Post-transplant outcomes in recipients of living donor kidneys and intended recipients of living donor kidneys.

BACKGROUND: Long-term kidney transplant survival at the population level is consistently favorable, but this survival varies widely at an individual level due to both recipient and donor factors. The distinct contribution of recipient and donor factors to individual post kidney transplant outcome remains unclear. Comparing outcomes in deceased donor (DD) recipients with potential but non-actualized living donors (DD1) to those recipients with actualized living donors (LD), and to DD recipients without potential living donors (DD0) may provide transplant candidates with more information about their own post-transplant prognosis. METHODS: We conducted an observational retrospective cohort study of kidney transplant candidates presenting to our centre for evaluation between 01/01/06 and 31/12/18, and who also received a transplant during that time. Patients were followed to 31/08/2019. Candidates were classified as DD0, DD1, or LD based on whether they had an identified living donor at the time of initial pre-transplant assessment, and if the donor actualized or not. Primary outcome was 5-year death-censored graft survival, adjusted for common pre- and post-transplant donor and recipient risk factors. Secondary outcomes analyzed included patient survival and graft function. RESULTS: There were 453 kidney transplant recipients (LD = 136, DD1 = 83, DD0 = 234) who received a transplant during the study period. DD0 and DD1 did not differ in key donor organ characteristics. The 5-year death censored graft survival of DD1 was similar to LD (p = 0.19). DD0 graft survival was inferior to LD (p = 0.005), but also trended inferior to DD1 (p = 0.052). By multivariate Cox regression analysis, LD demonstrated similar 5-year graft survival to DD1 (HR for graft loss 0.8 [95% CI 0.25-2.6], p = 0.72) but LD graft survival was superior to DD0 (HR 0.34 [0.16-0.72], p = 0.005). The 5-year patient survival in DD1 was similar to LD (p = 0.26) but was superior to DD0 (p = 0.01). CONCLUSIONS: DD recipients with potential but non-actualized living donors exhibit similar mid-term graft and patient survival compared to LD recipients. Having an identified living donor at the time of pre-transplant assessment portends a favorable prognosis for the recipient.

COVID-19 Outbreak in an Urban Hemodialysis Unit.

RATIONALE & OBJECTIVE: Hemodialysis patients are at increased risk for coronavirus disease 2019 (COVID-19) transmission due in part to difficulty maintaining physical distancing. Our hemodialysis unit experienced a COVID-19 outbreak despite following symptom-based screening guidelines. We describe the course of the COVID-19 outbreak and the infection control measures taken for mitigation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 237 maintenance hemodialysis patients and 93 hemodialysis staff at a single hemodialysis center in Toronto, Canada. EXPOSURE: Universal screening of patients and staff for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OUTCOMES: The primary outcome was detection of SARS-CoV-2 in nasopharyngeal samples from patients and staff using reverse transcriptase-polymerase chain reaction (RT-PCR). ANALYTICAL APPROACH: Descriptive statistics were used for clinical characteristics and the primary outcome. RESULTS: 11 of 237 (4.6%) hemodialysis patients and 11 of 93 (12%) staff members had a positive RT-PCR test result for SARS-CoV-2. Among individuals testing positive, 12 of 22 (55%) were asymptomatic at time of testing and 7 of 22 (32%) were asymptomatic for the duration of follow-up. One patient was hospitalized at the time of SARS-CoV-2 infection and 4 additional patients with positive test results were subsequently hospitalized. 2 (18%) patients required admission to the intensive care unit. After 30 days' follow-up, no patients had died or required mechanical ventilation. No hemodialysis staff required hospitalization. Universal droplet and contact precautions were implemented during the outbreak. Hemodialysis staff with SARS-CoV-2 infection were placed on home quarantine regardless of symptom status. Patients with SARS-CoV-2 infection, including asymptomatic individuals, were treated with droplet and contact precautions until confirmation of negative SARS-CoV-2 RT-PCR test results. Analysis of the outbreak identified 2 index cases with subsequent nosocomial transmission within the dialysis unit and in shared shuttle buses to the hemodialysis unit. LIMITATIONS: Single-center study. CONCLUSIONS: Universal SARS-CoV-2 testing and universal droplet and contact precautions in the setting of an outbreak appeared to be effective in preventing further transmission.

Safety and efficacy of prophylaxis for Pneumocystis jirovecii pneumonia involving trimethoprim-sulfamethoxazole dose reduction in kidney transplantation.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti-Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear. METHODS: We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed. RESULTS: Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26-0.83, p < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39-7.90, p = 0.006). CONCLUSIONS: TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.

