic status is associated with increased graft failure in liver transplantation

Background: Low socio-economic status (SES) has been shown to be associated with inferior liver graft outcomes. We aimed to characterize SES and liver graft survival in our Institution.

Predicting graft failure in pediatric liver transplantation based on early biomarkers using machine learning models

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged < 12 years at the Severance Hospital between January 2010 and September 2020 were included as data samples. Preoperative conditions of recipients and donors, intraoperative care, postoperative serial laboratory parameters, and events observed within seven days of surgery were collected as features. A least absolute shrinkage and selection operator (LASSO) -based method was used for feature selection to overcome the high dimensionality and collinearity of variables. Among 146 features, four variables were selected as the resultant features, namely, preoperative hepatic encephalopathy, sodium level at the end of surgery, hepatic artery thrombosis, and total bilirubin level on postoperative day 7. These features were selected from different times and represent distinct clinical aspects. The model with logistic regression demonstrated the best prediction performance among various machine learning methods tested (area under the receiver operating characteristic curve (AUROC) = 0.898 and area under the precision–recall curve (AUPR) = 0.882). The risk scoring system developed based on the logistic regression model showed an AUROC of 0.910 and an AUPR of 0.830. Together, the prediction of graft failure in pediatric liver transplantation using the proposed machine learning model exhibited superior discrimination power and, therefore, can provide valuable information to clinicians for their decision making during the postoperative management of the patients.