The Strategies Used to Balance Health and Work Across the Solid Organ Transplantation Trajectory.

Introduction: Workers who undergo solid organ transplantation report frequent conflicts between the unpredictable demands of their health condition and the rigid requirements of their employer and of health services. The present study aimed to describe the self-management strategies adopted by workers while staying at work before transplantation and during sustainable return-to-work posttransplantation. Methods: Fifteen employed kidney, liver, and lung transplant recipients were recruited from 2 large urban university health centers in Montreal, Canada. Three focus groups were held, and thematic analysis was performed. Findings: Seven strategies were identified: responding promptly and consistently to fatigue-related needs, planning ahead with immediate supervisors while remaining strategic about when to disclose transplantation, requesting work accommodations, requesting flexibility in healthcare provision, consulting physicians about work-related issues, informing co-workers about work limitations and immunosuppression and asking not to be treated differently in the workplace. Conclusion: Access to work accommodations, support from physicians and flexibility in treatment and appointment schedules supported workers' ability to manage their health while staying at work before and after undergoing solid organ transplantation. In light of findings, it may be useful for healthcare professionals to address workers' concerns about work limitations and work accommodation implementation, especially when the illness-management burden increases before transplantation and during posttransplantation sick leave. Future studies could describe the strategies used by other important stakeholders when attempting to provide support to workers.

Differences in excess mortality by recipient sex after heart transplant: An individual patient data meta-analysis.

BACKGROUND: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients. METHODS: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988-2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age. RESULTS: We analyzed 108,918 patients. When the donor was male, female recipients 0-12 years (Relative excess risk (RER) 1.13, 95% CI 1.00-1.26), 13-44 years (RER 1.17, 95% CI 1.10-1.25), and ≥45 years (RER 1.14, 95% CI 1.02-1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13-44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00-1.20), though not significantly (p = 0.05). CONCLUSIONS: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences.

A Multinational Cohort Study Examining Sex Differences in Excess Risk of Death With Graft Function After Kidney Transplant.

BACKGROUND: Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown. METHODS: In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age. RESULTS: Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity. CONCLUSIONS: Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss.

NephroCAGE-German-Canadian Consortium on AI for Improved Kidney Transplantation Outcome: Protocol for an Algorithm Development and Validation Study.

BACKGROUND: Recent advances in hardware and software enabled the use of artificial intelligence (AI) algorithms for analysis of complex data in a wide range of daily-life use cases. We aim to explore the benefits of applying AI to a specific use case in transplant nephrology: risk prediction for severe posttransplant events. For the first time, we combine multinational real-world transplant data, which require specific legal and technical protection measures. OBJECTIVE: The German-Canadian NephroCAGE consortium aims to develop and evaluate specific processes, software tools, and methods to (1) combine transplant data of more than 8000 cases over the past decades from leading transplant centers in Germany and Canada, (2) implement specific measures to protect sensitive transplant data, and (3) use multinational data as a foundation for developing high-quality prognostic AI models. METHODS: To protect sensitive transplant data addressing the first and second objectives, we aim to implement a decentralized NephroCAGE federated learning infrastructure upon a private blockchain. Our NephroCAGE federated learning infrastructure enables a switch of paradigms: instead of pooling sensitive data into a central database for analysis, it enables the transfer of clinical prediction models (CPMs) to clinical sites for local data analyses. Thus, sensitive transplant data reside protected in their original sites while the comparable small algorithms are exchanged instead. For our third objective, we will compare the performance of selected AI algorithms, for example, random forest and extreme gradient boosting, as foundation for CPMs to predict severe short- and long-term posttransplant risks, for example, graft failure or mortality. The CPMs will be trained on donor and recipient data from retrospective cohorts of kidney transplant patients. RESULTS: We have received initial funding for NephroCAGE in February 2021. All clinical partners have applied for and received ethics approval as of 2022. The process of exploration of clinical transplant database for variable extraction has started at all the centers in 2022. In total, 8120 patient records have been retrieved as of August 2023. The development and validation of CPMs is ongoing as of 2023. CONCLUSIONS: For the first time, we will (1) combine kidney transplant data from nephrology centers in Germany and Canada, (2) implement federated learning as a foundation to use such real-world transplant data as a basis for the training of CPMs in a privacy-preserving way, and (3) develop a learning software system to investigate population specifics, for example, to understand population heterogeneity, treatment specificities, and individual impact on selected posttransplant outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48892.