Severe and near-fatal anaphylactic reactions triggered by chlorhexidine-coated catheters in patients undergoing renal allograft surgery: a case series.

PURPOSE: Although intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation. CLINICAL FEATURES: Skin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30-69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter. CONCLUSIONS: Intraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

Effect of organ donation after circulatory determination of death on number of organ transplants from donors with neurologic determination of death.

BACKGROUND: To increase the available pool of organ donors, Ontario introduced donation after circulatory determination of death (DCD) in 2006. Other jurisdictions have reported a decrease in donations involving neurologic determination of death (NDD) after implementation of DCD, with a drop in organ yield and quality. In this study, we examined the effect of DCD on overall transplant activity in Ontario. METHODS: We examined deceased donor and organ transplant activity during 3 distinct 4-year eras: pre-DCD (2002/03 to 2005/06), early DCD (2006/07 to 2009/10) and recent DCD (2010/11 to 2013/14). We compared these donor groups by categorical characteristics. RESULTS: Donation increased by 57%, from 578 donors in the pre-DCD era to 905 donors in the recent DCD era, with a 21% proportion (190/905) of DCD donors in the recent DCD era. However, overall NDD donation also increased. The mean length of hospital stay before declaration for NDD was 2.7 days versus 6.0 days before withdrawal of life support and subsequent asystole in cases of DCD. The average organ yield was 3.73 with NDD donation versus 2.58 with DCD (p < 0.001). Apart from hearts, all organs from DCD donors were successfully transplanted. From the pre-DCD era to the recent DCD era, transplant activity in each era increased for all solid-organ recipients, including heart (from 158 to 216), kidney (from 821 to 1321), liver (from 477 to 657) and lung (from 160 to 305). INTERPRETATION: Implementation of DCD in Ontario led to increased transplant activity for all solid-organ recipients. There was no evidence that the use of DCD was pre-empting potential NDD donation. In contrast to groups receiving other organs, heart transplant candidates have not yet benefited from DCD.

The role of thrombectomy and diffusion-weighted imaging with MRI in post-transplant renal vein thrombosis: a case report.

BACKGROUND: Surgical thrombectomy in the context of acute renal vein thrombosis (RVT) post-transplantation has had limited success, with considerable variation in the surgical techniques used. Unfortunately, it is usually followed by allograft nephrectomy within a few days if rapid allograft recovery does not ensue. We report a case of acute RVT in which nephrectomy was not performed despite a prolonged requirement for dialysis post-thrombectomy, but with recovery of renal function 2 weeks later. We also report the findings of serial MRI with diffusion-weighted imaging (DW-MRI) throughout the patient's recovery, which provided novel insights into allograft microvascular perfusion changes post-thrombectomy. CASE PRESENTATION: A 65-year old patient underwent living-unrelated kidney transplantation complicated by acute RVT. Surgical thrombectomy and irrigation led to a delayed, but significant, recovery of renal function. Serial non-contrast DW-MRI scanning was used to non-invasively assess microvascular renal blood flow post-operatively. Unlike standard Doppler ultrasonography, DW-MRI documented reduced microvascular perfusion initially, with gradual but incomplete recovery that mirrored the partial improvement in renal function. CONCLUSIONS: Our findings suggest that surgical thrombectomy may be more effective than previously described if followed by careful patient observation. Moreover, diffusion-weighted MRI appears to provide important insights into the pathophysiology of delayed graft function and deserves further investigation.

Commercial kidney transplantation is an important risk factor in long-term kidney allograft survival.

Transplant tourism, a form of transplant commercialization, has resulted in serious short-term adverse outcomes that explain reduced short-term kidney allograft survival. However, the nature of longer-term outcomes in commercial kidney transplant recipients is less clear. To study this further, we identified 69 Canadian commercial transplant recipients of 72 kidney allografts transplanted during 1998 to 2013 who reported to our transplant center for follow-up care. Their outcomes to 8 years post-transplant were compared with 702 domestic living donor and 827 deceased donor transplant recipients during this period using Kaplan-Meier survival plots and multivariate Cox regression analysis. Among many complications, notable specific events included hepatitis B or C seroconversion (7 patients), active hepatitis and/or fulminant hepatic failure (4 patients), pulmonary tuberculosis (2 patients), and a type A dissecting aortic aneurysm. Commercial transplantation was independently associated with significantly reduced death-censored kidney allograft survival (hazard ratio 3.69, 95% confidence interval 1.88-7.25) along with significantly delayed graft function and eGFR 30 ml/min/1.73 m(2) or less at 3 months post-transplant. Thus, commercial transplantation represents an important risk factor for long-term kidney allograft loss. Concerted arguments and efforts using adverse recipient outcomes among the main premises are still required in order to eradicate transplant commercialization.

IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

Metabolic syndrome definitions and components in predicting major adverse cardiovascular events after kidney transplantation.

Metabolic syndrome (MetS) associates with cardiovascular risk post-kidney transplantation, but its ambiguity impairs understanding of its diagnostic utility relative to components. We compared five MetS definitions and the predictive value of constituent components of significant definitions for major adverse cardiovascular events (MACE) in a cohort of 1182 kidney transplant recipients. MetS definitions were adjusted for noncomponent traditional Framingham risk factors and relevant transplant-related variables. Kaplan-Meier, logistic regression, and Cox proportional hazards analysis were utilized. There were 143 MACE over 7447 patient-years of follow-up. Only the World Health Organization (WHO) 1998 definition predicted MACE (25.3 vs 15.5 events/1000 patient-years, P = 0.019). Time-to-MACE was 5.5 ± 3.5 years with MetS and 6.8 ± 3.9 years without MetS (P < 0.0001). MetS was independent of pertinent MACE risk factors except age and previous cardiac disease. Among MetS components, dysglycemia provided greatest hazard ratio (HR) for MACE (1.814 [95% confidence interval 1.26-2.60]), increased successively by microalbuminuria (HR 1.946 [1.37-2.75]), dyslipidemia (3.284 [1.72-6.26]), hypertension (4.127 [2.16-7.86]), and central obesity (4.282 [2.09-8.76]). MetS did not affect graft survival. In summary, although the WHO 1998 definition provides greatest predictive value for post-transplant MACE, most of this is conferred by dysglycemia and is overshadowed by age and previous cardiac disease.

A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers.

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once-daily tacrolimus extended release (Tac-ER) includes equivalent exposure [AUC(0-24 h) ] but lower Cmax versus twice-daily tacrolimus immediate release (Tac-IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once-daily Tac-ER and twice-daily Tac-IR in a prospective, randomized, two period, cross-over study. Tacrolimus was titrated to achieve trough levels of 8-12 ng/ml. Twenty four hours ERPF and GFR estimated by para-aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10-day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac-ER and Tac-IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac-ER compared with Tac-IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m(2) , P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac-ER at 114.5 ± 13.6 ml/min/1.73 m(2) compared with 108.9 ± 9.7 ml/min/1.73 m(2) for Tac-IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac-ER compared with Tac-IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).

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.

Effect of a Novel Multicomponent Intervention to Improve Patient Access to Kidney Transplant and Living Kidney Donation: The EnAKT LKD Cluster Randomized Clinical Trial.

Importance: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant. Objectives: To evaluate the effect of a multicomponent intervention designed to target several barriers that prevent eligible patients from completing key steps toward receiving a kidney transplant. Design, Setting, and Participants: This pragmatic, 2-arm, parallel-group, open-label, registry-based, superiority, cluster randomized clinical trial included all 26 CKD programs in Ontario, Canada, from November 1, 2017, to December 31, 2021. These programs provide care for patients with advanced CKD (patients approaching the need for dialysis or receiving maintenance dialysis). Interventions: Using stratified, covariate-constrained randomization, allocation of the CKD programs at a 1:1 ratio was used to compare the multicomponent intervention vs usual care for 4.2 years. The intervention had 4 main components, (1) administrative support to establish local quality improvement teams; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders. Main Outcomes and Measures: The primary outcome was the rate of steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant center for evaluation; step 2, had a potential living donor contact a transplant center for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor. Results: The 26 CKD programs (13 intervention, 13 usual care) during the trial period included 20 375 potentially transplant-eligible patients with advanced CKD (intervention group [n = 9780 patients], usual-care group [n = 10 595 patients]). Despite evidence of intervention uptake, the step completion rate did not significantly differ between the intervention vs usual-care groups: 5334 vs 5638 steps; 24.8 vs 24.1 steps per 100 patient-years; adjusted hazard ratio, 1.00 (95% CI, 0.87-1.15). Conclusions and Relevance: This novel multicomponent intervention did not significantly increase the rate of completed steps toward receiving a kidney transplant. Improving access to transplantation remains a global priority that requires substantial effort. Trial Registration: ClinicalTrials.gov Identifier: NCT03329521.

Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD): Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial.

Background: Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) is a quality improvement intervention designed to enhance access to kidney transplantation and living kidney donation. We conducted a cluster-randomized clinical trial to evaluate the effect of the intervention versus usual care on completing key steps toward receiving a kidney transplant. Objective: To prespecify the statistical analysis plan for the EnAKT LKD trial. Design: The EnAKT LKD trial is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized, superiority, clinical trial. Randomization was performed at the level of the chronic kidney disease (CKD) programs (the "clusters"). Setting: Twenty-six CKD programs in Ontario, Canada. Participants: More than 10 000 patients with advanced CKD (ie, patients approaching the need for dialysis or receiving maintenance dialysis) with no recorded contraindication to receiving a kidney transplant. Methods: The trial data (including patient characteristics and outcomes) will be obtained from linked administrative health care databases (the "registry"). Stratified covariate-constrained randomization was used to allocate the 26 CKD programs (1:1) to provide the intervention or usual care from November 1, 2017, to December 31, 2021 (4.17 years). CKD programs in the intervention arm received the following: (1) support for local quality improvement teams and administrative needs; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders. Outcomes: The primary outcome is completing key steps toward receiving a kidney transplant, where up to 4 unique steps per patient will be considered: (1) patient referred to a transplant center for evaluation, (2) a potential living kidney donor begins their evaluation at a transplant center to donate a kidney to the patient, (3) patient added to the deceased donor transplant waitlist, and (4) patient receives a kidney transplant from a living or deceased donor. Analysis plan: Using an intent-to-treat approach, the primary outcome will be analyzed using a patient-level constrained multistate model adjusting for the clustering in CKD programs. Trial Status: The EnAKT LKD trial period is November 1, 2017, to December 31, 2021. We expect to analyze and report the results once the data for the trial period is available in linked administrative health care databases. Trial Registration: The EnAKT LKD trial is registered with the U.S. National Institute of Health at clincaltrials.gov (NCT03329521 available at https://clinicaltrials.gov/ct2/show/NCT03329521). Statistical Analytic Plan: Version 1.0 August 26, 2022.

Contexte: EnAKT LKD est une intervention d'amélioration de la qualité visant à améliorer l'accès à la transplantation rénale et au don vivant de rein. Nous avons mené un essai clinique randomisé par grappes afin d'évaluer l'effet de l'intervention, par rapport aux soins habituels, sur le taux d'étapes clés réalisées dans le processus de réception d'une greffe de rein. Objectif: Exposer les grandes lignes du plan d'analyse statistique de l'essai EAKT LKD. Conception: EAKT LKD est un essai clinique pragmatique ouvert, à deux bras, en groupes parallèles, basé sur un registre, et randomisé en grappes. La randomisation a été réalisée au niveau des programmes d'insuffisance rénale chronique (IRC) (les « grappes ¼). Cadre: 26 programmes d'IRC en Ontario (Canada). Sujets: Plus de 10 000 patients atteints d'IRC de stade avancé (des patients approchant le besoin de dialyse ou recevant une hémodialyse d'entretien) sans contre-indication documentée à la greffe rénale. Méthodologie: Les données de l'essai (y compris les caractéristiques et les résultats des patients) seront obtenues à partir de bases de données administratives en santé (le « registre ¼). La randomisation stratifiée avec contraintes de covariables a servi à répartir les 26 programmes d'IRC (1:1) selon qu'ils allaient fournir l'intervention ou les soins habituels entre le 1er novembre 2017 et le 31 décembre 2021 (4,17 ans). Les programmes d'IRC du bras d'intervention ont eu droit au soutien suivant: (1) des équipes locales d'amélioration de la qualité et du soutien administratif; (2) de l'information et des ressources sur mesure pour le personnel, les patients et les donneurs vivants; (3) du soutien de la part de receveurs et de donneurs vivants; et (4) des rapports sur le rendement au niveau du programme et une surveillance assurée par les chefs de programme. Résultats: Le principal critère d'évaluation est le taux d'étapes clés accomplies vers la réception d'une greffe de rein, où jusqu'à quatre étapes uniques par patient seront comptabilisées: (1) le patient est aiguillé vers un centre de transplantation pour évaluation; (2) un possible donneur vivant de rein contacte un centre de transplantation pour un receveur en particulier et amorce son évaluation; (3) le patient est ajouté à la liste d'attente pour une transplantation d'un donneur décédé, et (4) le patient reçoit une greffe de rein d'un donneur vivant ou décédé. Plan d'analyse: Selon une approche fondée sur l'intention de traiter, le critère d'évaluation principal sera analysé au niveau du patient en utilisant un modèle multiétats contraint, corrigé dans les programmes d'IRC en fonction du regroupement. Statut de l'essai: L'essai EnAKT LKD s'est tenu du 1er novembre 2017 au 31 décembre 2021. Nous analyserons les résultats et en rendrons compte dès que les données seront disponibles dans les bases de données administratives couplées du système de santé.

