Donor-recipient Pairs Research Articles

Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.

After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.

Propensity Score-matched Donor and Recipient Outcomes: Robotic Versus Laparoscopic Donor Right Hepatectomy.

Few studies have examined the long-term outcomes of recipients in minimally invasive donor hepatectomies, particularly comparing robotic and laparoscopic donor procedures. Understanding these outcomes is crucial for optimizing surgical approaches and improving the overall success of living donor liver transplantation. This study aimed to compare the feasibility and safety of robotic donor right hepatectomy (RDRH) and laparoscopic donor right hepatectomy (LDRH) by evaluating total follow-up patient outcomes. This retrospective, single-center study included 117 and 118 donors who underwent RDRH and LDRH between March 2016 and June 2023, respectively. After performing 1:1 propensity score matching, 71 donor-recipient pairs were included in each group. Donor and recipient complications were divided into early (within 90 d) and late (after 90 d) biliary and vascular complications. In the matched cohort, major complication rates of donors were similar in both groups. Bile duct (BD) variation was not significantly different; however, the rates of multiple BD openings (26.8% versus 54.9%; P = 0.001) and major biliary complications in recipients were higher in the LDRH group (22.5% versus 42.3%; P = 0.012). The cumulative biliary complication rate was significantly higher in the LDRH group. Early biliary complications were not significantly different; however, the rate of late biliary complications was higher in the LDRH group (11.3 versus 23.9%; P = 0.047). RDRH demonstrated comparable postoperative complications to LDRH in donors but showed fewer recipient biliary complications. This could be attributed to the precision of robotic dissection and BD division, resulting in fewer multiple BD openings.

Resolving Ambiguities in Deceased Donor HLA Typing: Next Generation Sequencing’s Role in DPB1 Allele Discrimination and Immunological Implications

Abstract HLA typing is crucial for assessing immunological compatibility between donors and recipients before transplantation. Deceased donor (DD) typing, typically via real-time PCR (rtPCR), provides rapid results vital for organ allocation. rtPCR primarily targets exons encoding the highly polymorphic peptide binding region (PBR) of HLA molecules. rtPCR cannot target all polymorphic sequences. Consequently, several possibilities of allele combinations are provided, leading to ambiguous typing results. As recent evidence suggests antibody responses can target regions in exons outside the PBR, notably in Exon 3 of the DPB1 locus, typing ambiguities can lead to the inability to assess histocompatibility between a donor and recipient. Herein, the aim was to investigate the utility of Next Generation Sequencing (NGS) in resolving DPB1 ambiguities in DD typing. A retrospective analysis of DD typing from February 2022 to January 2024 examined instances where NGS was used to resolve ambiguities reported via rtPCR. Each case was reviewed to understand the reason for resorting to NGS typing. The study focused on DPB1 ambiguities and assessed whether NGS effectively reduced ambiguity and differentiated alleles with polymorphisms outside the PBR. In total, 29 DD cases were found to have NGS testing results. In 14 cases, NGS was specifically performed to resolve DPB1 ambiguities. The ambiguities were significantly reduced from hundreds detected in rtPCR to 4 or fewer possible allele combinations with NGS. Eleven cases demonstrated polymorphism in exons outside the PBRs. Of these, only 2 cases showed no typing ambiguity with NGS. In the remaining 9 cases, though polymorphisms could be resolved in the PBR, ambiguities remained in exon 3, specifically at codon 96. In these cases, NGS could not distinguish lysine (K) from arginine (R). For example, DPB1*835:01 with the 96R motif could not be distinguished from DPB1*34:01with the 96K motif. The current investigation found that NGS cannot resolve all ambiguities at position 96, likely due, at least in part, to persistent cis-trans ambiguities. Our results suggest that although NGS drastically limited the number of ambiguities in 9 of 11 cases, it still could not adequately distinguish all immunologically relevant alleles. Inability to resolve the 96R/K epitope, which has been shown to be immunogenic, could impact solid organ transplantation, potentially leading to rejection in mismatched recipient-donor pairs at this position. Sequencing methods that generate longer reads, such as nanopore, may help resolve some of these cases if they are indeed due to cis-trans ambiguities.

Identification of feline erythrocyte antigen 6 and lack of alloimmunization to feline erythrocyte antigen 4 in cats.