Calcineurin Inhibition in Deceased Organ Donors: A Systematic Review and Meta-analysis of Preclinical Studies.

Background: Preconditioning deceased organ donors with calcineurin inhibitors (CNIs) may reduce ischemia-reperfusion injury to improve transplant outcomes. Methods: We searched MEDLINE, EMBASE, Cochrane Library, and conference proceedings for animal models of organ donation and transplantation, comparing donor treatment with CNIs with either placebo or no intervention, and evaluating outcomes for organ transplantation. Reviewers independently screened and selected studies, abstracted data, and assessed the risk of bias and clinical relevance of included studies. Where possible, we pooled results using meta-analysis; otherwise, we summarized findings descriptively. Results: Eighteen studies used various animals and a range of CNI agents and doses and evaluated their effects on a variety of transplant outcomes. The risk of bias and clinical applicability were poorly reported. Pooled analyses suggested benefit of CNI treatment on early graft function in renal transplants (3 studies; serum creatinine: ratio of means [RoM] 0.54; 95% confidence interval [CI], 0.34-0.86) but not for liver transplants (2 studies; serum alanine transaminase: RoM 0.61; 95% CI, 0.30-1.26; and serum aspartate aminotransferase: RoM 0.58; 95% CI, 0.26-1.31). We found no reduction in graft loss at 7 d (2 studies; risk ratio 0.54; 95% CI, 0.08-3.42). CNI treatment was associated with reduced transplant recipient levels of interleukin-6 (4 studies; RoM 0.36; 95% CI, 0.19-0.70), tumor necrosis factor-alpha (5 studies; RoM 0.36; 95% CI, 0.12-1.03), and cellular apoptosis (4 studies; RoM 0.30; 95% CI, 0.19-0.47). Conclusions: Although this compendium of animal experiments suggests that donor preconditioning with CNIs may improve early kidney graft function, the limited ability to reproduce a true clinical environment in animal experiments and to assess for risk of bias in these experiments is a serious weakness that precludes current clinical application.

Predicting Time to and Average Quality of Future Offers for Kidney Transplant Candidates Declining a Current Deceased Donor Kidney Offer: A Retrospective Cohort Study.

Background: At the time a kidney offer is made by an organ donation organization (ODO), transplant physicians must inform candidates on the pros and cons of accepting or declining the offer. Although physicians have a general idea of expected wait time to kidney transplantation by blood group in their ODO, there are no tools that provide quantitative estimates based on the allocation score used and donor/candidate characteristics. This limits the shared decision-making process at the time of kidney offer as (1) the consequences of declining an offer in terms of wait-time prolongation cannot be provided and (2) the quality of the current offer cannot be compared with that of offers that could be made to the specific candidate in the future. This is especially relevant to older transplant candidates as many ODOs use some form of utility matching in their allocation score. Objective: We aimed to develop a novel method to provide personalized estimates of wait time to next offer and quality of future offers for kidney transplant candidates if they refused a current deceased donor offer from an ODO. Design: A retrospective cohort study. Setting: Administrative data from Transplant Quebec. Patients: All patients who were actively registered on the kidney transplant wait list at any point between March 29, 2012 and December 13, 2017. Measurements: The time to next offer was defined as the number of days between the time of the current offer and the next offer if the current one were declined. The quality of the offers was measured with the 10-variable Kidney Donor Risk Index (KDRI) equation. Methods: Candidate-specific kidney offer arrival was modeled with a marked Poisson process. To derive the lambda parameter for the marked Poisson process for each candidate, the arrival of donors was examined in the 2 years prior to the time of the current offer. The Transplant Quebec allocation score was calculated for each ABO-compatible offer with the characteristics that the candidate presented at the time of the current offer. Offers where the candidate's score was lower than the scores of actual recipients of the second kidneys transplanted were filtered out from the candidate-specific kidney offer arrival. The KDRIs of offers that remained were averaged to provide an estimate of the quality of future offers, to be compared with that of the current offer. Results: During the study period, there were 848 unique donors and 1696 transplant candidates actively registered. The models provide the following information: average time to next offer, time to which there is a 95% probability of receiving a next offer, average KDRI of future offers. The C-index of the model was 0.72. When compared with providing average group estimates of wait time and KDRI of future offers, the model reduced the root-mean-square error in the predicted time to next offer from 137 to 84 days and that of predicted KDRI of future offers from 0.64 to 0.55. The precision of the model's predictions was higher when observed times to next offer were 5 months or less. Limitations: The models assume that patients declining an offer remain wait-listed until the next one. The model only updates wait time every year after the time of an offer and not in a continuous fashion. Conclusion: By providing personalized quantitative estimates of time to and quality of future offers, our new approach can inform the shared decision-making process between transplant candidates and physicians when a kidney offer from a deceased donor is made by an ODO.

