Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study.

BACKGROUND: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely. METHODS: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up. RESULTS: The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94). CONCLUSIONS: Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

The role of renal resistive index as a prognostic tool in kidney transplantation: a systematic review.

BACKGROUND: In kidney transplant recipients (KTRs), observational data have reported conflicting findings about the utility of renal resistive index (RRI) in determining outcomes. This study aimed to synthesize the current literature and determine the prognostic role of RRI in KTRs. METHODS: The authors conducted a systematic review to assess the role of RRI in predicting death, graft failure, graft function and proteinuria. Of the 934 titles/abstracts reviewed, 26 studies were included. There was significant heterogeneity in RRI measurements and thresholds as well as in analytical methods, and a meta-analysis could not be performed. RESULTS: All included studies were observational and included 7049 KTRs. Eight studies analyzed death, of which five reported a significant association with higher RRI. In the remaining three, small sample sizes and lower/multiple RRI thresholds may have limited detection of a statistically significant difference. Three studies investigated all-cause graft failure, and an association with RRI was reported but varied by time of RRI measurement. Three out of five studies that analyzed a composite of patient and graft outcomes reported an association with RRI. Evidence analyzing death-censored graft failure, graft failure (unclear whether death-censored or all-cause), measures of graft function and proteinuria was conflicting. Most studies had a moderate to high risk of bias. CONCLUSIONS: RRI likely has a prognostic role in predicting patient outcomes, reflecting patient systemic vascular disease burden rather than graft hemodynamics. Since cardiovascular diseases are a major cause of death and graft loss, RRI may be explored as a noninvasive tool to risk-stratify KTRs.

Granulocyte colony-stimulating factor with or without immunosuppression reduction in neutropenic kidney transplant recipients.

INTRODUCTION: Neutropenia post-kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony-stimulating factor (G-CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. METHODS: In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. RESULTS: Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G-CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de-novo DSA, biopsy-proven acute rejection, and all-cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p = .93). When stratifying the cohort by G-CSF use alone, those who received G-CSF were more likely to have had severe neutropenia (<500/mm3 : 51.1% vs. 12.0%, p < .001), and immunosuppression reduction (51.1% vs. 28.0%, p = .003). However, the composite outcome was not different in the G-CSF and no G-CSF cohort (53.3% vs. 49.3%, p = .67), and in a multivariate model, G-CSF use was not associated with this outcome (aHR = 1.18, 95% CI: .61-2.30). However, a trend towards higher DSA production was noted in the G-CSF cohort (87.5% vs. 62.2%) and this observation warrants prospective evaluation. CONCLUSION: Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes.

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.

Renal resistance thresholds during hypothermic machine perfusion and transplantation outcomes - a retrospective cohort study.

Renal resistance (RR), of allografts undergoing hypothermic machine perfusion (HMP), is considered a measure of organ quality. We conducted a retrospective cohort study of adult deceased donor kidney transplant (KT) recipients whose grafts underwent HMP. Our aim was to evaluate whether RR is predictive of death-censored graft failure (DCGF). Of 274 KT eligible for analysis, 59% were from expanded criteria donor. RR was modeled as a categorical variable, using a previously identified terminal threshold of 0.4, and 0.2 mmHg/ml/min (median in our cohort). Hazard ratios (HR) of DCGF were 3.23 [95% confidence interval (CI): 1.12-9.34, P = 0.03] and 2.67 [95% CI: 1.14-6.31, P = 0.02] in univariable models, and 2.67 [95% CI: 0.91-7.86, P = 0.07] and 2.42 [95% CI: 1.02-5.72, P = 0.04] in multivariable models, when RR threshold was 0.4 and 0.2, respectively. Increasing risk of DCGF was observed when RR over the course of HMP was modeled using mixed linear regression models: HR of 1.31 [95% CI: 1.07-1.59, P < 0.01] and 1.25 [95% CI: 1.00-1.55, P = 0.05], in univariable and multivariable models, respectively. This suggests that RR during HMP is a predictor of long-term KT outcomes. Prospective studies are needed to assess the survival benefit of patients receiving KT with higher RR in comparison with staying wait-listed.

