Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Mycophenolic acid (MPA) is a commonly prescribed life-long immunosuppressant for kidney transplant recipients. The frequently observed large variations in MPA plasma exposure may lead to severe adverse outcomes; therefore, characterizations of contributing factors can potentially improve the precision dosing of MPA. Our group recently reported the potent inhibitory effects of p-cresol (a protein-bound uremic toxin that can be accumulated in kidney transplant patients) on the hepatic metabolism of MPA in human in vitro models. Based on these data, the hypothesis for this clinical investigation was that a direct correlation between p-cresol and MPA plasma exposure should be evident in adult kidney transplant recipients. METHODS: Using a prospective and observational approach, adult kidney transplant recipients within the first year after transplant on oral mycophenolate mofetil (with tacrolimus ± prednisone) were screened for recruitment. The exclusion criteria were cold ischemia time > 30 h, malignancy, pregnancy, severe renal dysfunction (i.e., estimated glomerular filtration rate, eGFR, < 10 mL/min/1.73 m2), active graft rejection, or MPA intolerance. Patients' demographic and biochemistry data were collected. Total and free plasma concentrations of MPA, MPA glucuronide (MPAG), and total p-cresol sulfate (the predominant, quantifiable form of p-cresol in the plasma) were quantified using validated assays. Correlational and categorical analyses were performed using GraphPad Prism. RESULTS: Forty patients (11 females) were included: donor type (living/deceased: 20/20), induction regimen (basiliximab/thymoglobulin/basiliximab followed by thymoglobulin: 35/3/2), post-transplant time (74 ± 60 days, mean ± standard deviation), age (53.7 ± 12.4 years), bodyweight (79.8 ± 18.5 kg), eGFR (51.9 ± 18.0 mL/min/1.73 m2), serum albumin (3.6 ± 0.5 g/dL), prednisone dose (18.5 ± 13.2 mg, n = 33), and tacrolimus trough concentration (9.4 ± 2.4 µg/L). Based on Spearman analysis, significant control correlations supporting the validity of our dataset were observed between total MPA trough concentration (C0) and total MPAG C0 (correlation coefficient [R] = 0.39), ratio of total MPAG C0-to-total MPA C0 and post-transplant time (R = - 0.56), total MPAG C0 and eGFR (R = - 0.35), and p-cresol sulfate concentration and eGFR (R = - 0.70). Our primary analysis indicated the novel observation that total MPA C0 (R = 0.39), daily dose-normalized total MPA C0 (R = 0.32), and bodyweight-normalized total MPA C0 (R = 0.32) were significantly correlated with plasma p-cresol sulfate concentrations. Consistently, patients categorized with elevated p-cresol sulfate concentrations (i.e., ≥ median of 3.2 µg/mL) also exhibited increased total MPA C0 (by 57 % vs those below median), daily dose-normalized total MPA C0 (by 89 %), and bodyweight-normalized total MPA C0 (by 62 %). Our secondary analyses with MPA metabolites, unbound concentrations, free fractions, and MPA metabolite ratios supported additional potential interacting mechanisms. CONCLUSION: We have identified a novel, positive association between p-cresol sulfate exposure and total MPA C0 in adult kidney transplant recipients, which is supported by published mechanistic in vitro data. Our findings confirm a potential role of p-cresol as a significant clinical variable affecting the pharmacokinetics of MPA. These data also provide the justifications for conducting subsequent full-scale pharmacokinetic-pharmacodynamic studies to further characterize the cause-effect relationships of this interaction, which could also rule out potential confounding variables not adequately controlled in this correlational study.

i-IFTA and chronic active T cell-mediated rejection: A tale of 2 (DeKAF) cohorts.

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsies is part of the diagnostic criteria for chronic active TCMR (CA TCMR -- i-IFTA ≥ 2, ti ≥ 2, t ≥ 2). We evaluated i-IFTA and CA TCMR in the DeKAF indication biopsy cohorts: prospective (n = 585, mean time to biopsy = 1.7 years); cross-sectional (n = 458, mean time to biopsy = 7.8 years). Grouped by i-IFTA scores, the 3-year postbiopsy DC-GS is similar across cohorts. Although a previous acute rejection episode (AR) was more common in those with i-IFTA on biopsy, the majority of those with i-IFTA had not had previous AR. There was no association between type of previous AR (AMR, TCMR) and presence of i-IFTA. In both cohorts, i-IFTA was associated with markers of both cellular (increased Banff i, t, ti) and humoral (increased g, ptc, C4d, DSA) activity. Biopsies with i-IFTA = 1 and i-IFTA ≥ 2 with concurrent t ≥ 2 and ti ≥ 2 had similar DC-GS. These results suggest that (a) i-IFTA≥1 should be considered a threshold for diagnoses incorporating i-IFTA, ti, and t; (b) given that i-IFTA ≥ 2,t ≥ 2, ti ≥ 2 can occur in the absence of preceding TCMR and that the component histologic scores (i-IFTA,t,ti) each indicate an acute change (albeit i-IFTA on the nonspecific background of IFTA), the diagnostic category "CA TCMR" should be reconsidered.

