Clinical Factors Associated With Failed Weaning From Intraoperative Extracorporeal Membrane Oxygenation Used During Lung Transplantation

Background: Extracorporeal membrane oxygenation (ECMO) promotes adequate oxygenation and hemodynamic stability during lung transplantation (LTx). However, some recipients cannot be weaned from ECMO following surgery. Thus, we evaluated the prognosis and risk factors of failed weaning from intraoperative ECMO during LTx.Methods: We retrospectively analyzed data from 274 patients receiving intraoperative ECMO during LTx. Risk factors were evaluated using logistic regression analyses.Results: Weaning failure occurred in 118 patients (43.1%). Intensive care unit stay was longer and mortality was higher in the failed weaning group than in the successful weaning group. The failed weaning group exhibited significantly older donor age, lower donor PaO2/FiO2 ratio, greater intraoperative transfusion volume, and longer operation time than the successful weaning group. Recipient age, body mass index, donor age, lower donor PaO2/FiO2 ratio, donor/recipient total lung capacity (TLC) ratio, greater intraoperative transfusion volume, and longer operation time were associated with weaning failure after adjustment. Conclusion: The failed weaning group showed a poor prognosis. Perioperative factors including donor age, donor PaO2/FiO2 ratio, donor/recipient TLC, operation time, and blood loss can predict postoperative ECMO weaning failure.

Kidney Function Decline Prediction and Risk Factor Analysis After Kidney Transplantation: Machine Learning and Network Analysis on Nationwide Cohort Data (Preprint)

BACKGROUND Early identification of graft loss risk and timely therapeutic intervention are crucial for preventing late renal allograft failure and improving long-term graft function. The one-year estimated glomerular filtration rate (eGFR) is the best predictor of long-term graft function in kidney transplant recipients; there is an increased risk of late graft failure in recipients with low one-year eGFR. OBJECTIVE To create a sparse model capable of predicting the one-year renal allograft dysfunction and to build a factor network suggesting risk control targets. METHODS Development data were constructed using the Korean Organ Transplant Registry (KOTRY), a national cohort data of 4317 recipients who underwent kidney transplantation between 2014 and 2019. The XGBoost algorithm was trained to predict the model outcome with 112 features, and the relevant factors were selected. The statistical significance of factors was calculated using multiple logistic regression for the development data. A factor correlation network was drawn and simplified by excluding spurious connections with LASSO (least absolute shrinkage and selection operator) regularization with EBIC (extended bayesian information criterium) model selection. The model outcome was one-year eGFR < 45 mL/min/1.73 m2, and model performance was measured using AUC, sensitivity, and specificity. A SHAP value plot was used to determine the feature importance of the model. The clinical importance of the model outcome was assessed using long-term graft survival and rejection-free survival. The factor network was built using inter-factor partial correlations and the statistical significance of each factor. RESULTS The model achieved an AUC of 0.82, a sensitivity of 0.8, and a specificity of 0.8 using seven pre- or peri-transplantation factors. Three pre-transplantation factors (donor age, recipient age, recipient-donor height difference) and four peri-transplantation factors (low eGFR at discharge, high eGFR at discharge, serum creatinine at discharge, post-transplantation stay) were chosen by the model. Model prediction was significantly associated with a five-year survival of graft and rejection-free survival (P = .02 and P = .007). Post-transplantation stay and discharge eGFR ≥ 88.0 were the most prominent risk and preventive nodes on the network, respectively. Donor age and discharge eGFR < 59.8 had a high impact on model prediction and could be effective risk control targets for their multiple connections to other risk nodes. CONCLUSIONS One-year renal allograft dysfunction could be predicted early after transplantation. The long-term outcomes of kidney transplantation might be improved by preemptive measures on donor age, kidney function at discharge, and post-transplantation stay. INTERNATIONAL REGISTERED REPORT RR2-doi: 10.1097/TXD.0000000000000678

Cellular Resilience as a Potential Predictor of Lifespan

The progressive decline of resilience during the aging process across multiple functional systems suggests basic biological mechanisms of regulation. We exploited a primary cell model to identify markers of cellular resilience or the ability of cells in culture to respond and return to homeostasis following acute challenge including metabolic, oxidative, or proteostatic stress. Using primary fibroblasts from minimally-invasive skin biopsies of genetically heterogeneous mice, we are able to determine individual cellular resilience as well as the normal lifespan and healthspan of each donor. Our studies suggest donor age and sex affect cellular resilience and that this measure of resilience can predict functional outcomes in some interventional studies. While longevity studies continue, these studies point to a potential highly important marker of healthspan and longevity as well as a model to delineate the biology of resilience in animal and translational models.