Contexte: Lorsqu'un organisme de don d'organes (ODO) propose un rein pour la transplantation, les médecins transplantologues se doivent d'informer les candidats des avantages et inconvénients d'accepter ou de refuser cette offre. Bien que les médecins aient une idée générale du temps d'attente à prévoir dans leur ODO pour une transplantation rénale selon le groupe sanguin, il n'existe aucun outil fournissant des estimations quantitatives fondées sur la cote d'attribution utilisée et les caractéristiques du donneur/candidat. Cela limite le processus partagé de prise de décision au moment d'une offre, car 1) les conséquences du refus relativement à la prolongation du temps d'attente ne peuvent être fournies; et 2) parce que la qualité de l'offre en cours ne peut être comparée à celle des offres qui pourraient être faites ultérieurement au même candidat. Ceci est particulièrement pertinent pour les candidats à une transplantation qui sont plus âgés, car de nombreux ODO utilisent une certaine forme de correspondance d'utilité dans leur cote d'attribution. Objectif: Nous souhaitions développer une nouvelle méthode pour fournir des estimations personnalisées du temps d'attente jusqu'à l'offre suivante et de la qualité des offres ultérieures pour les candidats à la transplantation rénale ayant refusé l'offre d'un ODO pour le rein d'un donneur décédé. Type d'étude: Étude de cohorte rétrospective. Cadre: Données administratives de Transplant Québec. Sujets: Tous les patients qui étaient activement inscrits sur la liste d'attente pour une greffe rénale à un moment donné entre le 29 mars 2012 et le 13 décembre 2017. Mesures: Le temps jusqu'à l'offre suivante a été défini comme le nombre de jours entre le moment de l'offre en cours et celui de la suivante, si la première est refusée. L'équation KDRI (Kidney Donor Risk Index) à 10 variables a servi à mesurer la qualité des offres. Méthodologie: L'arrivée d'une offre de rein spécifique à un candidat a été modélisée par un processus de Poisson marqué. L'arrivée des donneurs a été examinée pour les 2 ans précédant le moment de l'offre en cours afin de dériver le paramètre lambda du processus de Poisson marqué pour chaque candidat. La cote d'attribution de Transplant Québec a été calculée pour chaque offre compatible ABO avec les caractéristiques que le candidat présentait au moment de l'offre en cours. Les offres pour lesquelles la cote du candidat était inférieure aux cotes des receveurs réels des deuxièmes reins transplantés ont été retirées de l'arrivée des offres spécifiques à un candidat. La moyenne des valeurs KDRI des offres restantes a été calculée pour fournir une estimation de la qualité des offres futures, à comparer à celle de l'offre en cours. Résultats: Au cours de la période étudiée, 848 donneurs uniques et 1 696 candidats à la transplantation étaient inscrits activement. Les modèles fournissent les informations suivantes: le temps moyen jusqu'à l'offre suivante, délai au bout duquel il y a une probabilité de 95 % de recevoir la prochaine offre, la moyenne des valeurs KDRI des offres futures. L'indice C du modèle était de 0,72. Par rapport aux estimations moyennes du groupe en ce qui concerne le temps d'attente et la valeur KDRI des offres futures, le modèle a permis de réduire l'erreur quadratique moyenne de 137 à 84 jours pour le temps jusqu'à la prochaine offre, et de 0,64 à 0,55 pour la valeur KDRI prévue des offres futures. La précision des prédictions offertes par le modèle était plus élevée lorsque le temps jusqu'à l'offre suivante était de cinq mois ou moins. Limites: Le modèle suppose que les patients qui refusent une offre demeurent sur la liste d'attente jusqu'à l'offre suivante. Le modèle ne met à jour le temps d'attente que chaque année après la date de l'offre, et non de façon continue. Conclusion: En fournissant des estimations quantitatives personnalisées du temps jusqu'à l'offre suivante et de la qualité des offres futures, notre nouvelle approche peut éclairer le processus décisionnel partagé des candidats à la transplantation et des médecins lorsqu'une offre de rein provenant d'un donneur décédé est faite par le biais d'un ODO.