New feline erythrocyte antigens (FEAs) have been described based on the presence of naturally occurring alloantibodies (NOAb), but their immunogenicity and clinical relevance are poorly understood. Describe the immunogenicity of FEA 4 after sensitizing FEA 4-negative cats lacking NOAb and characterize anti-FEA 4 alloantibodies produced, including their rate of appearance, agglutination titer, and immunoglobulin class. Nineteen healthy type A cats were blood typed for FEAs 1 to 5 to identify suitable donor-recipient pairs for FEA 4 sensitization. Four FEA 4-negative cats were transfused with FEA 4-positive red blood cells. Using a gel column technique, posttransfusion samples were screened daily for a week, weekly for a month, and monthly thereafter for anti-FEA 4 alloantibodies. Alloantibodies were not detected in the first 3 recipients despite repeated transfusions (1 and 3 additional transfusions for 2 and 1 recipients, respectively). In the 4th recipient, alloantibodies against its donor red blood cells were detected 21 days postsensitization. However, they were not directed against FEA 4, but rather against a novel FEA not yet described. The alloantibodies, named anti-FEA 6, remained detectable for >4 months after sensitization and were determined to be mostly immunoglobulin M based on sulfhydryl treatment. Feline erythrocyte antigen 4 does not appear to be immunogenic because repeated sensitization of 4 cats failed to produce detectable anti-FEA 4 alloantibodies. A new immunogenic antigen, named FEA 6, has been discovered, but additional studies are needed to document its clinical importance.

Living donors kidney transplantation and oxidative stress: Nitric oxide as a predictive marker of graft function.

Glomerular filtration rate is the best indicator of renal function and a predictor of graft and patient survival after kidney transplantation. In a single-centre prospective analysis, we assessed the predictive performances of 4 oxidative stress biomarkers in estimating graft function at 6 months and 1 year after kidney transplantation from living donors. Blood samples were achieved on days (D-1, D1, D2, D3, D6 and D8), months (M1, M3 and M6) and after one year (1Y). For donors, a blood sample was collected on D-1. Malondialdehyde (MDA), nitric oxide (NO), glutathione s-transferase (GST), myeloperoxydase (MPO), and creatinine (Cr) were measured by spectrophotometric essays. The estimated glomerular filtration rate by the modification of diet in renal disease equation (MDRD-eGFR) was used to assess renal function in 32 consecutive donor-recipient pairs. Pearson's and Spearman's correlations have been applied to filter out variables and covariables that can be used to build predictive models of graft function at six months and one year. The predictive performances of NO and MPO were tested by multivariable stepwise linear regression to estimate glomerular filtration rate at six months. Three models with the highest coefficients of determination stand out, combining the two variables nitric oxide at day 6 and an MDRD-eGFR variable at day 6 or MDRD-eGFR at day 21 or MDRD-eGFR at 3 months, associated for the first two models or not for the third model with donor age as a covariable (P = 0.000, r2 = 0.599, r2adj = 0.549; P = 0.000, r2 = 0.548, r2adj = 0.497; P = 0.000, r2 = 0.553, r2adj = 0.517 respectively). Quantification of nitric oxide at day six could be useful in predicting graft function at six months in association with donor age and the estimated glomerular filtration rate in recipient at day 6, day 21 and 3 months after transplantation.

Associations Between Mental Disorders in Donors and Matched Recipients of Hematopoietic Stem Cell Transplants: A Population-Based Cohort Study

BackgroundImmunological mechanisms have been implicated in the development of mental disorders, and interestingly, case reports have suggested that hematopoietic stem cell transplantation (HSCT) can both transmit and cure psychotic disorders by replacing immune progenitor cells. MethodsUsing Danish registers, we followed patients who received HSCT from donors with a psychiatric diagnosis or psychotropic medication use. We assessed risk of incident mental disorders or psychotropic medication use compared with recipients with unaffected donors. We identified 464 donor-recipient pairs (51.3% male recipients). All donor-recipient pairs were related. ResultsReceiving HSCT from a donor with a psychiatric history was not significantly associated with incident psychiatric diagnoses (hazard rate ratio [HRR] 2.79, 95% CI, 0.83–9.39; p = .098) or incident use of psychotropics (HRR 1.43, 95% CI, 0.91–2.24; p = .118). Subgroup analysis showed an increased risk of antipsychotic use, which remained significant after adjusting for confounders (HRR 4.73, 95% CI, 1.26–17.78; p = .021); however, this was based on a small number of cases. For depression and antidepressant use, data were available to perform a meta-analysis of our and one additional study, which showed no significant difference (HRR 1.24, 95%, CI 0.66–2.35). ConclusionsReceiving HSCT from a donor with a psychiatric history did not affect risk of mental disorders. An increased risk of antipsychotic use was observed only in subgroup analyses; however, the exploratory nature of the study, the limited sample size, and family relationship between donors and recipients do not allow for causal conclusions, and external replication studies are warranted.

Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis.

Donor stem cell health may be critically important to the success of hematopoietic stem cell transplantation (HSCT). Herein, we performed this systematic review and meta-analysis including meta-regression to assess the impact of donor-engrafted clonal hematopoiesis (CH) in allogeneic HSCT (allo-HSCT) and impact of pre-transplant CH in autologous HSCT (auto-HSCT). We applied random-effects models to analyze 5 allo-HSCT studies with 3192 donor-recipient pairs and 9 auto-HSCT studies with 2854 patients. We found that donor-engrafted CH after allo-HSCT decreased the risk of disease relapse [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI): (0.67, 0.93)], but did not affect overall survival (OS) [HR = 0.91, 95% CI: (0.75, 1.11)], progression-free survival (PFS) [HR = 0.94, 95% CI: (0.63, 1.41)], or non-relapse mortality [HR = 1.06, 95% CI: (0.81, 1.39)]. In contrast, pre-transplant CH in auto-HSCT recipients resulted in inferior OS [HR = 1.30, 95% CI: (1.16, 1.46)], inferior PFS [HR = 1.35, 95% CI: (1.18, 1.54)], and higher risk for therapy-related myeloid neoplasm [HR = 4.85, 95% CI: (2.39, 9.82)] when compared to auto-HSCT recipients without CH. This study sheds light onto the debate about prospective "CHIP screening" for stem cell donors and addresses the impact of CH as a transmissible phenomenon.

When is microbial strain sharing evidence for transmission?

In humans and other social animals, social partners have more similar microbiomes than expected by chance, suggesting that social contact transfers microorganisms. However, social microbiome transmission can be difficult to identify if social partners also have other traits in common or live in a shared environment. Strain-resolved metagenomics has been proposed as a solution for tracking microbial transmission. Using a fecal microbiota transplant dataset, we show that strain sharing can recapitulate true transmission networks under ideal settings when donor-recipient pairs are unambiguous. However, gut metagenomes from a wild baboon population, where social networks predict compositional similarity, show that strain sharing is also driven by demographic and environmental factors that can override signals of social interactions. We conclude that strain-level analyses provide useful information about microbiome similarity, but other facets of study design, especially longitudinal sampling and careful consideration of host characteristics, are essential for conclusions about the underlying mechanisms.

Improved outcomes of ABO-incompatible living donor liver transplant with biologically related donors.

Liver transplantation is considered to be the only curative treatment for decompensated liver disease. Shortage of liver allografts is a major impediment to the widespread application of this procedure. ABO-incompatible (ABO-I) grafts have been used successfully, thereby increasing the living donor liver transplantation (LDLT) donor pool. However, ABO-I liver transplantation is associated with complications like acute liver rejection, hepatic artery thrombosis, and higher biliary stricture rates, leading to transplant failure, retransplantations, or sepsis-related complications. Various desensitization strategies have been adopted to improve outcomes. Biologically related donor-recipient pairs have the theoretical advantage of favorable HLA (human leukocyte antigen) match. We have analyzed the outcomes of ABO-I LDLT and compared the results of HLA-matched (biologically related) and HLA-unmatched (biologically unrelated) donor-recipient pairs. Retrospective data of 90 cases of ABO-I liver transplant recipients: HLA-matched (n = 35) and HLA-unmatched (n = 55) for comparison of preoperative and postoperative data. Peak bilirubin levels in HLA-unmatched recipients were higher. Platelet count was lower than HLA-matched recipients (7.3 vs. 8.9mg/dL). No significant difference in days-to-normal bilirubin, peak International Normalised Ratio, hospital stay, and discharge-day from transplant between both groups. Postoperatively, HLA-unmatched recipients required more pulse-steroids therapy than HLA-matched: 21/55 (38.2%) versus 11/35 (31.4%). Biliary complications and interventions were more prevalent in the HLA-unmatched group (12/55, 21.8%) than in the HLA-matched group (4/35, 11.4%). Renal complications requiring postoperative hemodialysis were more prevalent in the HLA-unmatched group than the HLA-matched group (9/55 [16.4%] vs. 3/35 [8.6%]). The incidence of vascular complications was similar. ABO-I LDLT is an effective and safe method for increasing the donor pool in the absence of an ABO-compatible liver donor. Long-term outcomes of recipients with biologically related donors are marginally better than biologically unrelated ABO-I LDLT recipients. However, the incidence of antibody-mediated graft rejection and biliary complications is higher in biologically unrelated ABO-I liver recipients.