Clinical factors associated with severe hypophosphataemia after kidney transplant

Background The mechanism by which hypophosphataemia develops following kidney transplantation remains debated, and limited research is available regarding risk factors. This study aimed to assess the association between recipient and donor variables, and the severity of post-transplantation hypophosphataemia. Methods We performed a single-centre retrospective observational study. We assessed the association between demographic, clinical and biochemical variables and the development of hypophosphataemia. We used linear regression analysis to assess association between these variables and phosphate nadir. Results 87.6% of patients developed hypophosphataemia. Patients developing hypophosphataemia were younger, had a shorter time on renal replacement therapy, were less likely to have had a parathyroidectomy or to experience delayed graft function, were more likely to have received a living donor transplant, from a younger donor. They had higher pre-transplantation calcium levels, and lower alkaline phosphatase levels. Receipt of a living donor transplant, lower donor age, not having had a parathyroidectomy, receiving a transplant during the era of tacrolimus-based immunosuppression, not having delayed graft function, higher pre-transplantation calcium, and higher pre-transplantation phosphate were associated with lower phosphate nadir by multiple linear regression. Conclusions This analysis demonstrates an association between variables relating to better graft function and hypophosphataemia. The links with biochemical measures of mineral-bone disease remain less clear.

Donor Age and Time in Culture Affect Dermal Fibroblast Contraction in a Hydrogel Skin Graft Model

Regenerating functional skin without the formation of scar tissue remains an important goal for Tissue Engineering. Current hydrogel-based grafts minimize contraction of full-thickness skin wounds and support skin regeneration using adult or neonatal foreskin dermal fibroblasts, which are often expanded in vitro and used after multiple passages. Based on the known effects of 2D tissue culture expansion on cellular proliferation and gene expression, we hypothesized that differences in donor age and time in culture may also influence the functionality of 3D skin constructs by affecting fibroblast-mediated graft contraction. To validate these predicted differences in fibroblast phenotype and resulting 3D graft model contraction, we isolated porcine dermal fibroblasts of varying donor age for use in a 2D proliferation assay and a 3D cell-populated collagen matrix contractility assay. In 2D cell culture, doubling time remained relatively consistent between all age groups from passage 1 to 6. In the contractility assays, fetal and neonatal groups contracted faster and generated more contractile force than the adult group at passage 1. However, after 5 passages in culture, there was no difference in contractility between groups. These results show how cellular responses differ based on donor age and time in culture, which could account for important differences in biomanufacturing of 3D hydrogel-based skin grafts. Future research and therapies using bioengineered skin grafts should consider how results may vary based on donor age and time in culture before seeding.

Predictive Factors and Outcomes after Allogeneic Stem-Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Introduction: Allogeneic stem-cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not negligible toxicity. Adult patients with ALL fare worse in developing countries with low data about the HSCT in this setting. In this study, we aim to describe outcomes and examine risk factors for overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers. Methods: This is a retrospective registry study. Patients with ALL or ambiguous lineage leukemia above 16 years who underwent a first HSCT in 5 Brazilian centers between January 2007 and December 2017 were included. Kaplan-Meier method and competing risk analysis were used. Multivariable analysis (MVA) was performed using Cox regression and the Akaike's information criteria was used for model selection. Cut-offs for continuous variables were calculated through "findcut" R function. Center effect was evaluated by using frailty model. Results: Overall, 275 patients were included with a median age of 31y (range, 16-65). Philadelphia chromosome was found in 35%. Baseline characteristics are summarized in Table 1. Matched sibling donor (MSD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical donor and umbilical cord were reported in 53%, 19%, 9%, 19%, and 5%, respectively. Total body irradiation (TBI) was used in 67% of myeloablative HSCT. Median time to HSCT in CR1 was 7.8 months. Engraftment failure rate was 1.5%. Median follow-up time was 6.4 y. Cumulative incidence of acute grade II-IV and chronic GVHD were 54.2% and 26.2%, respectively. In MVA, the use of MUD (HR=2.3) and increased donor age (HR=1.02) were associated with GVHD. Five-year CIR was 28.1% (95% CI 22.9-33.6) and 5-y NRM was 34.1% (95% CI 28.4-39.8). At D+100, NRM incidence was 22.6%. Central nervous system involvement at the diagnosis (HR=2.2), and disease status (HR 1.8 for CR2+, and HR 7.9 for refractory) increased relapse incidence, whereas the use of peripheral blood graft (HR=0.51) and haploidentical donor (HR=0.4) significantly decreased relapse incidence. In MVA, NRM was increased by patient's age (HR=1.04), refractory status (HR=4.2), MUD (HR=3.8) and donor age (HR=1.02). Center effect was significantly associated with relapse and NRM. Five-year OS and DFS were 40.7% (95% CI 35.1-47.1) and 37.8% (95% CI-32.3-44.1), respectively (Figure 1). Patient's age, donor age and disease status were independently associated with OS and DFS (Table 2). When GVHD (as a time-dependent variable) was introduced in the MVA for OS and DFS, it was associated with decreased OS (HR 4.2, p&lt;0.001) but not with DFS. Pre-HSCT positivity of minimal residual disease (&gt;0.01%) was associated with worse DFS in univariate analysis (HR=1.47) in available cases. Conclusions: This is the largest series of ALL adults receiving HSCT from Brazil. While OS and DFS were similar to published data, NRM was higher. Patient's age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT related to lower CIR, whereas the use of MUD was associated with higher NRM and GVHD rates. These results impact on donor selection strategy in our country, aiming to timely offer HSCT for high-risk ALL patients in our setting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Impact of Donor Age and Relationship on Outcomes of Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