Automated screening of potential organ donors using a temporal machine learning model.

Organ donation is not meeting demand, and yet 30-60% of potential donors are potentially not identified. Current systems rely on manual identification and referral to an Organ Donation Organization (ODO). We hypothesized that developing an automated screening system based on machine learning could reduce the proportion of missed potentially eligible organ donors. Using routine clinical data and laboratory time-series, we retrospectively developed and tested a neural network model to automatically identify potential organ donors. We first trained a convolutive autoencoder that learned from the longitudinal changes of over 100 types of laboratory results. We then added a deep neural network classifier. This model was compared to a simpler logistic regression model. We observed an AUROC of 0.966 (CI 0.949-0.981) for the neural network and 0.940 (0.908-0.969) for the logistic regression model. At a prespecified cutoff, sensitivity and specificity were similar between both models at 84% and 93%. Accuracy of the neural network model was robust across donor subgroups and remained stable in a prospective simulation, while the logistic regression model performance declined when applied to rarer subgroups and in the prospective simulation. Our findings support using machine learning models to help with the identification of potential organ donors using routinely collected clinical and laboratory data.

Immunogenicity, Safety, and Breakthrough Severe Acute Respiratory Syndrome Coronavirus 2 Infections After Coronavirus Disease 2019 Vaccination in Organ Transplant Recipients: A Prospective Multicenter Canadian Study.

Background: Solid organ transplant (SOT) recipients are at risk for severe coronavirus disease 2019 (COVID-19), despite vaccination. Our study aimed to elucidate COVID-19 vaccine immunogenicity and evaluate adverse events such as hospitalization, rejection, and breakthrough infection in a SOT cohort. Methods: We performed a prospective, observational study on 539 adult SOT recipients (age ≥18 years old) recruited from 7 Canadian transplant centers. Demographics including transplant characteristics, vaccine types, and immunosuppression and events such as hospitalization, infection, and rejection were recorded. Follow ups occurred every 4-6 weeks postvaccination and at 6 and 12 months from first dose. Serum was processed from whole blood to measure anti-receptor binding domain (RBD) antibodies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to assess immunogenicity. Results: The COVID-19 vaccines were found to be safe in SOT recipients with low rates of rejection requiring therapy (0.7%). Immunogenicity improved after the third vaccine dose, yet 21% developed no anti-RBD response. Factors such as older age, lung transplantation, chronic kidney disease, and shorter duration from transplant were associated with decreased immunogenicity. Patients with at least 3 doses were protected from hospitalization when experiencing breakthrough infections. Significantly increased anti-RBD levels were observed in patients who received 3 doses and had breakthrough infection. Conclusions: Three or four doses of COVID-19 vaccines were safe, increased immunogenicity, and protected against severe disease requiring hospitalization. Infection paired with multiple vaccinations significantly increased anti-RBD response. However, SOT populations should continue to practice infection prevention measures, and they should be prioritized for SARS-CoV-2 pre-exposure prophylactics and early therapeutics.