Early renal function recovery and long-term graft survival in kidney transplantation.

Following kidney transplantation (KTx), renal function improves gradually until a baseline eGFR is achieved. Whether or not a recipient achieves the best-predicted eGFR after KTx may have important implications for immediate patient management, as well as for long-term graft survival. The aim of this cohort study was to calculate the renal function recovery (RFR) based on recipient and donor eGFR and to evaluate the association between RFR and long-term death-censored graft failure (DCGF). We studied 790 KTx recipients between January 1990 and August 2014. The last donor SCr prior to organ procurement was used to estimate donor GFR. Recipient eGFR was calculated using the average of the best three SCr values observed during the first 3 months post-KTx. RFR was defined as the ratio of recipient eGFR to half the donor eGFR. 53% of recipients had an RFR ≥1. There were 127 death-censored graft failures (16%). Recipients with an RFR ≥1 had less DCGF compared with those with an RFR <1 (HR 0.56; 95% CI 0.37-0.85; P = 0.006). Transplant era, acute rejection, ECD and DGF were also significant determinants of graft failure. Early recovery of predicted eGFR based on donor eGFR is associated with less DCGF after KTx.

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.

Relative decrease in hemoglobin and outcomes in patients undergoing kidney transplantation surgery: A retrospective cohort study.

BACKGROUND: Recent surgical literature suggests that a relative decrease in hemoglobin (ΔHb) is predictive of adverse outcomes regardless of the absolute level. We aimed to examine the association between perioperative ΔHb and kidney transplantation (KT) outcomes. METHODS: This was a retrospective cohort study of transplant recipients, where ΔHb = [Hb0- Hb1Hb0]x 100 (Hb0 = hemoglobin pre-KT and Hb1 = lowest hemoglobin 24-h post-KT). The main outcome of interest was immediate graft function (IGF). RESULTS: Of the 899 eligible patients, 38% experienced IGF, and ΔHb was associated with 36% lower odds of IGF. Also, ΔHb was associated with higher all-cause graft failure and longer length of stay but not death-censored graft failure or mortality. ΔHb ≥30% was the threshold beyond which the odds of IGF were significantly lower even if Hb1 was ≥7 g/dL. CONCLUSION: ΔHb is associated with inferior outcomes independent of Hb1; whether it can be used to guide transfusion practices should be explored.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review.

PURPOSE OF REVIEW: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment. SOURCES OF INFORMATION: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors. METHODS: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies. KEY FINDINGS: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA. LIMITATIONS: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