Retrospective Analysis of Tacrolimus Intrapatient Variability as a Measure of Medication Adherence.

BACKGROUND: Increased intrapatient variability (IPV) in tacrolimus levels is associated with graft rejection, de novo donor-specific antibodies, and graft loss. Medication nonadherence may be a significant contributor to high IPV. OBJECTIVE: The objective of this study is to determine the utility of tacrolimus IPV in detecting nonadherence by examining the relationship between self-reported adherence and tacrolimus coefficient of variability (COV), a measure of IPV. DESIGN: Retrospective cohort study. SETTING: St. Michael's Hospital, Toronto, Ontario. PATIENTS: All patients who were at least 1-year post-kidney transplant as of March 31, 2019, prescribed tacrolimus as an immunosuppressant and had a self-reported adherence status. Patients were excluded from the primary analysis of examining the correlation between COV and self-reported adherence if they lacked a calculatable COV. MEASUREMENTS: Self-reported adherence, COV, demographic data, transplant, and medication history. METHODS: A modified Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) administered by healthcare professionals to assess self-reported adherence was used. The COV of tacrolimus trough levels was calculated and its correlation to BAASIS response was noted. The median COV was used as a cutoff to examine the characteristics of patients deemed "high COV" and "low COV." RESULTS: A total of 591 patients fit the initial criteria; however, only 525 had a recent calculatable COV. Overall, 92.38% of the population were adherent by self-report. Primary analysis identified a COV of 25.2% and 29.6% in self-reported adherent and nonadherent patients, respectively, though the result was not significant (P = .2). Secondary analyses showed a significant correlation between younger age at transplant and at the time of adherence self-reporting with nonadherence (P = .01). In addition, there was a strong correlation between those nonadherent with routine post-transplant blood work and younger age (P < .01). LIMITATIONS: The limitations included modified nonvalidated BAASIS questionnaire, social desirability bias, BAASIS only administered in English, and patients with graft failure not active in clinic not being captured. CONCLUSIONS: The COV should not be used as the sole method for determining medication adherence. However, COV may have some utility in capturing individuals who are not adherent to their blood work or patients who are having a poor response to tacrolimus and should be switched to another medication.

CONTEXTE: Une plus grande variabilité intra-individuelle des taux de tacrolimus est associée au rejet de la greffe, aux anticorps spécifiques au donneur de novo et à la perte du greffon. La non-observance du traitement médicamenteux pourrait être un facteur important de cette variabilité élevée. OBJECTIF: L'objectif de cette étude était d'évaluer la pertinence de la variabilité intra-individuelle des taux de tacrolimus pour la détection de la non-observance en examinant la relation entre l'observance autodéclarée et le coefficient de variabilité (CoV) du tacrolimus, une mesure de la variabilité intra-individuelle. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: L'hôpital St Michael's de Toronto (Ontario). SUJETS: Tous les patients qui, au 31 mars 2019, avaient subi une transplantation depuis au moins un an, à qui on avait prescrit du tacrolimus comme immunosuppresseur et qui déclaraient adhérer à leur traitement. Les patients qui ne disposaient pas d'un CoV calculable ont été exclus de l'analyse principale examinant la corrélation entre le CoV et l'observance autodéclarée. MESURES: L'observance autodéclarée, le CoV, les données démographiques, ainsi que les antécédents de transplantation et pharmaceutiques des patients. MÉTHODOLOGIE: Une version modifiée du questionnaire BAASIS (Basel Assessment of Adherence to Immunosuppressive Medications Scale) administrée par les professionnels de la santé a été employée pour évaluer l'observance autodéclarée. Le CoV des concentrations minimales de tacrolimus a été calculé et sa corrélation avec les réponses au questionnaire BAASIS a été notée. Le CoV médian a été employé comme mesure limite pour examiner les caractéristiques des patients réputés avoir un « CoV élevé ¼ ou un « CoV faible ¼. RÉSULTATS: Au total, 591 patients satisfaisaient aux critères initiaux, mais seulement 525 disposaient d'une mesure récente et calculable du CoV. Dans l'ensemble, 92,38 % de la population étudiée déclarait adhérer au traitement. L'analyse primaire a permis d'établir le CoV à 25,2 % chez les patients adhérents et à 29,6 % chez les patients non-adhérents; bien que les résultats n'aient pas été jugés significatifs (p = 0,2). Les analyses secondaires ont montré une corrélation significative entre la non-observance autodéclarée au traitement et le fait d'être plus jeune au moment de la transplantation (p = 0,01). On a en outre observé une forte corrélation entre la non-observance des bilans sanguins habituels post-transplantation et un plus jeune âge (p < 0,01). LIMITES: La version modifiée du questionnaire BAASIS n'a pas été validée, l'étude comporte de possibles biais de désirabilité sociale, le questionnaire BAASIS n'a été passé qu'en anglais et les patients avec échec de la greffe qui étaient inactifs en clinique n'ont pu être saisis. CONCLUSION: Le coefficient de variabilité ne devrait pas être le seul élément à considérer pour déterminer l'adhérence au traitement. Ce coefficient peut cependant avoir une certaine utilité pour repérer les patients qui ne font pas leurs bilans sanguins ou les patients qui répondent peu au tacrolimus et qui devraient passer à un autre médicament.

