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Holly Mansell,1 Nicola Rosaasen,2 Jenny Wichart,3 Patricia West-Thielke,4 David Blackburn,1 Juxin Liu,5 Rahul Mainra,6 Ahmed Shoker,6 Brianna Groot,7 Kevin Wen,8 Anita Wong,9 Bita Bateni,10 Cindy Luo,11 Paraag Trivedi12 1College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada; 2Saskatchewan Transplant Program, Saskatchewan Health Authority, Saskatoon, SK, Canada; 3Department of Pharmacy, Alberta Health Services, Calgary, AB, Canada; 4University of Illinois Health Sciences System, Chicago, IL, USA; 5Department of Mathematics and Statistics, College of Arts and Science, University of Saskatchewan, Saskatoon, SK, Canada; 6Saskatchewan Transplant Program; Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada; 7Canadian Hub for Applied and Social Research, University of Saskatchewan, Saskatoon, SK, Canada; 8Division of Nephrology and Transplant Immunology, Department of Medicine University of Alberta, Edmonton, AB, Canada; 9Department of Pharmacy, University of Alberta Hospital, Edmonton, AB, Canada; 10St. Paul’s Hospital, and University of British Columbia, Vancouver, BC, Canada; 11Vancouver General Hospital; Faculty of Pharmaceutical Sciences, the University of British Columbia, Vancouver, BC, Canada; 12Transplant Recipient/Patient Advisor, Regina, SK, CanadaCorrespondence: Holly Mansell, College of Pharmacy and Nutrition, Health Sciences Building (E3208), 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada, Email holly.mansell@usask.caAbstract: Sub-optimal adherence to immunosuppressant medications reduces graft survival for kidney transplant recipients and adherence-enhancing interventions are resource and time intensive. We performed a multi-center randomized controlled trial to investigate the impact of an electronically delivered intervention on adherence. Of 203 adult kidney transplant recipients who received a de novo kidney transplant n = 173 agreed to participate (intent-to-treat population) and were randomized to the intervention (video education plus behavior contract n = 91) or the control (standard education, n = 82). No significant differences were found between the groups for medication adherence measured by the Basel Assessment of Adherence to Immunosuppressive Medications Scale, intrapatient variability in tacrolimus levels, time in therapeutic range for any immunosuppressant, knowledge, self-efficacy, QOL, or hospitalizations. Among a subgroup of 64 participants randomized to the intervention group who completed a post-intervention questionnaire, two-thirds (67%, n = 43) reported watching at least 80% of the videos and 58% (n = 37) completed the electronic goal setting exercise and adherence contract. An autonomous goal setting exercise and electronic behavioural contract added to standard of care did not improve any outcomes. Our findings reiterate that nonadherence in transplantation is a difficult multifactorial problem that simple solutions will not solve. Trial registration number NCT03540121.Keywords: kidney transplant, solid organ transplant, medication adherence, immunosuppression

Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to poly-cystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BI< virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific anti-bodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibod-ies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting β2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease. Methods/Design After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting β2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrolment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function. Discussion If inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.