Hypothermic Perfusion Modifies the Association Between Anti-LG3 Antibodies and Delayed Graft Function in Kidney Recipients.

We previously reported associations between autoantibodies to the LG3 fragment of perlecan, anti-LG3, and a higher risk of delayed graft function (DGF) in kidney transplant recipients. Here, we aimed to determine whether some factors that modulate ischemia-reperfusion injury (IRI) can modify this association. We performed a retrospective cohort study in kidney transplant recipients in 2 university-affiliated centers. In 687 patients, we show that high pre-transplant anti-LG3 are associated with DGF when the kidney is transported on ice (odds ratio (OR): 1.75, 95% confidence interval 1.02-3.00), but not when placed on hypothermic perfusion pump (OR: 0.78, 95% CI 0.43-1.37). In patients with DGF, high pre-transplant anti-LG3 are associated with a higher risk of graft failure (subdistribution hazard ratio (SHR): 4.07, 95% CI: 1.80, 9.22), while this was not the case in patients with immediate graft function (SHR: 0.50, 95% CI 0.19, 1.29). High anti-LG3 levels are associated with a higher risk of DGF in kidneys exposed to cold storage, but not when hypothermic pump perfusion is used. High anti-LG3 are also associated with a higher risk of graft failure in patients who experience DGF, a clinical manifestation of severe IRI.

Double Pretransplant Positivity for Autoantibodies to LG3 and Angiotensin II Type 1 Receptor Is Associated With Alloimmune Vascular Injury in Kidney Transplant Recipients.

Both angiotensin II receptor autoantibodies (ATRabs) and autoantibodies to LG3 have been linked to kidney graft rejection with alloimmune vascular injury (AVI). We aimed to examine whether positivity for both anti-LG3 and ATRabs is associated with rejection with AVI in kidney transplant recipients. Methods: We performed a retrospective cohort study including consecutive kidney transplant recipients between 2013 and 2017 at a single center. The primary outcome was acute rejection with AVI (Banff grade 2 or 3 T-cell-mediated rejection and/or antibody-mediated rejection) in the first 3 mo posttransplant. The secondary outcome was death-censored allograft loss. The independent variables, anti-LG3 and ATRab, were measured pretransplant. Results: Among the 328 study participants, 68 experienced acute rejection with AVI and 23 experienced graft loss over a median follow-up of 4.5 y. In a multivariable model, double pretransplant positivity for anti-LG3/ATRab was associated with acute rejection with AVI (odds ratio: 2.73, 95% confidence interval: 1.06-7.05). We did not observe an association between double positivity for anti-LG3/ATRab and death-censored graft loss. Conclusions: Double positivity for anti-LG3/ATRabs pretransplant is associated with a higher risk of acute rejection with AVI. Whether therapies that remove antibodies could decrease that risk remains to be studied.Supplemental Visual Abtract: http://links.lww.com/TXD/A494.

A multinational cohort study uncovered sex differences in excess mortality after kidney transplant.

Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988-2019). When the donor was male, female recipients 0-12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20-1.99), 13-24 years (1.17, 1.01-1.34), 25-44 years (1.11, 1.05-1.18) and 60 years and older (1.05, 1.02-1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females.

Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort.

BACKGROUND: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. METHODS: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. RESULTS: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). CONCLUSIONS: The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

BACKGROUND: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS: This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION: Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

University of Montreal's Clinician-Investigator Program: A 10-Year Descriptive Evaluation.

