Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delayed graft function study: study protocol of the CINERGY Pilot randomised controlled trial.

INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.

Immune checkpoint inhibitors and risk of immune-mediated adverse events: a cohort study comparing extended versus standard interval administration.

The COVID-19 pandemic precipitated the implementation of extended interval immune checkpoint inhibitors (ICIs) in an effort to limit hospital visits, but few studies have examined their safety. This study aimed to compare in oncology outpatients, immune-mediated adverse events (IMAEs) in terms of total number, incidence, severity, and time to occurrence, based on exposure to standard or extended interval ICIs. A retrospective cohort study was conducted in patients who received at least one dose of an ICI between 2015 and 2021. Data were collected from patient records and pharmacy software. Adjusted logistic, Poisson, and Cox regression models were estimated. A total of 310 patients with a mean age of 67.1 years were included, 130 of whom had the extended interval. No statistically significant differences were observed between the groups. With the standard and extended intervals, the mean total number of IMAE per participant was 1.02 and 1.18, respectively; the incidence of an IMAE was 62% and 64%. Of the 147 IMAE episodes in the standard interval group, 14 (9.5%) were grade 3 or higher, while there were 15 (12.4%) among the 121 IMAE episodes in the extended interval group. Compared with standard interval, the use of extended interval did not increase the risk of having a first IMAE (adjusted hazard ratio 0.92 (95% CI 0.67-1.26)). This study suggests that the administration of an ICI according to extended interval is as safe as the administration according to standard interval in oncology outpatients.

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.

Organ donor management and delayed graft function in kidney transplant recipients: A multicenter retrospective cohort study.

Meeting donor management goals (DMGs) has been reported to decrease the incidence of delayed graft function (DGF) after kidney transplant, but whether this relationship is independent of cold machine perfusion is unclear. We aimed to determine whether meeting DMGs is associated with a reduced incidence of DGF, independent of the use of machine perfusion. We collected data on consecutive brain-dead donors and their KT recipients (KTRs) between June 2013 and December 2016 in 5 adult transplant centers. We evaluated whether DMGs were met at donor neurologic death (DND) and later time points. We defined a priori meeting optimal DMG as achieving ≥7 DMGs. Generalized estimating equations were used to predict DGF. Among 122 donors, 34% were extended-criteria donors (ECDs). The number of DMGs met increased over time (5.6 ± 1.4 at DND and 6.1 ± 1.3 at organ procurement [P < .001]). DGF occurred in 23% of 214 KTRs, and 55% received organs placed on machine perfusion. In multivariate analysis, ECD (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.13-4.45), use of machine perfusion (OR 0.45, 95% CI 0.22-0.94), and optimal DMG at DND (OR 0.39, 95% CI 0.16-0.99) were associated with DGF. Early achievement of DMGs was associated with a reduced risk of the development of DGF, independent of the use of machine perfusion.

Trichodysplasia spinulosa in a renal transplant patient.

BACKGROUND: Trichodysplasia spinulosa (TS) is a rare skin affection seen in immunocompromised patients, mainly those with solid organ tranplants. OBJECTIVE: To report a case of a patient with classic clinical and pathologic findings for the disease so that physicians caring for this population are aware of the clinical presentation. METHOD: We report the case of a female patient we saw at our clinic with a diagnosis of TS. RESULTS: The diagnosis of TS was confirmed by pathologic findings. CONCLUSION: TS should be considered in any immunocompromised patient with a papular facial eruption reminiscent of acne vulgaris and with keratotic spiny papules as a distinctive feature.

Modifiable factors predicting patient survival in elderly kidney transplant recipients.