Background Poor health literacy is associated with inferior outcomes in kidney transplant recipients, and knowledge remains suboptimal in this population. The goal of this study was to characterize the health literacy, kidney transplant knowledge, medication beliefs, and education satisfaction in a cohort of patients waiting to undergo kidney transplantation. Methods All patients on the wait-list in 1 Canadian center were invited to participate in the study. A research assistant administered the Short Test of Functional Health Literacy in Adults and its numeracy section, the Beliefs about Medicines Questionnaire, the Kidney Transplant Understanding Tool, and questions regarding satisfaction. Descriptive and univariate statistics were calculated between demographic variables and the assessments. Results Thirty-nine percent of patients (41 of 106) patients participated in the study. Overall, 95% and 86% were defined as having adequate health literacy and numeracy, respectively. The mean score on the Kidney Transplant Understanding Tool was 79%, and the majority (97.4%) had strong beliefs regarding the necessity of medication and little concern about adverse effects (73.8%). Participants with higher literacy scores had increased knowledge ( r = 0.52; P = .05), understanding of why antirejection pills are necessary ( r = 0.38; P = .05), and confidence about taking posttransplant medications ( r = 0.32; P = .05). Overall, 30.7% were unsatisfied with their education regarding medications, and 22.5% were unsatisfied with what to expect after the transplant. Conclusions Before transplantation, health literacy, transplant knowledge, and scores on the Beliefs about Medicines Questionnaire were high in this cohort of patients. However, patient satisfaction regarding educational content remained suboptimal. [ABSTRACT FROM AUTHOR]

Background: Kidney transplant recipients with graft failure (KTR-GF) and those with a failing graft are an increasingly prevalent group of patients. Their clinical management is complex, and outcomes are worse than transplant naïve patients on dialysis. In 2023, the Kidney Disease: Improving Global Outcomes (KDIGO) organization reported findings from a controversies conference and identified several clinical practice priorities for KTR-GF., Objective: As an exercise in needs assessment, we aimed to collate and summarize current practices in adult Canadian kidney transplant programs around these KDIGO-identified clinical practice priorities., Design: Environmental scan followed by content analysis., Setting: Canadian adult kidney transplant programs., Measurements: We categorized the themes of our content analysis around 7 clinical practice priorities: (1) determining prognosis and kidney failure trajectory; (2) immunosuppression management; (3) management of medical complications; (4) preparing for return to dialysis; (5) evaluation and listing for re-transplantation; (6) management of psychological effects; and (7) transition to supportive care., Methods: We solicited documents that identified each program's current care practices for KTR-GF or patients with a failing graft, including policies, procedures, pathways, and protocols. A content analysis of documents and informal correspondence (email or telephone conversations) was done to extract information surrounding the 7 practice priorities., Results: Of the 18 programs contacted, 12 transplant programs participated in this study and a document from a provincial organization (where 2 non-responding programs are located) was procured and included in this analysis. Overall, practice gaps and discrepancies were noted. Many participants highlighted the lack of evidence or consensus to guide the management of KTR-GF as the key reason. Immunosuppression management was the most frequently addressed priority. Six programs and the provincial document recommended a nuanced approach to immunosuppressant management based on clinical factors and re-transplant candidacy. Two programs used the Kidney Failure Risk Equation and eGFR to determine referral trajectories and prepare patients for return to dialysis. Exact processes outlining medical management during the transition were not found except for nephrectomy indications and in 1 program that has a specific transition clinic for KTR-GF. All programs have a formal or informal policy that KTR-GF should be assessed for re-transplantation. Referrals for psychological support and transition to supportive care were made on a case-by-case basis., Limitations: Our environmental scan was at risk of non-response bias and restricted to transplant programs. Kidney clinics and dialysis units may have relevant policies and procedures that were not examined., Conclusion: The findings from our environmental scan suggest gaps in care and potential areas for quality improvement, including a lack of multidisciplinary care, structured dialysis preparation and psychological support. There is also a need to prioritize research that generates evidence to guide the management of KTR-GF and contributes to the aim of developing clinical practice guidelines., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr S.S. has received an education grant from Amgen Canada to improve the outcomes of patients with graft failure. The rest of the authors have no relevant disclosure., (© The Author(s) 2024.)