JUSTIFICATION: La microangiopathie thrombotique (MAT) est suspectée chez les patients présentant une thrombocytopénie et la preuve d'une anémie hémolytique microangiopathique (AHMA). Les patients atteints de MAT peuvent être gravement malades, il est donc essentiel de déterminer rapidement et précisément l'étiologie sous-jacente. Grâce à une meilleure connaissance de la physiopathologie et des causes de la MAT, nous pouvons désormais classer les MAT par catégorie: purpura thrombocytopénique thrombotique (PTT), syndrome hémolytique urémique post-infectieux (SHU) principalement induit par STEC (Escherichia coli produisant la toxine Shiga), ou MAT associée à une affection coexistante ou à un SHU atypique (SHUa). Nous avons constaté un besoin dans la communauté médicale pour guider à la fois la détection rapide et précise de la MAT, la sélection des tests pour clarifier son étiologie et la séquence des étapes menant à l'initiation du traitement. SOURCES: Des recherches documentaires sur PubMed et les connaissances antérieures des auteurs ont permis de colliger les principales études publiées portant sur la détection, la classification et le traitement de la MAT chez les enfants ou les adultes. MÉTHODOLOGIE: Cet examen est le résultat d'un processus de consultation qui reflète le consensus des experts du Canada, des États-Unis et des Émirats arabes Unis. Les membres représentent des cliniciens, des chercheurs et des enseignants en médecine pédiatrique et adulte dans les domaines de l'hématologie, de la néphrologie et de la médecine de laboratoire. Les auteurs, par le biais d'un processus d'examen itératif, ont colligé et synthétisé l'information provenant des études publiées jugées pertinentes. PRINCIPAUX RÉSULTATS: Le PTT survient lors d'une activité insuffisante de la protéase du facteur Willebrand connue sous le nom d'ADAMTS13. Le SHU-STEC, aussi appelé SHU « typique ¼, est causé par des infections gastro-intestinales dues à des bactéries produisant la toxine Shiga (initialement appelée vérocytotoxine). Plusieurs états pathologiques ou expositions à des médicaments peuvent déclencher la MAT. Quant au SHU atypique (SHUa), il survient en présence d'anomalies héréditaires ou acquises de la voie du complément alternatif qui mènent à un dérèglement de l'activation du complément, souvent à la suite d'un événement déclencheur comme une infection. On peut diviser le processus de diagnostic étiologique de la MAT en deux étapes distinctes. La première couvre la présentation initiale et le diagnostic, y compris les processus de détection de la MAT, les tests initiaux et aiguillages appropriés, ainsi que les traitements empiriques si nécessaire. La deuxième étape consiste à confirmer le diagnostic étiologique et à procéder au traitement définitif. Pour de nombreuses formes de MAT, la réponse ultime aux traitements et le résultat du patient dépendent de la détection rapide et précise de la MAT et ensuite, d'une approche standardisée pour la recherche du diagnostic étiologique. Nous présentons une approche structurée pour détecter la présence de MAT ainsi qu'une démarche pour rechercher l'étiologie, y compris des tableaux de laboratoire normalisés. Nous soulignons l'importance d'une consultation précoce avec les spécialistes appropriés en hématologie et en néphrologie, et de la détermination d'un éventuel besoin d'échange de plasma (PLEX) pour le patient. Les cliniciens devraient envisager les traitements empiriques appropriés tout en suivant la démarche que nous recommandons pour le diagnostic étiologique définitif et la gestion de la MAT. LIMITES: La base factuelle de nos recommandations est constituée de petites études cliniques, de rapports de cas et de séries de cas. Ces études ne sont généralement pas contrôlées ou randomisées et ne se prêtent pas à une méthodologie plus stricte basée sur des lignes directrices ni à une approche fondée sur le GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Predicting Clinical Outcome in Expanded Criteria Donor Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: The gaps in organ supply and demand necessitate the use of expanded criteria donor (ECD) kidneys. OBJECTIVE: To identify which pre-transplant and post-transplant predictors are most informative regarding short- and long-term ECD transplant outcomes. DESIGN: Retrospective cohort study. SETTING: Single center, Quebec, Canada. PATIENTS: The patients were 163 consecutive first-time ECD kidney only transplant recipients who underwent transplantation at McGill University Health Centre (MUHC) between January 1, 2008 and December 31, 2014 and had frozen section wedge procurement biopsies. MEASUREMENTS: Short-term graft outcomes, including delayed graft function and 1-year estimated glomerular filtration rate (eGFR), as well as long-term outcomes including all-cause graft loss (defined as return to dialysis, retransplantation, and death with function). METHODS: Pre-transplant donor, recipient, and transplant characteristics were assessed as predictors of transplant outcomes. The added value of post-transplant predictors, including longitudinal eGFR, was also assessed using time-varying Cox proportional hazards models. RESULTS: In univariate analyses, among the pre-transplant donor characteristics, histopathologic variables did not show evidence of association with delayed graft function, 1-year post-transplant eGFR or all cause graft loss. Recipient age was associated with all-cause graft loss (hazard ratio: 1.038 [95% confidence interval: 1.002-1.075] and the model produced only modest discrimination (C-index: 0.590; standard error [SE]: 0.045). Inclusion of time-dependent post-transplant eGFR improved the model's prediction accuracy (C-index: 0.711; SE = 0.047). Pre-transplant ECD characteristics were not associated with long-term survival, whereas post-transplant characteristics allowed better model discrimination. LIMITATIONS: Single-center study, small sample size, and potential incomplete capture of all covariate data. CONCLUSIONS: Incorporation of dynamic prediction models into electronic health records may enable timely mitigation of ECD graft failure risk and/or facilitate planning for renal replacement therapies. Histopathologic findings on preimplantation biopsies have a limited role in predicting long-term ECD outcomes. TRIAL REGISTRATION: Not applicable.