Incidence, Risk Factors, and Outcomes of Kidney Transplant Recipients Treated With Both Basiliximab and Antithymocyte Globulin.

BACKGROUND: Kidney transplant recipients are given induction therapy to rapidly reduce the immune response and prevent rejection. Guidelines recommend that an interleukin-2 receptor antibody (basiliximab) be the first-line agent and that a lymphocyte-depleting agent (antithymocyte globulin [ATG]) be reserved for those at high immunologic risk. OBJECTIVE: To determine the incidence, risk factors, and outcomes for patients who receive both basiliximab and ATG for induction compared to either agent alone. DESIGN: Retrospective cohort study. SETTING: We used the transplant electronic medical record at the University of Alberta Hospital in Edmonton, Canada. PATIENTS/SAMPLES/PARTICIPANTS: We included incident adult kidney transplant recipients from 2013 to 2018. MEASUREMENTS: We measured baseline characteristics, type, and dose of induction therapy used, estimated glomerular filtration rate (eGFR) at 1-year posttransplant, and outcomes of all-cause graft failure, death-censored graft failure, all-cause mortality, and death with a functioning graft. METHODS: Differences between induction groups were compared using chi-square test for categorical variables and Kruskal-Wallis tests for continuous variables. We performed multivariable logistic regression modeling with type of induction therapy as the dependent variable and the case-level factors as the predictors (adjusted odds ratio). We estimated the Kaplan-Meier failure functions and used log-rank tests to assess statistical significance of differences in unadjusted incidence across induction therapy types. We compared cumulative incidence functions using a Fine and Gray competing risk regression model. RESULTS: In all, 430 kidney transplant recipients were followed for a mean of 3.9 years (standard deviation 1.5). Of these, 71% (n = 305) received basiliximab alone, 22% (n = 93) received ATG alone, and 7% (n = 32) received both basiliximab and ATG. After adjusting for age and sex, compared to the basiliximab alone group, patients were more likely to receive dual-induction therapy if they were sensitized (calculated panel reactive antibody ≥80%), had diabetes mellitus or peripheral vascular disease, or experienced delayed graft function. Compared to the ATG alone group, the dual-induction therapy group had worse graft function at 1 year (mean eGFR 42 vs. 59 mL/min/1.73 m2, P = .0008) and an increased risk of all-cause graft failure (31% vs. 13%, P = .02) and death-censored graft failure (16% vs. 4%, P = .03). LIMITATIONS: There is a risk of confounding by indication, as patients who received dual-induction therapy likely had worse outcomes due to the indication for dual-induction therapy (such as delayed graft function). CONCLUSIONS: In our study, 1 out of 10 recipients who were treated with basiliximab also received ATG for induction therapy. These patients experienced worse outcomes than those treated with ATG alone. TRIAL REGISTRATION: Not applicable (cohort study).