Background: Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada., Methods: We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen., Results: A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing ( n = 190), compared with not needing ( n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5-69.5 yr v. median 55.5 yr, IQR 47.5-66.5; p < 0.001) and number of comorbidities (median 3, IQR 2-3 v. median 2, IQR 1-3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants ( n = 48) were more likely to have severe disease with a high mortality rate ( n = 15, 31.3%) compared with recipients of other organ transplants, including kidney ( n = 48, 14.8%), heart ( n = 1, 4.4%), liver ( n = 9, 11.4%) and kidney-pancreas ( n = 3, 12.0%) transplants ( p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.07) and number of comorbidities (OR 1.63, 95% CI 1.30-2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly., Interpretation: Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants., Competing Interests: Competing interests: Geneviève Huard reports payment from Gilead and AbbVie, and participation on a data safety monitoring board with Paladin. Ruth Sapir-Pichhadze reports grants from the Canadian Institutes of Health Research, Fonds de recherche du Québec, Genome Canada and Kidney Foundation of Canada, as well as speaker fees from the Korean Society of Nephrology. Atul Humar reports fees from Roche, Astellas and Merck. Deepali Kumar reports grants from Roche, GSK, Takeda, Qiagen, Amplyx and Atara Biotherapeutics, as well as fees from Roche, GSK, Takeda, Exevir, Astellas and Meducom. Deepali Kumar is the 2022–2023 president of the American Society of Transplantation. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: Solid organ transplant (SOT) recipients are at high risk for complications from coronavirus disease 2019 (COVID-19). Vaccination may mitigate this risk; however, immunogenicity appears to be significantly impaired, with reports of increased risk of breakthrough infection. It is unknown if vaccine breakthrough infections are milder or as severe as infections in unvaccinated patients., Methods: We performed a multicenter matched cohort study between March 2020 and September 2021 to assess influence of COVID-19 vaccination on outcomes of COVID-19 infection. Treatment characteristics and disease severity outcomes were compared on the basis of vaccine status; breakthrough infections versus unvaccinated infections. Variable ratio propensity score matching based on age, sex, transplant type, and number of comorbidities, was used to develop the analytic cohort. Logistic regression was used to assess the influence of vaccination status on the selected outcomes., Results: From a cohort of 511 SOT patients with COVID-19, we matched 77 partially or fully vaccinated patients with 220 unvaccinated patients. Treatment characteristics including use of dexamethasone, remdesivir, and antibiotics did not differ. Vaccinated participants were more likely to receive tocilizumab, 15 of 77 (19.5%) versus 5 of 220 (2.3%), P  < 0.001. Disease severity outcomes including oxygen requirement, mechanical ventilation, and mortality were similar among medically attended vaccine breakthroughs compared with unvaccinated patients., Conclusions: SOT recipients who develop medically attended COVID-19 following 1- or 2-dose vaccination seem to have similar disease severity to unvaccinated patients who develop infection. This is consistent with the requirement that SOT recipients need 3 or more vaccine doses and emphasizes the importance of alternate strategies for this population., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely., Methods: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up., Results: The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94)., Conclusions: Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft., (Copyright © 2022 by the American Society of Nephrology.)

Background: A concerning number of kidneys (eg, expanded donor criteria, extended criteria, or marginal kidneys) are discarded yearly while patients experience significant morbidity and mortality on the transplant waitlist. Novel solutions are needed to solve the shortage of kidneys available for transplant. Patient perceptions regarding the use of these less than ideal kidneys remain unexplored., Objective: To explore the perspectives of patients who have previously received a less than ideal kidney in the past and patients awaiting transplant who could potentially benefit from one., Design: Qualitative description study., Setting: 2 provinces in Canada participated (Saskatchewan and Manitoba)., Patients: Patients with end-stage kidney disease who were awaiting kidney transplant and were either (a) aged 65 years and older, or (b) 55 years and older with other medical conditions (eg, diabetes)., Methods: Criterion sampling was used to identify participants. Semi-structured, one-on-one interviews were conducted virtually, which explored perceived quality of life, perceptions of less than ideal kidneys, risk tolerance for accepting one, and educational needs to make such a choice. The interviews were transcribed verbatim and thematic analysis was used to analyze the data., Results: 15 interviews were conducted with usable data (n = 10 pretransplant; n = 5 posttransplant). Participants were a mean of 65.5 ± 8.8 years old. Four interrelated