PURPOSE: Clinician-investigators have an important role in the development and implantation of new therapies and treatment modalities; however, there have been several reports highlighting a pending shortage in the clinician-investigators' workforce. In Canada, the Royal College has promoted the development of clinician-investigators programs (CIP) to facilitate the training of these individuals. There is currently a paucity of data regarding the outcomes of such programs. This study aims to identify the strengths and areas of improvement of the Montreal University CIP.  Methods: An internet-based 51-question survey was distributed to all the alumni from the University of Montreal CIP. Participation was voluntary and no incentives were provided. The response rate was 64%.  Results: Among respondents, 50% (n=16) had completed their clinical residency and all CIP requirements. The majority of these individuals (63%) had become independent investigators and had secured provincial and national funding. Satisfaction of the respondents was high regarding the overall program (85%), the research skills developed during the CIP (84%) and the financial support obtained during the program (72%). The satisfaction rate regarding career planning was lower (63%).  Conclusion: This survey demonstrates that, while indicators are favorable, some areas still require improvement. Several steps to improve the CIP have been identified; notably, the transition from the CIP to early independent career has been identified as critical in the development of clinician-investigators and steps have been taken to improve this progression.

Severity of COVID-19 among solid organ transplant recipients in Canada, 2020-2021: a prospective, multicentre cohort study.

BACKGROUND: Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada. METHODS: We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen. RESULTS: A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n = 190), compared with not needing (n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5-69.5 yr v. median 55.5 yr, IQR 47.5-66.5; p < 0.001) and number of comorbidities (median 3, IQR 2-3 v. median 2, IQR 1-3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n = 48) were more likely to have severe disease with a high mortality rate (n = 15, 31.3%) compared with recipients of other organ transplants, including kidney (n = 48, 14.8%), heart (n = 1, 4.4%), liver (n = 9, 11.4%) and kidney-pancreas (n = 3, 12.0%) transplants (p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.07) and number of comorbidities (OR 1.63, 95% CI 1.30-2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly. INTERPRETATION: Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

Factors Associated With the Use of Hypothermic Machine Perfusion in Kidney Transplant Recipients: A Multicenter Retrospective Cohort Study.

Background: Delayed graft function (DGF) is associated with an increased risk of graft loss. The use of cold hypothermic machine perfusion (HMP) has been shown to reduce the incidence of DGF in kidney transplant recipients (KTRs), especially when extended-criteria donors (ECDs) are used. HMP can also improve graft survival. However, there is a paucity of data on the determinants of HMP use in clinical practice. Objective: We aimed to determine the factors associated with the use of HMP in a cohort of donors and KTRs. Design: Multicenter retrospective cohort study. Setting: 5 transplant centers in Quebec. Patients: 159 neurologically deceased donors (NDD) and 281 KTR. Measurements: Use of HMP. Methods: We collected data on consecutive NDD admitted to a dedicated donor unit in a single university-affiliated center and their KTRs between June 2013 and December 2018 in 5 adult transplant centers across the province of Quebec, Canada. All organs were recovered in a single hospital center where a HMP device was available for every organ recovered and the decision to use HMP was left at the discretion of the procurement surgeon. Generalized estimating equations were used to predict the use of HMP. Results: The cohort included 159 NDDs and their 281 KTRs. Thirty-three percent of donors were ECDs, and 59% of KTRs received organs placed on HMP. The median cold ischemia time (CIT) was 12.5 (IQR 7.9-16.3) hours. In univariate analysis, none of the donors' characteristics were associated with the use of HMP. ECD represented 33% of KTR on HMP vs 35% of those not placed on HMP (P = .77). In univariate analysis, the use of HMP was associated with KTR race (non-Caucasian), longer CIT, use of basiliximab/alemtuzumab, year of transplant, and transplant center. The use of HMP varied largely across transplant centers, ranging from 15% to 82%. In multivariate analysis, use of HMP was associated with longer CIT (odds ratio [OR] 1.15, 95% confidence interval [CI] = 1.07-1.25), transplant center as well as transplantations performed after 2013. Limitations: One dedicated donor unit including NDD only, absence of specific data on surgeons' experience and personal or logistic reasons for using or not HMP. Conclusions: We found that use of HMP remains low and varies largely across transplant centers. The use of HMP was strongly associated with the transplant center where the surgeons practiced, suggesting that surgeon preference/training plays an important role in determining the use of HMP. Availability of HMP at the time of organ procurement might also be limited by logistic issues such as difficulty in returning the device. Further studies aimed at determining the reasons underlying the barriers precluding the use of HMP could help increasing its use and improve transplant outcomes.