CONTEXTE: Les receveurs d'une greffe rénale reçoivent un traitement par induction pour réduire la réponse immunitaire et prévenir le rejet. Les lignes directrices recommandent qu'un anticorps du récepteur de l'interleukine-2 (basiliximab) soit l'agent de première ligne et qu'un agent de déplétion immunitaire (immunoglobulines anti-thymocytes [ATG]) soit réservé aux patients présentant un risque immunologique élevé. OBJECTIF: Connaître l'incidence d'une double induction (basiliximab + ATG), les facteurs de risque et l'issue des patients l'ayant reçue comparativement aux patients n'ayant reçu qu'un seul des deux agents. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Nous avons consulté les dossiers médicaux électroniques de transplantation du University of Alberta Hospital d'Edmonton (Canada). SUJETS: Ont été inclus les adultes receveurs d'une greffe rénale entre 2013 et 2018. MESURES: Nous avons mesuré les caractéristiques démographiques initiales, le type et la dose du traitement d'induction administré, le débit de filtration glomérulaire estimé (DFGe) mesuré un an post-greffe, de même que les résultats cliniques de dysfonction du greffon de toutes causes, de dysfonction du greffon censurée par le décès, de mortalité toutes causes ou de décès avec un greffon fonctionnel. MÉTHODOLOGIE: Les différences entre les groupes d'induction ont été comparées à l'aide du test de Chi-Deux (variables catégorielles) et des tests de Kruskal-Wallis (variables continues). Nous avons procédé à une modélisation de régression logistique multivariable avec le type de traitement d'induction comme variable dépendante et les facteurs de risque pour chaque cas comme prédicteurs (rapport de cote corrigé). Nous avons évalué les défaillances de fonction avec une courbe de Kaplan-Meier, et des tests logarithmiques par rangs ont été employés pour évaluer la signification statistique des différences dans l'incidence non corrigée entre les types de traitements d'induction administrés. Un modèle de régression des risques concurrents Fine and Gray a été employé pour comparer les fonctions d'incidence cumulée. RÉSULTATS: En tout, 430 receveurs d'une greffe rénale ont été suivis sur une période moyenne de 3,9 ans (écart type: 1,5 an). De ceux-ci, 71 % (n = 305) n'avaient reçu que du basiliximab, 22 % (n = 93) n'avaient reçu que des ATG et 7 % (n = 32) avaient reçu le double traitement par induction. Après la correction pour l'âge et le sexe, et lorsque comparés aux patients n'ayant reçu que du basiliximab, les patients sensibilisés (allo-anticorps calculés d'au moins 80 %), diabétiques, atteints de maladie vasculaire périphérique ou ayant vécu un délai dans la reprise de la fonction du greffon se sont avérés plus susceptibles de recevoir le double traitement par induction. Le groupe ayant reçu le double traitement par induction présentait une moins bonne fonction du greffon un an après l'intervention (DFGe moyen: 42 vs 59 ml/min/1,73 m2; P = .0008), avaient un risque accru de dysfonction du greffon toutes causes (31 % vs 13 %; P =.02) et un taux de dysfonction du greffon censurée par le décès plus élevé (16 % vs 4 %; P = .03) lorsque comparé au groupe traité par les ATG seulement. LIMITES: Un risque de confusion par indication existe puisque les patients ayant reçu le double traitement par induction ont probablement eu de moins bons résultats, notamment un retard dans la reprise de la fonction du greffon, en raison de cette indication. CONCLUSION: Dans notre étude, un patient sur dix avait reçu le double traitement par induction (basiliximab et ATG). Ces patients ont cependant eu de moins bons résultats de santé que les patients traités aux ATG seulement. ENREGISTREMENT DE L'ESSAI: Sans objet (étude de cohorte).

Inflammation in areas of fibrosis: The DeKAF prospective cohort.

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsy specimens has been associated with decreased death-censored graft survival (DC-GS). Additionally, an i-IFTA score ≥ 2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i-IFTA and t-IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90 days posttransplant (n = 598); mean (SD) 1.7 ± 1.4 years posttransplant. I-IFTA, present in 196 biopsy specimens, was strongly correlated with t-IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score = 0. Unlike previous studies, i-IFTA = 1 (vs 0) was associated with worse 3-year DC-GS: (i-IFTA = 0, 81.7%, [95% CI 77.7 to 85.9%]); i-IFTA = 1, 68.1%, [95% CI 59.7 to 77.6%]; i-IFTA = 2, 56.1%, [95% CI 43.2 to 72.8%], i-IFTA = 3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i-IFTA with decreased DC-GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T-IFTA was similarly associated with decreased DC-GS. Of these indication biopsies, those with i-IFTA ≥ 2, without meeting other criteria for CA TCMR had similar postbiopsy DC-GS as those with CA TCMR. Those with i-IFTA = 1 and t ≥ 2, ti ≥ 2 had postbiopsy DC-GS similar to CA TCMR. Biopsies with i-IFTA = 1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i-IFTA and t-IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.

Outcomes Following Macrolide Use in Kidney Transplant Recipients.

BACKGROUND: Calcineurin inhibitors (CNI; cyclosporine, tacrolimus) are critical for kidney transplant immunosuppression, but have multiple potential drug interactions, such as with macrolide antibiotics. Macrolide antibiotics (clarithromycin, erythromycin, and azithromycin) are often used to treat atypical infections. Clarithromycin and erythromycin inhibit CNI metabolism and increase the risk of CNI nephrotoxicity, while azithromycin does not. OBJECTIVE: To determine the frequency of CNI-macrolide co-prescriptions, the proportion who receive post-prescription monitoring, and the risk of adverse drug events in kidney transplant recipients. DESIGN: Retrospective cohort study. SETTING: We used linked health care databases in Alberta, Canada. PATIENTS: We included 293 adult kidney transplant recipients from 2008-2015 who were co-prescribed a CNI and macrolide. MEASUREMENTS: The primary outcome was a composite of all-cause hospitalization, acute kidney injury (creatinine increase ≥0.3 mg/dL or 1.5 times baseline), or death within 30 days of the macrolide prescription. METHODS: We identified CNI-macrolide co-prescriptions and compared outcomes in those who received clarithromycin/erythromycin versus azithromycin. We used a linear mixed-effects model to examine the mean change in serum creatinine and estimated glomerular filtration rate (eGFR). RESULTS: Of the 293 recipients who were co-prescribed a CNI and a macrolide, 38% (n = 112) were prescribed clarithromycin/erythromycin while 62% (n = 181) were prescribed azithromycin. Compared with azithromycin users, clarithromycin/erythromycin users were less likely to have outpatient serum creatinine monitoring post-prescription (56% vs 69%, P = .03). There was no significant difference in the primary outcome between the 2 groups (17% vs 11%, P = .11); however, the risk of all-cause hospitalization was higher in the clarithromycin/erythromycin group (10% vs 3%, P = .02). The mean decrement in eGFR was significantly greater in the clarithromycin/erythromycin versus azithromycin group (-5.4 vs -1.9 mL/min/1.73 m2, P < .05). LIMITATIONS: We did not have CNI levels to correlate with the timing of CNI-macrolide co-prescriptions. We also did not have information regarding the indications for macrolide prescriptions. CONCLUSION: Clarithromycin and erythromycin were frequently co-prescribed in kidney transplant recipients on CNIs despite known drug interactions. Clarithromycin/erythromycin use was associated with a higher risk of hospitalization compared with azithromycin users. Safer prescribing practices in kidney transplant recipients are warranted.