Effects of Various Concentrations of Pronase on Flow Cytometric Crossmatching Patients Treated With Rituximab and Donor HLA-Specific Antibodies.

Pronase pretreatment can reduce rituximab (RTX) interference by degrading CD20 in B-cell flow cytometry crossmatch (FCXM) testing. However, it may also reduce the assay sensitivity by degrading HLA molecules. We investigated the effects of various pronase concentrations on RTX interference and the analytical sensitivity of B-cell FCXM testing. Using 59 patient serum samples and 38 donor lymphocyte samples, we designed 97 recipient-donor pairs and divided them into three groups according to RTX use and the presence of weak-to-moderate donor HLA-specific antibody (DSA) reactions: RTX+/DSA-, RTX+/DSA+, and RTX-/DSA+. FCXM was performed after pretreating lymphocytes with six different pronase concentrations (0, 0.5, 1, 2, 3, and 4 mg/mL). With B-FCXM testing, false-positive results due to RTX in the RTX+/DSA- group markedly decreased with increasing pronase concentrations. The median channel shift values in the RTX+/DSA+ and RTX-/DSA+ groups did not significantly decrease when the pronase concentration was increased from 1 mg/mL to 2 or 3 mg/mL. All eight RTX+/DSA+ cases that were positive at 1 mg/mL pronase but negative at 2 or 3 mg/mL had mean fluorescence intensity (MFI) DSA values of less than 3,000 except for DQ5 (MFI: 5,226). With T-cell FCXM, false-positive results were observed in 2.9% of 315 FCXM tests with pronase pretreatment. Higher concentrations (2 or 3 mg/mL) of pronase effectively eliminated RTX interference but still carried a risk for false negativity for weak DSA reactions in B-cell FCXM. Higher pronase concentrations can be used as an auxiliary method to detect moderate-to-strong DSA reactions in RTX-treated patients.

Alloreactive T cells temporarily increased in the peripheral blood of patients before liver allograft rejection.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T-cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cell samples spanning from pre-LTx to 1 year after LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial peripheral blood mononuclear cell samples were collected from 96 nonrejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors, and they were longitudinally compared to nonrejected patients. Donor-reactive T-cell clone was identified and tracked by cross-matching with the mappable donor-reactive T-cell receptor repertoire of each donor-recipient pair in 9 rejectors and 5 nonrejectors. Before transplantation, the naive T-cell percentage and T-cell receptor repertoire diversity of rejectors was comparable to that of healthy control, but it was reduced in nonrejectors. After transplantation, the naïve T-cell percentages decreased, and T-cell receptor repertoires were skewed in rejectors; the phenomenon was not observed in nonrejectors. Alloreactive clones increased in proportion in the peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T-cell decline and memory T-cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre-LTx and post-LTx peripheral blood mononuclear cell samples revealed that the pretransplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases and may facilitate disease prediction and management.

HLA Genotype Imputation Results in Largely Accurate Epitope Mismatch Risk Categorization Across Racial Groups.