Contexte: Les retards dans la reprise de fonction du greffon (RRFG) sont associés à un risque accru d'échec de la greffe. Il a été démontré que la perfusion hypothermique mécanisée (PHM) peut réduire l'incidence d'un RRFG chez les receveurs d'une greffe rénale (RGR), particulièrement dans les cas où des donneurs à critères étendus (DCÉ) sont impliqués. La PHM pourrait également améliorer la survie du greffon. Il existe cependant peu de données sur les facteurs déterminant l'utilisation de la PHM dans la pratique clinique. Objectifs: Déterminer les facteurs associés à l'utilisation de la PHM dans une cohorte de donneurs et de RGR. Type d'étude: Étude de cohorte rétrospective multicentrique. Cadre: Cinq centres de transplantation au Québec. Sujets: L'étude a inclus 159 donneurs neurologiquement décédés (DND) et 281 RGR. Mesures: L'utilisation de la PHM. Méthodologie: Nous avons recueilli les données de DND consécutifs admis entre juin 2013 et décembre 2018 dans une unité spécialisée dans le don d'organes d'un centre hospitalier universitaire, de même que les données de leurs RGR respectifs. Les sujets provenaient de cinq centres de transplantation pour adultes de la province de Québec, au Canada. Tous les organes ont été prélevés dans un centre hospitalier où un dispositif de PHM était disponible pour chaque organe prélevé, et la décision de recourir à la PHM a été laissée à la discrétion du chirurgien chargé du prélèvement. Des équations d'estimation généralisées ont été employées pour prédire l'utilisation de la PHM. Résultats: La cohorte était composée de 159 DND et de leurs 281 RGR. Les DCÉ constituaient 33 % des DND et 59 % des RGR avaient reçu un organe placé sur PHM. La durée médiane de l'ischémie froide (DmIF) était de 12,5 heures (ÉIQ: 7,9-16,3 heures). Dans l'analyse univariée, aucune des caractéristiques des donneurs n'a été associée à l'utilisation de la PHM. Des RGR de la cohorte qui avaient reçu un rein provenant d'un DCÉ, 33 % ont reçu un organe qui avait été placé sous PHM et 35 % avaient reçu un rein non perfusé à froid (p = 0,77). L'analyse univariée a également révélé une association entre l'utilisation de la PHM et l'origine ethnique du RGR (non caucasien), une DmIF prolongée, l'administration de basiliximab/alemtuzumab, l'année de la greffe et le centre de transplantation. L'utilisation de la PHM variait grandement d'un centre à un autre, allant de 15 % à 82 %. Dans l'analyse multivariée, l'utilisation de la PHM a été associée à une DmIF prolongée (rapport de cotes [RC]: 1,15; [IC95 %]: 1,07-1,25), au centre de transplantation ainsi qu'aux transplantations réalisées après 2013. Limites: Étude tenue dans une seule unité spécialisée en don d'organes et portant uniquement sur des DND. Absence de données précises sur l'expérience des chirurgiens et sur les raisons personnelles ou logistiques justifiant l'utilisation ou non de la PHM. Conclusion: Nous avons constaté que l'utilisation de la PHM demeure faible et qu'elle varie fortement d'un centre de transplantation à un autre. L'utilisation de la PHM a été fortement associée au centre de transplantation où exerçaient les chirurgiens, ce qui laisse penser que les préférences personnelles et la formation du chirurgien sont des facteurs déterminants pour son utilisation. La disponibilité de la PHM au moment du prélèvement des organes peut également être limitée par des questions logistiques telles que la difficulté de retourner l'appareil. D'autres études se penchant sur les raisons sous-jacentes aux obstacles empêchant l'utilisation de la PHM pourraient aider à en accroître l'utilisation et à améliorer les résultats de la transplantation.

Association between circulating PCSK9 and proteinuria in nephrotic syndrome: A cross-sectional study.