CONTEXTE: Les inhibiteurs de la calcineurine (CNI : cyclosporine, tacrolimus) sont essentiels à l'immunosuppression suivant une transplantation rénale. Ils présentent toutefois de nombreux risques d'interactions médicamenteuses avec les antibiotiques macrolides (clarithromycine, érythromycine et azithromycine) employés couramment pour traiter les infections atypiques. La clarithromycine et l'érythromycine inhibent le métabolisme des CNI et augmentent leurs risques de néphrotoxicité, ce qui n'est pas le cas de l'azithromycine. OBJECTIFS: Déterminer la fréquence de co-prescription d'un CNI et d'un macrolide chez les receveurs d'une greffe rénale, la proportion de patients ayant fait l'objet d'un suivi post-prescription et le risque d'effets indésirables attribuables aux médicaments. TYPE D'ÉTUDE: Une étude de cohorte rétrospective. CADRE: Les banques de données couplées du système de santé de l'Alberta (Canada). SUJETS: Nous avons inclus 293 adultes receveurs d'un rein entre 2008 et 2015 et à qui on avait co-prescrit un CNI et un macrolide. MESURES: Le principal résultat attendu était une combinaison d'hospitalisation toutes causes, d'insuffisance rénale aigüe (hausse minimale de 0,3 mg/dL de la créatinine sérique ou équivalente à 1,5 fois la valeur mesurée initialement), ou de décès du patient dans les 30 jours suivant la prescription d'un macrolide. MÉTHODOLOGIE: Nous avons répertorié les co-prescriptions CNI-macrolide et comparé les résultats des patients traités par clarithromycine/érythromycine à ceux traités avec l'azithromycine. Nous avons employé un modèle linéaire à effets mixtes pour établir les variations moyennes dans les mesures de créatinine sérique et de DFGe. RÉSULTATS: Des 293 receveurs d'un rein ayant reçu une co-prescription CNI-macrolide, 38 % (n = 112) ont été traités avec la clarithromycine/érythromycine et 62 % (n = 181) avec l'azithromycine. Les patients ayant reçu de la clarithromycine/érythromycine étaient moins susceptibles de faire l'objet d'un suivi ambulatoire du taux de créatinine sérique post-prescription (56 % contre 69 % pour l'azithromycine, p = 0,03). Aucune différence significative n'a été observée entre les deux groupes quant au principal résultat attendu (17 % contre 11 %; p = 0,11). Cependant, les patients traités par clarithromycine/érythromycine présentaient un risque supérieur d'hospitalisation toutes causes (10 % contre 3 %; p = 0,02), et la moyenne de décroissance du DFGe pour ces patients était significativement supérieure (-5,4 mL/min/1,73 m2 contre -1,9 mL/min/1,73 m2 pour l'azithromycine; p < 0,05). LIMITES: Nous n'avions pas les niveaux de CNI corrélés avec le moment de la co-prescription CNI-macrolide, ni les indications justifiant l'ordonnance de macrolide. CONCLUSION: La clarithromycine et l'érythromycine ont été fréquemment co-prescrites aux receveurs d'une greffe rénale traités avec des CNI, malgré la connaissance des interactions médicamenteuses. Les patients recevant de la clarithromycine/érythromycine sont plus susceptibles d'être hospitalisés que ceux recevant de l'azithromycine. L'adoption de pratiques de prescription plus sûres est justifiée chez les receveurs d'une greffe rénale.

Long-term follow-up of the DeKAF cross-sectional cohort study.