Introduction: Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly utilized therapy for a variety of hematologic malignancies. Determining which donor characteristics affect transplant outcomes is of particular interest in haplo-HCT, as there are often multiple donors available for a given patient. A survival benefit with younger donors has been reported in some recent observational studies (DeZern et. al., Blood Advances, March 2021); (Canaani et. al., AJH, Sep. 2017). A decrease in non-relapse mortality (NRM) and increase in relapse with no overall survival difference associated with younger donors has also been observed (Mariotti et. al., Blood Advances, June 2020). These previous studies have utilized populations with bone marrow as the predominant stem cell source. Solomon et al. (BBMT Sep. 2018) observed poorer survival, increased relapse, and worse NRM with parent donors relative to children in a largely peripheral blood population. HLA DR and DP mismatch were noted to be associated with improved survival. Here we describe outcomes in peripheral blood haplo-HCT and their association with potentially selectable donor characteristics including age and relationship to the patient. Patients and Methods: We performed a retrospective review of patients who underwent peripheral blood haplo-HCT with PtCy from July 2009 through May 2021. A total of 323 patients were identified with AML (205), ALL (43), MDS (26), and other (49). Univariate and multivariate analyses (MVA) were conducted examining the effect of donor characteristics on overall survival (OS), NRM, relapse, acute and chronic GVHD. Donor characteristics included age, relationship, ABO status, CMV status, and HLA match grade. We controlled for patient characteristics known to affect outcomes including disease type, DRI, HCT CI, KPS, active disease at transplant, myeloablative conditioning, and prior HCT. Results: Median donor age was 40 (range 15-71) with male predominance (64%). Most were ABO compatible (63%) - 12% had major ABO mismatch, 20% minor, and 4% bidirectional. Donor-recipient CMV status matched in 61% of pairs, 13% were donor positive-recipient negative, 26% donor negative-recipient positive. Most were 5/10 HLA matched (51%) with 20% 6/10 and 13% 7-9/10. Univariate analysis revealed that increasing donor age was associated with higher NRM (HR 2.29, p=0.005 for donors age 30-44; HR 2.06, p=0.012 age &gt; 44) but lower relapse risk (HR 0.56, p=0.012 age 30-44; HR 0.69, p=0.10 age &gt; 44). There were no differences in aGVHD or cGVHD based on donor characteristics in univariate analysis. In MVA, relapse risk was lower in patients with older donors , p=0.046). In contrast, NRM was higher in patients with older donors (HR 1.73 age 30-44, HR 1.69 age &gt; 44, p=0.010). There was no difference in overall survival based on donor age (HR 1.23 age 30-44, HR 1.38 age &gt; 44, p=0.11). We next examined the effect of donor relationship on outcomes while controlling for donor age, patient age, and patient disease risk factors. We found no difference in outcomes between parent, sibling, or child donors. Conclusions: Increasing donor age was associated with lower relapse risk but higher NRM. These competing effects resulted in no difference in OS based on donor age. Other donor factors including relationship (parent / sibling / child), CMV status, ABO mismatch, donor sex, and HLA match grade were not associated with outcomes. Solomon et al. reported better outcomes with child compared to parent donors, a finding not replicated here, however our analysis controlled for donor age which could have been a proxy for relationship in their study. These data suggest that in peripheral blood haplo-HCT, younger donors may be preferred in patients with high risk of transplant related complications. In contrast, older donors may be preferred in patients where relapse risk is high. Data on HLA-DR and DP match is being analyzed and will be presented at the ASH 2021 meeting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.