BACKGROUND: Nephrotic syndrome (NS) is associated with both hypercholesterolemia and hypertriglyceridemia, which could exacerbate disease progression and accelerate atherosclerosis. It has been reported that PCSK9, a proprotein convertase involved in hypercholesterolemia, was increased in patients with NS. OBJECTIVE: To investigate the association between PCSK9 concentrations and the magnitude of proteinuria. METHODS: A total of 168 patients from nephrology and lipid clinics of the Centre Hospitalier de l'Université de Montreal were included in this cross-sectional observational study. Proteinuria level was classified in three groups: nephrotic syndrome (n = 51), proteinuria (n = 66), and control (n = 51) according to proteinuria and albuminemia concentrations. Plasma PCSK9 concentration was measured by an in-house ELISA and the lipid profile was assayed using an automated biochemical analyzer (COBAS INTEGRA 400, Roche Diagnostic). RESULTS: Plasma PCSK9 concentration was highest in the NS group (170.9 ng/mL), intermediate in the proteinuria group (156.4 ng/mL) and lowest in the control group (136.0 ng/mL), P = 0.005. We observed an association between the protein/creatinine (P/C) ratio and plasma PCSK9 concentrations in the whole cohort (ß = 0.205, P = 0.006) after adjustment for age, sex, LDL-C, statin use, other lipid-lowering therapy use, diabetes, and eGFR. CONCLUSIONS: Patients with nephrotic syndrome have an increased risk of cardiovascular complications. PCSK9 is significantly elevated in NS and is associated with a detrimental lipid profile that could contribute to a worse prognosis of the disease. Future studies evaluating the efficacy of PCSK9 inhibitors in patients with NS would be justified.

Humoral immune responses against SARS-CoV-2 Spike variants after mRNA vaccination in solid organ transplant recipients.

Although SARS-CoV-2 mRNA vaccination has been shown to be safe and effective in the general population, immunocompromised solid organ transplant recipients (SOTRs) were reported to have impaired immune responses after one or two doses of vaccine. In this study, we examined humoral responses induced after the second and the third dose of mRNA vaccine in different SOTR (kidney, liver, lung, and heart). Compared to a cohort of SARS-CoV-2 naïve immunocompetent health care workers (HCWs), the second dose induced weak humoral responses in SOTRs, except for the liver recipients. The third dose boosted these responses but they did not reach the same level as in HCW. Interestingly, although the neutralizing activity against Delta and Omicron variants remained very low after the third dose, Fc-mediated effector functions in SOTR reached similar levels as in the HCW cohort. Whether these responses will suffice to protect SOTR from severe outcome remains to be determined.

The promise of machine learning applications in solid organ transplantation.

Solid-organ transplantation is a life-saving treatment for end-stage organ disease in highly selected patients. Alongside the tremendous progress in the last several decades, new challenges have emerged. The growing disparity between organ demand and supply requires optimal patient/donor selection and matching. Improvements in long-term graft and patient survival require data-driven diagnosis and management of post-transplant complications. The growing abundance of clinical, genetic, radiologic, and metabolic data in transplantation has led to increasing interest in applying machine-learning (ML) tools that can uncover hidden patterns in large datasets. ML algorithms have been applied in predictive modeling of waitlist mortality, donor-recipient matching, survival prediction, post-transplant complications diagnosis, and prediction, aiming to optimize immunosuppression and management. In this review, we provide insight into the various applications of ML in transplant medicine, why these were used to evaluate a specific clinical question, and the potential of ML to transform the care of transplant recipients. 36 articles were selected after a comprehensive search of the following databases: Ovid MEDLINE; Ovid MEDLINE Epub Ahead of Print and In-Process & Other Non-Indexed Citations; Ovid Embase; Cochrane Database of Systematic Reviews (Ovid); and Cochrane Central Register of Controlled Trials (Ovid). In summary, these studies showed that ML techniques hold great potential to improve the outcome of transplant recipients. Future work is required to improve the interpretability of these algorithms, ensure generalizability through larger-scale external validation, and establishment of infrastructure to permit clinical integration.