The DeKAF study was developed to better understand the causes of late allograft loss. Preliminary findings from the DeKAF cross-sectional cohort (with follow-up < 20 months) have been published. Herein, we present long-term outcomes in those recipients (mean follow-up ± SD, 6.6 ± 0.7 years). Eligibility included being transplanted prior to October 1, 2005; serum creatinine ≤ 2.0 mg/dL on January 1, 2006; and subsequently developing new-onset graft dysfunction leading to a biopsy. Mean time from transplant to biopsy was 7.5 ± 6.1 years. Histologic findings and DSA were studied in relation to postbiopsy outcomes. Long-term follow-up confirms and expands the preliminary results of each of 3 studies: (1) increasing inflammation in area of atrophy (irrespective of inflammation in nonscarred areas [Banff i]) was associated with increasingly worse postbiopsy death-censored graft survival; (2) hierarchical analysis based on Banff scores defined clusters (entities) that differed in long-term death-censored graft survival; and (3) C4d-/DSA- recipients had significantly better (and C4d+/DSA+ worse) death-censored graft survival than other groups. C4d+/DSA- and C4d-/DSA+ had similar intermediate death-censored graft survival. Clinical and histologic findings at the time of new-onset graft dysfunction define high- vs low-risk groups for long-term death-censored graft survival, even years posttransplant. These findings can help differentiate groups for potential intervention studies.

Follow-up Care of Living Kidney Donors in Alberta, Canada.

BACKGROUND: Previous guidelines recommend that living kidney donors receive lifelong annual follow-up care to assess renal health. OBJECTIVE: To determine whether these best practice recommendations are currently being followed. DESIGN: Retrospective cohort study using linked health care databases. SETTING: Alberta, Canada (2002-2014). PATIENTS: Living kidney donors. MEASUREMENTS: We determined the proportion of donors who had annual outpatient physician visits and laboratory measurements for serum creatinine and albuminuria. RESULTS: There were 534 living kidney donors with a median follow-up of 7 years (maximum 13 years). The median age at the time of donation was 41 years and 62% were women. Overall, 25% of donors had all 3 markers of care (physician visit, serum creatinine, albuminuria measurement) in each year of follow-up. Adherence to physician visits was higher than serum creatinine or albuminuria measurements (67% vs 31% vs 28% of donors, respectively). Donors with guideline-concordant care were more likely to be older, reside closer to the transplant center, and receive their nephrectomy in more recent years. LIMITATIONS: Our results may not be generalizable to other countries that do not have a similar universal health care system. CONCLUSIONS: These findings suggest significant evidence-practice gaps, in that the majority of donors saw a physician, but the minority had measurements of kidney function or albuminuria. Future interventions should target improving follow-up care for all donors.

CONTEXTE: Des recommandations émises antérieurement préconisaient de faire le suivi médical à vie, sur une base annuelle, des donneurs de rein vivants afin d'évaluer leur santé rénale. OBJECTIF DE L'ÉTUDE: L'étude visait à vérifier si ces recommandations de bonnes pratiques étaient suivies. TYPE D'ÉTUDE: Une étude de cohorte rétrospective pour laquelle on a utilisé les bases de données interreliées en soins de santé. CADRE DE L'ÉTUDE: L'étude concerne des patients de la province de l'Alberta, au Canada, et couvre la période allant de 2002 à 2014. PATIENTS: Des donneurs de rein vivants. MESURES: Nous avons établi la proportion de donneurs qui avaient été vus par un médecin en consultation externe et pour qui des mesures de la créatinine et de l'albuminurie avaient été faites. RÉSULTATS: Nous avons répertorié 534 donneurs de rein vivants dont la durée médiane du suivi médical était de sept ans (treize ans maximum). L'âge médian au moment du don d'organe était de 41 ans et la cohorte était constituée à 62 % de donneuses. Dans l'ensemble, 25 % des donneurs montraient les trois indicateurs recherchés (visite chez le médecin, mesure de la créatinine et de l'albuminurie) pour chaque année de suivi. La proportion des donneurs qui voyaient un médecin annuellement s'est avérée nettement supérieure (67 %) à celle des donneurs présentant des mesures de la créatinine (31 %) et de l'albuminurie (28 %). Enfin, on a observé que les donneurs qui suivaient les recommandations étaient plus susceptibles d'être plus âgés, de résider près du centre de greffe et d'avoir subi leur néphrectomie plus récemment. LIMITES DE L'ÉTUDE: Nos résultats pourraient ne pas être généralisables aux pays n'ayant pas un système universel des soins de santé similaire à celui du Canada. CONCLUSION: Ces constatations laissent entrevoir des écarts significatifs entre les données probantes et la pratique, en ce sens que la majorité des donneurs avaient consulté un médecin, mais que peu d'entre eux présentaient des mesures de la fonction rénale ou de l'albuminurie. Dès lors, les prochaines interventions devraient cibler l'amélioration du suivi médical de tous les donneurs.

Late graft failure after kidney transplantation as the consequence of late versus early events.

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later-onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long-term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events.

Complications in the 90-day postoperative period following kidney transplant and the relationship of the Charlson Comorbidity Index.