A Quality Improvement Intervention to Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) in Patients With Chronic Kidney Disease: Clinical Research Protocol of a Cluster-Randomized Clinical Trial.

BACKGROUND: Many patients with kidney failure will live longer and healthier lives if they receive a kidney transplant rather than dialysis. However, multiple barriers prevent patients from accessing this treatment option. OBJECTIVE: To determine if a quality improvement intervention provided in chronic kidney disease (CKD) programs (vs. usual care) enables more patients with no recorded contraindications to kidney transplant to complete more steps toward receiving a kidney transplant. DESIGN: This protocol describes a pragmatic 2-arm, parallel-group, open-label, registry-based, cluster-randomized clinical trial-the Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) trial. SETTING: All 26 CKD programs in Ontario, Canada, with a trial start date of November 1, 2017. The original end date of March 31, 2021 (3.4 years) has been extended to December 31, 2021 (4.1 years) due to the COVID-19 pandemic. PARTICIPANTS: During the trial, the 26 CKD programs are expected to care for more than 10 000 adult patients with CKD (including patients approaching the need for dialysis and patients receiving dialysis) with no recorded contraindications to a kidney transplant. INTERVENTION: Programs were randomly allocated to provide a quality improvement intervention or usual care. The intervention has 4 main components: (1) local quality improvement teams and administrative support; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders. PRIMARY OUTCOME: The primary outcome is the number of key steps completed toward receiving a kidney transplant analyzed at the cluster level (CKD program). The following 4 unique steps per patient will be counted: (1) patient referred to a transplant center for evaluation, (2) at least one living kidney donor candidate contacts a transplant center for an intended recipient and completes a health history questionnaire to begin their evaluation, (3) patient added to the deceased donor transplant wait list, and (4) patient receives a kidney transplant from a living or deceased donor. PLANNED PRIMARY ANALYSIS: Study data will be obtained from Ontario's linked administrative healthcare databases. An intent-to-treat analysis will be conducted comparing the primary outcome between randomized groups using a 2-stage approach. First stage: residuals are obtained from fitting a regression model to individual-level variables ignoring intervention and clustering effects. Second stage: residuals from the first stage are aggregated at the cluster level as the outcome. LIMITATIONS: It may not be possible to isolate independent effects of each intervention component, the usual care group could adopt intervention components leading to contamination bias, and the relatively small number of clusters could mean the 2 arms are not balanced on all baseline prognostic factors. CONCLUSIONS: The EnAKT LKD trial will provide high-quality evidence on whether a multi-component quality improvement intervention helps patients complete more steps toward receiving a kidney transplant. TRIAL REGISTRATION: Clinicaltrials.gov; identifier: NCT03329521.