BACKGROUND: Elderly transplant candidates represent an increasingly important group on the waiting list for kidney transplantation. Yet the factors that determine posttransplantation outcomes in this population remain poorly defined. METHODS: We performed a population-based retrospective cohort study involving all patients aged 60 years or older who received a first cadaveric kidney transplantation between 1985 and 2000 in the province of Quebec. The main outcomes were patient survival, overall graft survival, and treatment failure (patient death or graft loss within the first posttransplant year). Survival analyses were performed using a Cox proportional hazard model. Logistic regression identified factors predicting treatment failure. RESULTS: On multivariate analysis, the modifiable factors associated with patient survival were active smoking at transplantation [hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.22-3.60)], body mass index (BMI) (HR 1.34 for a 5-point increase, 95% CI 1.05-1.67), and time on dialysis before transplantation (HR 1.10 for a 1-year increase, 95% CI 1.02-1.18). The only modifiable factor associated with graft survival was active smoking at transplantation (HR 2.04, 95% CI 1.24-3.30). Treatment failure was associated with time on dialysis before transplantation (odds ratio for dialysis >/=2 years 3.28, 95% CI 1.34-7.9). CONCLUSION: Our results show that active smoking, obesity, and time on dialysis before transplantation are modifiable risk factors associated with an increased risk of mortality after transplantation in elderly recipients. They represent potential targets for interventions aimed at improving patient and graft survival in elderly patients.

Soluble Fas: a novel predictor of atherosclerosis in dialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD). Disregulation of apoptosis within the vessel wall and upregulation of the Fas/Fas-ligand (Fas-L) system contribute to the development of atherosclerosis. Cross-sectional studies have suggested that elevated plasma levels of the soluble form of Fas (sFas) are associated with CVD. However, the role of sFas and sFas-L in predicting future cardiovascular events has yet to be defined. METHODS: We evaluated the role of plasma sFas and sFas-L levels as predictors of CVD in a prospective cohort of 107 chronic hemodialysis patients. RESULTS: During the study period (27 months), 53 patients (49.5%) presented with at least one cardiovascular end point. On univariate analysis, baseline sFas levels were significantly associated with the occurrence of cardiovascular end points, whereas sFas-L levels were not. Using Cox proportional hazards, increased sFas levels were associated with a significantly greater risk for cardiovascular end points (P = 0.03). This effect was independent of baseline CVD history, classic risk factors for atherosclerosis (diabetes, hypercholesterolemia, hypertension, and smoking), and markers of inflammation (C-reactive protein [CRP], soluble intercellular adhesion molecule-1). Increased CRP levels also were associated with cardiovascular end points (P = 0.04). In addition, increased cardiovascular mortality was found in patients in the highest sFas tertile compared with those in the lowest tertile (27.8% versus 8.6%; P = 0.04). CONCLUSION: Increased plasma sFas levels are predictive of future CVD. These results suggest that sFas is a novel and independent predictor of active atherosclerotic disease in patients with ESRD.

Soluble Fas is a marker of peripheral arterial occlusive disease in haemodialysis patients.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) including lower-extremity and cerebrovascular atherosclerosis is a leading cause of morbidity in haemodialysis patients. Recent evidence suggests that the expression of Fas, a molecule implicated in the initiation of apoptosis in various cell types, is increased at sites of atherosclerotic plaques. However, the significance of plasma levels of the soluble form of Fas (sFas) as a marker of peripheral arterial disease has yet to be defined. METHODS: The present report is based on a cross-sectional analysis of baseline data from an ongoing prospective study designed to evaluate the role of sFas as marker of PAOD in end-stage renal disease (ESRD). We evaluated the association between sFas levels and evidence of PAOD in a cohort of 107 chronic haemodialysis patients. RESULTS: Compared with subjects without evidence of disease (n=56), subjects with PAOD (n=51) had significantly higher plasma levels of sFas (30.0+/-8.9 vs 26.4+/-9.5 ng/ml; P=0.04). Using multiple regression, sFas was found to be associated with PAOD independently of classical risk factors for atherosclerosis (hypercholesterolaemia, diabetes, hypertension, and smoking), markers of inflammation (e.g. C-reactive protein, intercellular cell adhesion molecule type 1), and other risk factors (e.g. age, gender). An increase of one quintile in the plasma concentration of sFas was associated with an odds ratio of PAOD of 1.69 (95% CI: 1.09--2.63, P=0.01). In addition, models that incorporated sFas were significantly better at predicting PAOD than models limited to classical risk factors for atherosclerosis, alone or in combination with CRP levels (P=0.01). CONCLUSIONS: Increased plasma levels of sFas are associated with established PAOD. These results suggest that sFas may represent a novel and independent marker of atherosclerosis.