INTRODUCTION: Renal transplant experiences widespread success, but little is published regarding the postoperative complications. The Charlson Comorbidity Index (CCI) is a system of mortality risk assessment. Our purpose is to assess the 90-day postoperative complications after renal transplantation. The secondary objective is to clarify whether CCI predicts complications. We hypothesized increased CCI corresponds to worse complication on the Clavien scale. METHODS: This is a retrospective analysis of renal recipients at our institution (2011-2013) who were ≥18 years old and received complete follow up. CCI, age, gender, body mass index (BMI), and graft type were extracted from the electronic medical records. Complications were scored using the Clavien scale. Descriptive statistics and logistic regression were used to analyze 198 patients. RESULTS: The mean age was 53 (standard deviation [SD] 14), mean BMI 27.4 (SD 14), median CCI 1. Grade 2 or higher (significant) complications occurred in 60% of patients and Grade 3b or higher (severe) in 15% of patients in the 90-day postoperative period. Sixty-eight different complications were identified, the most common being blood transfusion (19%). Logistic regression suggests a predictive value of CCI (odds ratio [OR] 1.70; 95% confidence interval [CI] 1.3-2.3) for severe complications, with diabetes mellitus and peripheral vascular disease conferring increased risk. CONCLUSIONS: Renal transplant carries significant risk. This data can be used to improve patient counselling on the likely postoperative course. Study limitations include the retrospective design, predisposing to potential bias in data capture.

Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria. METHODS: In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m(2) or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m(2)). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473. FINDINGS: Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio [HR] 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m(2) (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02). INTERPRETATION: Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population. FUNDING: Canadian Institutes of Health Research.

Magnetic resonance imaging artifact following anterior cervical discectomy and fusion with a trabecular metal cage.

OBJECT: This study was undertaken to evaluate the impact of postoperative MRI artifact on the assessment of ongoing spinal cord or nerve root compression after anterior cervical discectomy and fusion (ACDF) using a trabecular tantalum cage or bone autograft or allograft. METHODS: The authors conducted a retrospective review of postoperative MRI studies of patients treated surgically for cervical disc degenerative disease or cervical instability secondary to trauma. Standard ACDF with either a trabecular tantalum cage or interbody bone graft had been performed. Postoperative MR images were shown twice in random order to each of 3 assessors (2 spine surgeons, 1 neuroradiologist) to determine whether the presence of a tantalum interbody cage and/or anterior cervical fixation plate or screws imparted MRI artifact significant enough to prevent reliable postoperative assessment of ongoing spinal cord or nerve root compression. RESULTS: A total of 63 patients were identified. One group of 29 patients received a tantalum interbody cage, with 13 patients (45%) undergoing anterior plate fixation. A second group of 34 patients received bone auto- or allograft, with 23 (68%) undergoing anterior plate fixation. The paramagnetic implant construct artifact had minimal impact on visualization of postoperative surgical level spinal cord compression. In the cage group, 98% (171/174) of the cases were rated as assessable versus 99% in the bone graft group (201/204), with high intraobserver reliability. In contrast, for the assessment of ongoing surgical level nerve root compression, the presence of a tantalum cage significantly decreased visualization of nerve roots to 70% (121/174) in comparison with 85% (173/204) in the bone graft group (p < 0.001). When sequences using turbo spin echo (TSE), a T2-weighted axial sequence, were acquired, nerve roots were rated as assessable in 88% (69/78) of cases; when only axial T2-weighted sequences were available, the nerve roots were rated as assessable in 54% (52/96) of cases (p < 0.01). The presence of anterior plate fixation had minimal impact on visualization of the spinal cord (99% [213/216] for plated cases vs 98% [159/162] for nonplated cases; p = 1.0) or nerve roots (79% [170/216] for plated cases vs 77% [124/162] for nonplated cases; p = 0.62). CONCLUSIONS: Interbody fusion with tantalum cage following anterior cervical discectomy imparts significant paramagnetic artifact, which significantly decreases visualization and assessment of ongoing surgical level nerve root, but not spinal cord, compression. Anterior plate constructs do not affect visualization of these structures. TSE T2-weighted sequences significantly improve nerve root visualization and should be performed as part of a standard postoperative protocol when imaging the cervical spine following interbody implantation of materials with potential for paramagnetic artifact.

Exercise training improves aerobic capacity, muscle strength, and quality of life in renal transplant recipients.