CONTEXTE: Plusieurs patients atteints d'insuffisance rénale vivront plus longtemps et en meilleure santé s'ils reçoivent une greffe de rein plutôt que des traitements de dialyze. De nombreux obstacles empêchent cependant les patients d'accéder à la transplantation. OBJECTIF: Déterminer si une intervention visant l'amélioration de la qualité menée dans les programs d'insuffisance rénale chronique (IRC) permettrait à davantage de patients sans contre-indications à une greffe d'aller plus loin (comparativement aux soins habituels) dans le processus menant à la transplantation. TYPE D'ÉTUDE: Ce protocole décrit un essai clinique pragmatique ouvert, à deux bras, en groupes parallèles, à répartition aléatoire en grappes et fondé sur un registre ­ l'essai Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD). CADRE: Les 26 programs d'IRC de l'Ontario (Canada). L'essai a débuté le 1er novembre 2017 et devait initialement se terminer le 31 mars 2021 (3,4 ans); cette date a été reportée au 31 décembre 2021 (4,1 ans) en raison de la pandémie de COVID-19. SUJETS: Au cours de l'essai, on estime que les 26 programs d'IRC prendront en charge plus de 10 000 adultes atteints d'IRC (y compris des patients approchant le besoin de dialyze et des patients dialysés) sans contre-indications à une greffe. INTERVENTIONS: Les programs ont été répartis aléatoirement pour intégrer une intervention d'amélioration de la qualité ou pour prodiguer les soins habituels. L'intervention consiste en quatre composantes principales: (1) des équipes locales d'amélioration de la qualité et de soutien administratif; (2) de l'information et des ressources sur mesure pour le personnel, les patients et les donneurs vivants; (3) du soutien pour les receveurs et les donneurs vivants; et (4) des rapports sur le rendement au niveau du program et une surveillance assurée par les chefs de program. PRINCIPAUX RÉSULTATS: Le principal critère d'évaluation est le nombre d'étapes clés complétées en vue de la réception d'une greffe de rein tel qu'analysé au niveau de la grappe (program d'IRC). Pour chaque patient, quatre étapes spécifiques seront comptabilisées: (I) le patient est aiguillé vers un center de transplantation pour évaluation; (II) au moins un donneur vivant de rein contacte un center de transplantation pour un receveur en particulier et amorce son évaluation en remplissant un questionnaire sur ses antécédents médicaux; (III) le patient est ajouté à la liste d'attente pour une transplantation d'un donneur décédé, et (IV) le patient reçoit une greffe de rein d'un donneur vivant ou décédé. PRINCIPALE ANALYZE ENVISAGÉE: Les données sont tirées des bases de données administratives du système de santé ontarien. Une analyze en intention de traiter sera effectuée en comparant le principal critère d'évaluation entre les groupes répartis aléatoirement à l'aide d'une approche en deux étapes. Première étape: obtention de valeurs résiduelles en adaptant un modèle de régression aux variables de niveau individuel et en ignorant les effets de l'intervention et du regroupement. Deuxième étape: les valeurs résiduelles de la première étape agrégées au niveau du groupe constitueront le résultat. LIMITES: Il pourrait ne pas être possible d'isoler les effets indépendants de chaque composante de l'intervention. L'équipe prodiguant les soins habituels pourrait adopter des composantes de l'intervention menant à un biais de contamination. Le nombre relativement faible de groupes pourrait signifier que les deux bras ne sont pas équilibrés sur tous les facteurs pronostiques de base. CONCLUSION: L'essai EnAKT LKD fournira des données de haute qualité sur la question de savoir si une intervention à composantes multiples visant l'amélioration de la qualité aide effectivement les patients à franchir davantage d'étapes vers une transplantation rénale.

The First North American Experience Using Glycosorb Immunoadsorption Columns for Blood Group-Incompatible Kidney Transplantation.