themes became prominent including (1) patient awareness and understanding of their situation or context, (2) a desire for information, (3) a desire for freedom from dialysis, and (4) trust. Subthemes of transparency, clarity, standardization, and autonomy were deemed important for participant education. The majority of pretransplant participants (n = 8/10) indicated that between 3 and 5 years off of dialysis would make the risk of accepting a less than ideal kidney feel worthwhile., Limitation: The study setting was limited to 2 Canadian provinces, which limits the generalizability. Furthermore, the participants were homogenous in demographics such as ethnicity., Conclusion: These findings indicate that patients are comfortable to accept a less than ideal kidney for transplant in situations where their autonomy is respected, they are provided clear, standardized, and transparent information, and when they trust their physician. These results will be used to inform the development of a new national registry for expanding access to deceased-donor kidney transplant., Trial Registration: Not registered., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.R. received payment from Canadian Blood Services as a summer student to complete the study; N.R., A.T., and S.D. report no conflicts of interest; R.M. is the Chair-Kidney Transplant Advisory Committee; J.H. has received funding from the Canadian Institutes for Health Research and Canada Foundation for Innovation, received support for travel from the Transplant Manitoba Adult Kidney Program, was Vice-Chair of the Institute Advisory Board for Canadian Institutes for Health Research, Institute for Nutrition, Metabolism and Diabetes, Scientific Co-Chair, Canadian Transplant Summit 2019, Banff Canada for the Canadian Society of Transplantation, Editorial Board, Canadian Journal of Kidney Health and Disease, Guest Editor, Frontiers in Immunology and received assay reagents from Thermo Fisher Scientific and Echelon Biosciences. None of these activities are related to the work in this manuscript; C.P. received support from Canadian Blood Services for meetings to arrange this project; H.M. received support from Canadian Blood Services to conduct this research. She also received funding from the Respiratory Research Center and a speaker honorarium from Astra Zeneca for work unrelated to this project., (© The Author(s) 2022.)

Poor patient knowledge about transplantation is a significant problem following kidney transplant. A video-based educational intervention was developed to supplement standard education provided by transplant teams., Methods: A multicenter randomized controlled trial tested the intervention delivered to patients undergoing assessment or waitlisted for kidney transplant. Adult participants were randomized to the control (standard education) or the intervention group, consisting of electronic access to the videos (or digital video disks if no internet) plus standard education. Differences between groups in changes in transplant knowledge (measured by the Kidney Transplant Understanding Tool), education satisfaction, self-efficacy, and quality of life (secondary outcomes) were evaluated by a preintervention and postintervention survey. Video viewing habits were tracked and described for patients in the intervention group., Results: One hundred sixty-two patients were enrolled, with 132 completing both questionnaires (n = 64 intervention and n = 68 control), with similar enrollment from 3 Canadian sites. Video viewing statistics in the complete cases indicated that 78% (50/64) watched the videos, with 70% (45/64) viewing them electronically, while 8% (5/64) received digital video disks and self-reported participation. Baseline knowledge scores in the intent-to-treat population were 55.4 ± 6.5 and 55.7 ± 7.1 in the intervention and control, respectively. The mean knowledge change in the intervention (2.1 ± 3.6) was significantly higher than in the control group (0.8 ± 3.4, P < 0.02). In the per-protocol analysis (patients with objective evidence of watching at least 80% of the videos), the knowledge improvements were 3.4 ± 3.8. Video group participants reported higher satisfaction with education ( P < 0.02) and expressed positive comments in open-ended feedback., Conclusions: Electronic video education in the pretransplant setting improved knowledge and satisfaction., Competing Interests: H.M., N.R., R.M., and A.S. developed the video intervention used in this project. The other authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The coronavirus 2019 (COVID-19) pandemic has disrupted health systems worldwide, including solid organ donation and transplantation programs. Guidance on how best to screen patients who are potential organ donors to minimize the risks of COVID-19 as well as how best to manage immunosuppression and reduce the risk of COVID-19 and manage infection in solid organ transplant recipients (SOTr) is needed., Methods: Iterative literature searches were conducted, the last being January 2021, by a team of 3 information specialists. Stakeholders representing key groups undertook the systematic reviews and generation of recommendations using a rapid response approach that respected the Appraisal of Guidelines for Research and Evaluation II and Grading of Recommendations, Assessment, Development and Evaluations frameworks., Results: The