Renal transplant recipients (RTR) have reduced peak aerobic capacity, muscle strength, arterial function and an unfavorable cardiovascular disease risk (CVD) profile. This study compared the effects of 12 weeks of supervised endurance and strength training (EST, n = 16) versus usual care (UC, n = 15) on peak aerobic capicity, cardiovascular and skeletal muscle function, CVD risk profile, and quality of life (QOL) in RTR (55 ± 13 years). Peak aerobic capacity and exercise hemodynamics, arterial compliance, 24-h blood pressure, muscle strength, lean body mass, CVD risk score, and QOL were assessed before and after 12 weeks. The change in peak aerobic capacity (EST: 2.6 ± 3.1 vs. UC: -0.5 ± 2.5 mL/(kg·min)), cardiac output (EST: 1.7 ± 2.6 vs. UC: -0.01 ± 0.8 L/min), leg press (EST: 48.7 ± 34.1 vs. UC: -10.5 ± 37.7 kg) and leg extension strength (EST: 9.5 ± 10.3 vs. UC: 0.65 ± 5.5 kg) improved significantly after EST compared with UC. The overall change in QOL improved significantly after 12 weeks of EST compared with UC. No significant difference was found between groups for lean body mass, arterial compliance, 24-h blood pressure or CVD risk score. Supervised EST is an effective intervention to improve peak exercise aerobic capacity and cardiac output, muscle strength and QOL in clinically stable RTR.

The potential impact of delayed radiation therapy on patients with glioblastoma.

BACKGROUND: Radiation therapy (RT) is the major component of glioblastoma treatment; however, the time to initiate RT after surgical intervention varies between institutions. Our study examined the time from diagnosis to the initiation of RT and its effects on overall patient survival. METHODS: We retrospectively examined 267 patients with glioblastoma who received RT as part of their therapy in two Canadian tertiary care centers. The primary goal of the study is to assess if time to RT can predict/impact survival in glioblastoma patients. RESULTS: The following variables were associated with an increased risk of death: hazard ratio (HR) of time to RT was 0.95 [95% confidence interval (CI), 0.91­0.99] for every extra week. HRs for the type of surgery (resection or biopsy) and type of management received (standard of care in comparison with RT regardless of chemotherapeutic agents other than concomitant and adjuvant temozolomide) were 0.50 (95% CI, 0.37­0.66) and 0.53 (95% CI, 0.38­0.75), respectively. HR for age was 1.02 (95% CI, 1.01­1.03) for every extra year. Standard 60 Gy RT HR was 0.70 [95% confidence interval (CI), 0.51­0.97] in younger patients. CONCLUSIONS: The time from diagnosis to the initiation of RT was found to be a significant prognostic factor for overall patient survival. The addition of temozolomide to the treatment protocol, age, standard RT dose in younger patients and extent of surgery are others factors associated with longer survival periods.Impact potentiel de la radiothérapie différée chez les patients atteints d'un glioblastome.

Effectiveness of adjuvant temozolomide treatment in patients with glioblastoma.

OBJECTIVE: To examine whether adjuvant temozolomide treatment improved glioblastoma patients` survival in a large Canadian cohort. METHODS: We retrospectively studied 364 glioblastoma patients who received different modalities of treatment in 2 Canadian tertiary care centers in Edmonton and Halifax, Canada, between January 2000 and December 2006. The primary outcome was survival following the treatment protocol. RESULTS: The following variables were associated with an increased risk of death: The hazard risk (HR) of on-gross total resection was 0.50 (95% confidence interval [CI]: 0.39-0.64). The HR for the surgery-only group was 5.2 (95% CI: 3.85-7.06). The standard treatment group (surgery, radiation therapy [RT], and temozolomide) had an HR of 0.52 (95% CI: 0.37-0.74). The HR for patients who presented with seizure or whose presentation included seizures was 0.88 (95% CI: 0.55-0.89). Patient entry into trials had an HR of 0.74 (95% CI: 0.57-0.96). Finally, the HR for age was 1.02 (95% CI: 1.01-1.03) for every extra year. CONCLUSION: Concomitant temozolomide with RT and surgery was associated with longer survival compared with RT with surgery alone. We also found that younger age, surgical resection, seizure presence, and entry into trials are important prognostic factors for longer survival.

Prediction of kidney graft failure using clinical scoring tools.

BACKGROUND: Donor organ quality is a key determinant of graft function, and considerable efforts have been made to identify donor and transplant factors predicting inferior outcomes. This has resulted in the development of various scoring tools to aid in allocation of kidneys. METHODS: The performance of four donor quality scoring systems in predicting delayed graft function, and death-censored graft failure was examined in a single-center cohort of 730 consecutive deceased donor kidneys transplanted between 1990 and 2004. The predictive accuracy of the variables was analyzed with receiver operating characteristic curves and graft survival distribution. RESULTS: The three outcome tools, that is, deceased donor score (DDS; Am J Transplant, 3, 2003, 715), donor risk score (DRS; Am J Transplant, 5, 2005, 757) and kidney donor risk index (KDRI; Transplantation, 88, 2009, 231) provided a significant and equivalent prediction of graft failure by using variables available at time of transplantation (p < 0.01). The risk of delayed graft function was predicted by the (DGF) nomogram (J Am Soc Nephrol, 14, 2003, 2967; Am J Transplant 10, 2010, 2279) with a high degree of discrimination (concordance index of 0.69, p < 0.01). CONCLUSIONS: Our findings validate four pre-operative clinical scoring tools to predict early and late graft outcome in an independent, single-center set of kidney transplants.