CONTEXTE: Les écarts entre l'offre et la demande d'organes nécessitent le recours à des donneurs répondant à des critères élargis (DCÉ). OBJECTIF: Déterminer les prédicteurs pré- et post-transplantation qui s'avèrent les plus instructifs quant aux résultats à court et à long terme des greffes d'organes provenant de DCÉ. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Étude monocentrique tenue au Québec (Canada). SUJETS: L'étude porte sur 163 patients consécutifs greffés d'un rein seulement au center universitaire de santé McGill (CUSM) entre le 1er janvier 2008 et le 31 décembre 2014. L'organe reçu provenait d'un DCÉ et la biopsie avait été effectuée sur des sections congelées de l'organe. MESURES: Les résultats à court terme, notamment la reprise retardée de la fonction du greffon et le débit de filtration glomérulaire estimé (DFGe) après un an. Les résultats à long terme dont la perte du greffon toute cause (retour en dialyse, retransplantation ou décès avec greffon fonctionnel). MÉTHODOLOGIE: Les caractéristiques du donneur, du receveur et de la transplantation ont été examinées avant l'intervention comme prédicteurs de l'issue de la greffe. Des modèles des risques proportionnels de Cox variant dans le temps ont servi à évaluer la valeur ajoutée des prédicteurs post-greffe, notamment du DFGe longitudinal. RÉSULTATS: Dans l'analyse univariée des caractéristiques pré-transplantation, les variables histopathologiques n'ont montré aucune association avec la fonction retardée du greffon, le DFGe un an après la greffe ou la perte du greffon. L'âge du receveur a été associé à la perte du greffon toute cause (RR : 1,038 [IC 95 % : 1,002-1,075]) et le pouvoir discriminant du modèle s'est avéré modeste (indice C : 0,590; ÉT = 0,045). L'inclusion du DFGe post-greffe en fonction du temps a amélioré la précision prédictive du modèle (indice C : 0,711; ÉT = 0,047). Les caractéristiques pré-greffe du DCÉ n'ont pas été associées à la survie à long terme, alors que les caractéristiques post-greffe ont permis d'améliorer le pouvoir discriminant du modèle. LIMITES: Étude monocentrique sur un faible échantillon et dont la saisie des données sur les covariables est potentiellement incomplète. CONCLUSION: L'incorporation de modèles prédictifs dynamiques aux dossiers médicaux électroniques pourrait permettre, en temps opportun, d'atténuer les risques de défaillance du greffon provenant d'un DCÉ et faciliter la planification d'une thérapie de remplacement rénal. Les résultats histopathologiques des biopsies pré-transplantation jouent un rôle mineur pour prédire les résultats à long terme des DCÉ. ENREGISTREMENT DE L'ESSAI: Sans objet.

Rib Exostoses Presenting as Mediastinal Masses: A Rare Presentation and Minireview of the Literature.