systematic reviews addressed multiple questions of interest. In this guidance document, we make 4 strong recommendations, 7 weak recommendations, 3 good practice statements, and 3 statements of "no recommendation.", Conclusions: SOTr and patients on the waitlist are populations of interest in the COVID-19 pandemic. Currently, there is a paucity of high-quality evidence to guide decisions around deceased donation assessments and the management of SOTr and waitlist patients. Inclusion of these populations in clinical trials of therapeutic interventions, including vaccine candidates, is essential to guide best practices., Competing Interests: The authors have no relevant conflicts of interest to disclose., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background and Objectives: Many patients, providers, and potential living donors perceive the living kidney donor evaluation process to be lengthy and difficult to navigate., Design, Setting, Participants, & Measurements: We sought consensus on key terms and process and outcome indicators that can be used to measure how efficiently a transplant center evaluates persons interested in becoming a living kidney donor. Using a RAND-modified Delphi method, 77 participants (kidney transplant recipients or recipient candidates, living kidney donors or donor candidates, health care providers, and health care administrators) completed an online survey to define the terms and indicators. The definitions were then further refined during an in-person meeting with ten stakeholders., Results: We identified 16 process indicators ( e.g. , average time to evaluate a donor candidate), eight outcome indicators ( e.g. , annual number of preemptive living kidney donor transplants), and two measures that can be considered both process and outcome indicators ( e.g. , average number of times a candidate visited the transplant center for the evaluation). Transplant centers wishing to implement this set of indicators will require 22 unique data elements, all of which are either readily available or easily collected prospectively., Conclusions: We identified a set of indicators through a consensus-based approach that may be used to monitor and improve the performance of a transplant center in how efficiently it evaluates persons interested in becoming a living kidney donor., (Copyright © 2020 by the American Society of Nephrology.)

Purpose of Review: To review an international guideline on the evaluation and care of living kidney donors and provide a commentary on the applicability of the recommendations to the Canadian donor population., Sources of Information: We reviewed the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors and compared this guideline to the Canadian 2014 Kidney Paired Donation (KPD) Protocol for Participating Donors., Methods: A working group was formed consisting of members from the Canadian Society of Transplantation and the Canadian Society of Nephrology. Members were selected to have representation from across Canada and in various subspecialties related to living kidney donation, including nephrology, surgery, transplantation, pediatrics, and ethics., Key Findings: Many of the KDIGO Guideline recommendations align with the KPD Protocol recommendations. Canadian researchers have contributed to much of the evidence on donor evaluation and outcomes used to support the KDIGO Guideline recommendations., Limitations: Certain outcomes and risk assessment tools have yet to be validated in the Canadian donor population., Implications: Living kidney donors should be counseled on the risks of postdonation outcomes given recent evidence, understanding the limitations of the literature with respect to its generalizability to the Canadian donor population., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Limited data exist regarding the impact of prevalent vascular disease after live-donor kidney transplantation. We aimed to determine the associations between the number of prevalent vascular diseases, allograft, and patient outcomes following live-donor transplantation. This cohort study used data from the Australia and New Zealand Dialysis and Transplant Registry. Rates between recipients of live-donor kidney transplants ± prevalent vascular disease prior to transplantation were calculated. The associations between vascular disease, allograft failure, and all-cause mortality were assessed using Cox regression modeling. Kaplan-Meier proportions were used to calculate all-cause mortality and death with a function graft stratified by vascular disease burden. Of 4742 live-donor recipients, 428 (9%) and 84 (2%) had prevalent vascular disease at 1 and ≥2 sites, respectively. Compared to recipients without vascular disease, the respective adjusted hazard ratios (95% confidence intervals) for patients with vascular disease at 1 and ≥2 sites were 1.78 (1.41-2.25) and 3.02 (2.03-4.50) for all-cause mortality; and 1.54 (1.26-1.88) and 2.28 (1.54-3.38) for allograft failure. All-cause mortality in recipients with vascular disease at 0, 1 and ≥2 sites was 0.028 (0.025, 0.031), 0.090 (0.073, 0.106) and 0.247 (0.196, 0.282) over the first 5-year post-transplant. There was an incremental association between the number of prevalent vascular disease sites and risk of allograft failure and all-cause mortality in live-donor kidney transplant recipients., (© 2019 Steunstichting ESOT.)