Biomarkers that predict posttransplant alloimmunity could lead to improved long-term graft survival. Evaluation of the number of mismatched epitopes between donor and recipient HLA proteins, termed molecular mismatch analysis, has emerged as an approach to classify transplant recipients as having high, intermediate, or low risk of graft rejection. When high-resolution genotypes are unavailable, molecular mismatch analysis requires algorithmic assignment, or imputation, of a high-resolution genotyping. Although imputation introduces inaccuracies in molecular mismatch analyses, it is unclear whether these inaccuracies would impact the clinical risk assessment for graft rejection. Using renal transplant patients and donors from our center, we constructed cohorts of surrogate donor-recipient pairs with high-resolution and low-resolution HLA genotyping that were racially concordant or discordant. We systemically assessed the impact of imputation on molecular mismatch analysis for cohorts of 180-200 donor-recipient pairs for each of 4 major racial groups. We also evaluated the effect of imputation for a racially diverse validation cohort of 35 real-world renal transplant pairs. In the surrogate donor-recipient cohorts, imputation preserved the molecular mismatch risk category for 90.5%-99.6% of racially concordant donor-recipient pairs and 92.5%-100% of racially discordant pairs. In the validation cohort, which comprised 72% racially discordant pairs, we found that imputation preserved the molecular mismatch risk category for 97.1% of pairs. Overall, these data demonstrate that imputation preserves the molecular mismatch risk assessment in the vast majority of cases and provides evidence supporting imputation in the performance of molecular mismatch analysis for clinical assessment.

Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation

Allogeneic Tcell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor Tcells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the Tcell repertoire. We developed a Bayesian model using donor and recipient Tcell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of Tcell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ Tcell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific Tcells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic Tcell expansion and the induction of GVHD independent of donor-recipient genetics.

Robotic living donor hepatectomy is associated with superior outcomes for both the donor and the recipient compared with laparoscopic or open - A single-center prospective registry study of 3448 cases

Minimally invasive donor hepatectomy is an emerging surgical technique in living donor liver transplantation (LDLT). We examined outcomes across open, laparoscopic, and robotic LDLT using a prospective registry. We analyzed 3448 cases (1724 donor-recipient pairs) from January 2011 to March 2023 (NCT06062706). Among donors, 520 (30%) were female. Adult-to-adult LDLT comprised 1061 (62%) cases. A total of 646 (37%) of the donors underwent open, 165 (10%) laparoscopic, and 913 (53%) robotic hepatectomies. Primary outcomes: donor overall morbidity was 4% (35/903) for robotic, 8% (13/165) laparoscopic, and 16% (106/646) open (P < .001) procedures. Pediatric and adult recipient mortality was similar among the 3 donor hepatectomy approaches: robotic 1.5% and 7.0%, compared with 2.3% and 8.3% laparoscopic, and 1.6% and 5.5% for open donor surgery, respectively (P = .802, P = .564). Secondary outcomes: pediatric and adult recipients major morbidity after robotic hepatectomy was 15% and 23%, compared with 25% and 44% for laparoscopic surgery and 19% and 31% for open surgery, respectively (P = .033, P < .001). Graft and recipient 5-year survival were 90% and 93% for pediatrics and 79% and 80% for adults, respectively. In conclusion, robotic LDLT was associated with superior outcomes when compared with the laparoscopic and open approaches. Both donors and, for the first time reported, recipients benefitted from lower morbidity rates in robotic surgery, emphasizing its potential for further advancing this field.

Characterization of Perioperative Serotonin in Patients Undergoing Orthotopic Liver Transplantation.

Background: Platelets were shown to be relevant for liver regeneration. In particular, platelet-stored serotonin (5-HT) proved to be a pro-regenerative factor in this process. The present study aimed to investigate the perioperative course of 5-HT and evaluate associations with patient and graft outcomes after othotopic liver transplantation (OLT). Methods: 5-HT was quantified in plasma and serum of 44 OLT recipients perioperatively, and in their respective donors. Olthoff's criteria for early allograft dysfunction (EAD) were used to evaluate postoperative outcomes. Results: Patients with higher donor intra-platelet 5-HT per platelet (IP 5-HT PP) values had significantly lower postoperative transaminases (ASAT POD1: p = 0.006, ASAT POD5: p = 0.006, ASAT POD10: p = 0.02, ALAT POD1: p = 0.034, ALAT POD5: p = 0.017, ALAT POD10: p = 0.04). No significant differences were seen between postoperative 5-HT values and the occurrence of EAD. A tendency was measured that donor IP 5-HT PP is lower in donor-recipient pairs that developed EAD (p = 0.07). Conclusions: Donor IP 5-HT PP might be linked to the postoperative development of EAD after OLT, as higher donor levels are correlated with a more favorable postoperative course of transaminases. Further studies with larger cohorts are needed to validate these findings.