Costal osteocartilaginous exostoses, also known as osteochondromas, are the most common neoplasms of the long bones but are rare tumors of the ribs. Osteochondroma is often asymptomatic and incidentally observed. Tumors typically begin to grow before puberty and continue until bone maturation is reached. Our paper presents the case of a 16-year-old young male who was admitted to the hospital with nonspecific symptoms and having a family history of exostosis. Chest X-ray and computed tomography imaging revealed multiple costosternal exostoses, manifested as mediastinal masses, with protrusion into the thoracic cavity, exerting compressive effects on the ascending aorta and pulmonary parenchyma. Surgery is required in childhood if lesions are painful. But if tumor formation occurs in adulthood, such pathological bony outgrowths should always be resected for avoiding further complications. In this patient, surgical intervention removed the tumoral masses and improved the symptoms. Subsequently, histological exam confirmed the diagnosis of osteocartilaginous exostoses and showed the lack of dysplastic changes.

Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.

Assessment of vulnerable and unstable carotid atherosclerotic plaques on endarterectomy specimens.

The types of lesion instability responsible for the majority of acute coronary events frequently include plaque disruption and plaque erosion with superimposed thrombosis. The term 'vulnerable plaque is used to describe atherosclerotic (ATS) plaques that are particularly prone to rupture and susceptible to thrombus formation, such as the thin-cap fibroatheroma (TCFA). The aim of the present study was to assess the morphological and histological differences between plaques that are unstable and those that are vulnerable to instability. Carotid artery endarterectomy specimens were obtained from 26 patients with carotid artery stenosis, consisting of 20 men and 6 women (age range, 35-80 years). Histological and morphometric methods were used to visualize and characterize the ATS plaques. Among the 26 carotid ATS plaques, 23% were stable, 23% were unstable and 54% were vulnerable. With regard to morphometric characteristics, the following mean values were obtained for the TCFA and unstable plaques, respectively: Fibrous cap thickness, 21.91 and 11.66 µM; proportion of necrotic core area in the total plaque area, 25.90 and 22.03%; and the proportion of inflammatory area in the total plaque area, 8.41 and 3.04%. No plaque calcification was observed in any of them. Since ATS coronary artery disease is considerably widespread and fatal, it is crucial to further study ATS lesions to obtain an improved understanding of the nature of vulnerable and unstable plaques. The methods used to detect plaque size, necrotic core area and fibrous cap thickness are considered to be particularly useful for identifying vulnerable and unstable plaques.

Preoperative graft assessment in aortocoronary bypass surgery.

Coronary artery bypass graft (CABG) is a surgical procedure able to improve the blood supply to the myocardium. In the present study, the distal segments of grafts taken from the internal thoracic artery (ITA), radial artery (RA) and saphenous vein (SV) for use in aortocoronary bypass surgery were examined. The morphologies of the grafts were investigated in order to draw conclusions concerning their patency and viability. In addition, clinical and laboratory risk factors considered to be significant predictors of lesion severity in graft vessels used in CABGs were investigated. In total, 54 distal graft segments of ITAs, RAs and SVs from 20 men and 6 women aged between 42 and 78 years, were evaluated. Histological analyses were used to visualize graft lesions. Morphometrically, the intimal thickness index (ITI) and luminal narrowing were assessed as an indication of graft patency. The histological changes observed in the graft vessel walls included the presence of distinct atheromatous plaques (fatty streaks in 2 cases) or thickening of the intima (20 cases) and media (17 cases). Morphometric analysis showed that the mean ITI of the vessel conduits was 0.37 in the SVs, 0.95 in the RAs, and 1.66 in the ITAs. No patient had >50% conduit stenosis. By assessing the association between risk factors and graft lesions, it was found that all the patients showed risk factors for atherosclerosis, such as age (61.54%), arterial hypertension (65.38%), hyperlipidemia (65.38%), smoking (34.61%), diabetes mellitus (38.46%) and obesity (15.38%). The presence of pre-existing lesions in bypass grafts may contribute to a reduction in their viability, particularly in the case of venous grafts. Further long-term follow-ups are mandatory to evaluate the consequences of such lesions upon the patency of the grafts.