BACKGROUND: Blood group incompatibility (ABOi) is the most common barrier to living donor kidney transplantation. Options for such recipients include kidney paired donation (KPD) or desensitization methodology to reduce blood antibody response. OBJECTIVE: The objective of this study is to report on the first North America experience in ABOi living donor kidney transplantation using Glycosorb ABO immunoadsorption columns. DESIGN: Retrospective observational cohort study. SETTING: Renal transplant program at St. Michael's Hospital, Unity Health Toronto, University of Toronto. PATIENTS: Twenty-six ABOi living donor transplants from August 2011 through February 2020 were undertaken at our center. MEASUREMENTS: Renal allograft and patient survival postdesensitization for ABOi living donor transplants and isohemagglutinin titer reduction. METHODS: Preoperative immunosuppressive regimen consisted of a single dose of Rituximab 375 mg/m2 IV on day -28; tacrolimus, mycophenolic acid, and prednisone to start on day -7. Immunoadsorption treatments with Glycosorb A or B columns were performed on day -7 through day -1 based on anti-A or anti-B titers on Spectra Optia Apheresis System. Immunosuppression included basiliximab, solumedrol followed by oral prednisone, once-daily tacrolimus, and mycophenolic acid. The mean follow-up was 53 months (3-96 months). RESULTS: A total of 26 individuals underwent an attempt at desensitization of whom 24 patients underwent immediate transplant. One patient had a rebound in titers and subsequently was transplanted from a blood group compatible living donor. A second patient had an unrelated medical issue and desensitization was discontinued. Five-year patient survival was 96% and death censored allograft survival was 92%. Posttransplant anti-A or anti-B titers were monitored daily for the first 7 days posttransplant and every 2 days from days 7 to 14. There were no acute rejections seen in this cohort of transplant recipients. LIMITATIONS: As our protocol was first initiated as proof of concept, a few recipients had low initial isohemagglutinin titers. This may have contributed to improved clinical outcomes. CONCLUSIONS: ABO column immunoadsorption with specific columns is a safe and effective method for ABOi living donor kidney transplantation, and an option when KPD is less than ideal.Trial not registered as this was a retrospective cohort review.

CONTEXTE: L'incompatibilité du système ABO (ABOi) est l'obstacle le plus fréquent à la transplantation d'un rein provenant d'un donneur vivant. Un don croisé ou une désensibilisation visant à atténuer la réponse immunitaire constituent les seules options pour les receveurs de ce type de greffe. OBJECTIF: Faire état de la première expérience nord-américaine d'utilisation des colonnes d'immunoadsorption Glycosorb ABO pour la transplantation d'un rein ABOi provenant d'un donneur vivant. TYPE D'ÉTUDE: Étude de cohorte observationnelle rétrospective. CADRE: Le programme de transplantation rénale du centre hospitalier universitaire St Michael's de l'Unity Health Toronto. SUJETS: L'étude porte sur les 26 transplantations de reins ABOi provenant de donneurs vivants pratiquées à notre centre entre août 2011 et février 2020. MESURES: La survie du patient et de l'allogreffe après une désensibilisation en vue de la transplantation d'un rein ABOi provenant d'un donneur vivant, ainsi que la réduction du titre d'isohémagglutinine. MÉTHODOLOGIE: Le traitement préopératoire immunosuppressif consistait en une dose unique de 375 mg/m2 de Rituximab par voie intraveineuse (IV) au jour -28; et l'administration de tacrolimus, d'acide mycophénolique et de prednisone à partir du jour -7. Les traitements d'immunoadsorption avec les colonnes Glycosorb A ou B ont été effectués du jour -7 au jour -1 en fonction des titres anti-A ou anti-B obtenus avec le système d'apharèse Spectra Optia. Le traitement immunosuppressif était constitué de basiliximab, de solumédrol suivi de prednisone par voie orale, et d'une dose quotidienne de tacrolimus et d'acide mycophénolique. Le suivi s'est étalé sur une moyenne de 53 mois (3 à 96 mois). RÉSULTATS: En tout, 26 patients avaient tenté une désensibilisation, desquels 24 ont immédiatement subi une transplantation. Un rebond des titres a été observé chez un patient, lequel a par la suite été transplanté avec un organe provenant d'un donneur de groupe sanguin compatible. La désensibilisation a dû être interrompue chez un autre patient en raison d'un problème médical non relié. Cinq ans après la greffe, 96% des patients et 92% des allogreffes avaient survécu. Les titres d'anti-A et d'anti-B post-transplantation avaient été mesurés quotidiennement pour les sept premiers jours suivant l'intervention, puis tous les deux jours entre le jour 7 et le jour 14. Aucun rejet aigu n'est survenu dans la cohorte étudiée. LIMITES: Notre protocole ayant d'abord été utilisé comme preuve de concept, certains patients présentaient de faibles titres initiaux d'isohémagglutinine, ce qui pourrait avoir contribué à l'amélioration des résultats cliniques. CONCLUSIONS: L'immunoadsorption sur colonne ABO avec colonnes spécifiques s'avère une méthode sûre et efficace pour la transplantation d'un rein ABOi provenant d'un donneur vivant, et constitue une option valable lorsque le don croisé n'est pas idéal.Essai non enregistré puisqu'il s'agit d'une étude de cohorte rétrospective.