BRIDGING DIVIDES: SWAP AND DOMINO ORGAN TRANSPLANTATION ACROSS SOCIOCULTURAL AND POLITICAL FRONTIERS

Swap and domino organ transplantation represents a groundbreaking approach to address organ shortages by facilitating organ exchanges among incompatible donor-recipient pairs or utilizing organs from deceased donors to trigger multiple transplant chains. This paper explores the socio-cultural and political implications of swap and domino organ transplantation, transcending traditional boundaries and challenging existing norms in the field of organ donation and transplantation. Through a multidisciplinary lens, it examines the ethical considerations, legal frameworks, and societal attitudes surrounding swap and domino transplantation, highlighting both the opportunities and challenges inherent in this innovative approach. By fostering collaboration and cooperation across sociocultural and political divides, swap and domino transplantation offers a promising pathway to expand access to life-saving organ transplants and promote global health equity.

Donor Age More Than 20 Years Greater Than Recipient Age Is Associated With Worse 5-Year Survival in Young Adult Heart Transplantation.

Prior studies indicate donor age-recipient age (DA-RA) difference may be of prognostic value in adolescents, although not adults. We aim to analyze the relationship between DA-RA difference and long-term survival of young adult heart transplantation (HTx) recipients. First-time, single-organ HTx recipients aged 18-30 who underwent HTx between 2010 and 2020 were analyzed from the United Network for Organ Sharing (UNOS) registry. Four cohorts were created based on DA-RA difference. The primary outcome was 5 year post-HTx survival. Secondary outcome was post-HTx complications. One thousand eight hundred three donor-recipient pairs were divided into four groups: DA-RA < 0, 0 ≤ DA-RA < 10, 10 ≤ DA-RA < 20, and DA-RA ≥ 20 with 682 (37.8%), 651 (36.1%), 356 (19.7%), 114 (6.3%) pairs in each cohort, respectively. The estimated 5 year survival of the DA-RA ≥ 20 cohort was 66.5% compared to the other three groups at ~75%. After adjustment, DA-RA ≥ 20 was independently associated with worse survival compared to DA-RA < 0 (adjusted hazard ratio [HR] = 1.55; 95% confidence interval [CI] = 1.06-2.27; log-rank p = 0.008). There was no significant difference in complication incidence across cohorts. Among young adults, accepting a donor heart more than 20 years older than the recipient was associated with worse 5 year survival. We did not detect a significant difference up to 20 years. This information may help guide appropriate donor selection in the young adult population.

National Trends in Utilization of Normothermic Machine Perfusion in DCD Liver Transplantation.

In liver transplantation, advances in ex situ normothermic machine perfusion (NMP) have improved outcomes compared with traditional static cold storage (SCS) in donation after circulatory death (DCD) organs. We aimed to characterize trends in the utilization of NMP versus SCS in DCD liver transplantation in the United States. This retrospective cohort study used data from the United Network for Organ Sharing database to identify recipient-donor adult liver transplant pairs from DCD donors from January 2016 to June 2022. Utilization of NMP and changes in donor risk index (DRI) and components between NMP and SCS were assessed across transplant year eras (2016-2018, 2019-2020, and 2021-2022). Statistical comparisons were made using the Kruskal-Wallis test or the chi-square test. A total of 3937 SCS and 127 NMP DCD donor transplants were included. Utilization of NMP ranged from ~0.4% to 3.5% from 2016 to 2021 and rose significantly to 11.2% in early 2022. Across transplant eras, median DRI increased significantly for SCS and NMP, but the magnitude of the increase was larger for NMP. With NMP DCDs, there were significant increases in median donor age, national share proportion, and "cold ischemic time" over time. Finally, there was a shift toward including higher DRI donors and higher model for end-stage liver disease score transplant recipients with NMP in later transplant eras. In recent years, NMP utilization has increased and expanded to donors with higher DRI and recipients with higher model for end-stage liver disease score at transplant, suggesting increasing familiarity and risk tolerance with NMP technology. As NMP remains a relatively new technique, ongoing study of patient outcomes, organ allocation practices, and utilization patterns is critical.

Donor KIR genotype based outcome prediction after allogeneic stem cell transplantation: no land in sight.

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.

Umbilical Cord Blood Transplantation for Fanconi Anemia With a Special Focus on Late Complications: a Study on Behalf of Eurocord and SAAWP-EBMT

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.