Evaluating the utility of ambulatory blood pressure monitoring in kidney transplant recipients.

Hypertension is a major risk factor for graft dysfunction and cardiovascular disease in kidney transplant recipients (KTX). Accurate monitoring is therefore essential to provide optimal therapy. We evaluated whether 24-h ambulatory blood pressure monitoring (ABPM) is superior to clinic blood pressure (CBP) measurement in prevalent KTX. Twenty-four-hour ABPM was performed in 244 prevalent KTX. The average clinic systolic blood pressure (SBP) was 137.1 ± 19.4 mm Hg, and diastolic blood pressure (DBP) was 79.9 ± 10.5 mm Hg. The ABPM average SBP was 131.3 ± 15.4 mm Hg and DBP was 75.37 ± 8.8 mm Hg; daytime ABPM average SBP was 133.5 ± 15.0 mm Hg and DBP 77.4 ± 9.1 mm Hg. The correlations between CBP, 24-h ABPM, and daytime ABPM were approximately 0.5. CBP measurements overestimate both 24-h and daytime ABPM by linear regression (p < 0.001). In this largest study to date evaluating blood pressure monitoring in KTX, we found that CBP overestimates ABPM, highlighting the prevalence of white coat hypertension. The improved accuracy of ABPM will decrease overprescribing of BP medications to avoid hypotension, drug interactions, and non-adherence. In contrast, identifying the nocturnal "non-dippers", not evident by CBP, facilitates appropriate management, as under-treatment of hypertension could lead to accelerated graft dysfunction, cardiovascular disease, and mortality. These data suggest the improved accuracy of 24-h ABPM is beneficial for BP monitoring in KTX recipients.

The role of proton pump inhibitors on early mycophenolic acid exposure in kidney transplantation: evidence from the CLEAR study.

INTRODUCTION: Proton pump inhibitors (PPIs) are often prescribed posttransplantation to prevent gastrointestinal complications. A series of recent studies have reported a relationship between PPI comedication and decreased mycophenolic acid (MPA) exposure. The objective of this subanalysis of the CLEAR data set was to determine the impact of PPI therapy on full MPA area under the curve exposures at Day 5 post kidney transplant. MATERIAL AND METHODS: Patients were randomized to receive either intensified dosing of mycophenolate mofetil (1.5 g twice daily on Days 1-5, then 1.0 g twice daily, n = 68) or standard dosing (1.0 g twice daily, n = 67). All recipients received tacrolimus and prednisone. RESULTS: In the modified intention-to-treat population, 57.9% of patients (73 of 126) received PPI therapy. The most frequently administered therapies were pantoprazole and omeprazole. There was no significant difference in mean MPA area under the curve at Day 5 for patients receiving PPI therapy as compared with those not receiving PPI therapy (51.3 versus 55.8 mg.h/L, P = 0.265). However, the MPA concentration-time curve analysis demonstrated a significant decrease in MPA concentrations at 2 hours and 12 hours postdose in patients receiving PPI therapy (P = 0.0009 and P = 0.034). No significant differences were identified in the 3-g arm specifically. In the multivariate model, only serum creatinine and albumin significantly predicted MPA area under the curve less than 30 mg.h/L at Day 5. DISCUSSION AND CONCLUSION: PPI therapy in combination with mycophenolate mofetil does not appear to have a significant impact on full MPA exposure. Because MPA pharmacokinetics were not significantly impacted when a 3-g, 5-day loading dose of mycophenolate mofetil was used in combination with PPI therapy, this strategy may be required for adequate MPA exposure whether or not a patient receives PPI comedication.

Attitudes and opinions on organ donation: an opportunity to educate in a Canadian city.

BACKGROUND: Patients on organ transplant waiting lists continue to far exceed donor rates. We seek to understand the barriers preventing people in a Canadian city from donating organs for transplantation. METHODS: One thousand adults were surveyed assessing knowledge, personal involvement, and attitudes about organ donation in an urban center in Canada. Primary outcomes of interest were a signed organ donor card and willingness to donate. RESULTS: Of those surveyed, 64% did not realize that they possessed an organ donor card; 90% would consider being a donor if a friend was in need of an organ. Of the 36% who did know, 72% had signed it. Those who had misconceptions about the organ donation process were less likely to be donors. INTERPRETATION: There is a tremendous lack of knowledge about organ donation. While the majority of people are interested in organ donation, they lack a means to express this interest - most do not even realize they possess an organ donor card. A significant proportion of people who were not supportive of donation were misinformed in critical areas of knowledge that likely influenced this decision including the rich being preferentially transplanted, the consent process, disfigurement, and donors receiving worse medical care.

Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure.

BACKGROUND: Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. METHODS: One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. RESULTS: Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. CONCLUSIONS: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.