Gene therapy with an E2F transcription factor decoy inhibits cell cycle progression in rat anti-Thy 1 glomerulonephritis.

Mesangial cell (MC) proliferation is a central feature of many glomerular diseases. Various growth factors and cytokines are known to trigger MC proliferation both in vitro and in vivo. Regardless of the initial stimulus, proliferation is ultimately dependent upon the coordinated activation of cell cycle regulatory genes whose transcription is tightly controlled in mammalian cells. The transcription factor E2F plays an important role in the transactivation of the cell cycle regulatory genes proliferating-cell nuclear antigen (PCNA) and cdk2 kinase. To test whether or not E2F inhibition would blunt glomerular cell cycling in vivo, we treated rats with anti-Thy 1 antibody to induce glomerular injury, and that infused hemagglutinating virus of Japan (HVJ)-liposomes containing synthetic double stranded oligonucleotides (ODN) with high affinity for E2F (E2F decoy) directly into one kidney. First, we confirmed that with HVJ-liposome method fluorescence isothiocynate (FITC)-labeled ODN could be efficiently introduced into rat glomerular cells via renal artery. E2F decoy ODN treatment specifically inhibited mRNA expression of PCNA and cdk2 kinase in kidneys injured with anti-Thy 1 antibody as assessed by RT-PCR. This was associated with a significant decrease in number of glomerular cells in S phase as assessed by 5'-bromo-2'-deoxy-uridine labeling method, and attenuation of glomerular injury assessed histologically. The evidence suggests that intra-renal delivery of E2F decoy ODN by HVJ-liposome method prevents the induction of cell cycle regulatory gene expression and MC proliferation. These data also demonstrate the feasibility and the potential benefit of in vivo gene therapy as a novel strategy in the treatment of glomerular diseases.

Impact of early graft function on 10-year graft survival in recipients of kidneys from standard- or expanded-criteria donors.

BACKGROUND: The use of kidneys from expanded-criteria donors (ECD) is regarded with caution. METHODS: We compared 279 kidney transplant recipients (KTxR) from standard-criteria donors (SCD) and 237 from ECD, transplanted between January 1990 and December 2006. We evaluated the impact of immediate graft function (IGF), slow graft function (SGF), and delayed graft function (DGF) and the drop in estimated glomerular filtration rate (ΔeGFR) ≤ 30% or > 30% during the first year after transplantation on long-term patient and death-censored graft survival (DCGS). RESULTS: Ten-year patient survival was similar in SCD- or ECD-KTxR (P = 0.38). DCGS was better in SCD-KTxR versus ECD-KTxR (77.3% vs. 67.3%; P = 0.01). DCGS did not differ in either group experiencing IGF (P = 0.17) or DGF (P = 0.12). However, DCGS was worse in ECD-KTxR experiencing SGF (84.9% vs. 73.7%; P = 0.04). Predictors of DCGS were 1-year serum creatinine (hazard ratio, 1.03; P < 0.0001) and ΔeGFR > 30% between 1 and 12 months (Δ1-12eGFR) after transplantation (hazard ratio, 2.2; P = 0.02). In ECD-KTxR with IGF and more than 1-year follow-up, 10-year DCGS was better in those with Δ1-12eGFR ≤ 30% versus those with Δ1-12eGFR > 30% (83.8% vs. 53.6%; P = 0.01). CONCLUSION: Recipients of SCD or ECD kidneys with IGF or DGF had similar 10-year patient survival and DCGS. SGF had a worse impact on DCGS in ECD-KTxR. In addition to 1-year serum creatinine, Δ1-12eGFR > 30% is a negative predictor of DCGS. Larger studies should confirm if increasing the use of ECD, avoiding factors that contribute to SGF or DGF, and/or a decline in eGFR during the first year after transplantation may expand the donor pool and result in acceptable long-term outcomes.