Introduction: Non-adherence after kidney transplantation contributes to increased rejections, hospitalisations and healthcare expenditures. Although effective adherence interventions are sorely needed, increasing education and support to transplant recipients demands greater use of care providers' time and resources in a healthcare system that is stretched. The objective of this clinical trial is to determine the effectiveness of an electronically delivered video series and adherence behaviour contract on improving medication adherence to immunosuppressant medications., Methods and Analysis: A multicentre, parallel arm, randomised controlled trial will be conducted with four sites across North America (Saskatoon, Calgary, Halifax, Chicago). Adult patients will be randomised (1:1) to either the intervention (ie, home-based video education +behaviour contract plus usual care) or usual care alone. De novo transplant recipients will be enrolled prior to their hospital discharge and will be provided with electronic access to the video intervention (immediately) and adherence contract (1 month post-transplant). Follow-up electronic surveys will be provided at 3 and 12 months postenrolment. The primary outcome will be adherence at 12 months post-transplant, as measured by self-report Basel Assessment of Adherence to Immunosuppressive medications and immunosuppressant levels. Secondary outcomes include the difference in knowledge score between the intervention and control in groups (measured by the Kidney Transplant Understanding Tool); differences in self-efficacy (Generalised Self-efficacy Scale), Beliefs of Medicine Questionnaire (BMQ), quality of life (Short Form-12), patient satisfaction and cost utilisation. The study aims to recruit at least 200 participants across participating sites., Ethics and Dissemination: Ethical approval was obtained from the University of Saskatchewan Behavioural Ethics Committee (Beh 18-63), and all patients provide informed consent prior to participating. This educational intervention aims to improve information retention and self-efficacy, leading to improved medication adherence after kidney transplantation, at low cost, with little impact to existing healthcare personnel. If proven beneficial, delivery can be easily implemented into standard of care., Trial Registration Number: NCT03540121; Pre-results., Competing Interests: Competing interests: HM, NR, RM and AS developed the video intervention used in this project., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Secondary hyperparathyroidism (SHPT) in chronic kidney disease is associated with cardiovascular and bone pathology. Measures to achieve parathyroid hormone (PTH) target values and control biochemical abnormalities associated with SHPT require complex therapies, and severe SHPT often requires parathyroidectomy or the calcimimetic cinacalcet. In Australia, cinacalcet was publicly funded for dialysis patients from 2009 to 2015 when funding was withdrawn following publication of the EVOLVE study, which resulted in most patients on cinacalcet ceasing therapy. We examined the clinical and biochemical outcomes associated with this change at Australian renal centres., Aim: To assess changes to biochemical and clinical outcomes in dialysis patients following cessation of cinacalcet., Methods: We conducted a retrospective study of dialysis patients who ceased cinacalcet after August 2015 in 11 Australian units. Clinical outcomes and changes in biochemical parameters were assessed over a 24- and 12-month period, respectively, from cessation of cinacalcet., Results: A total of 228 patients was included (17.7% of all dialysis patients from the units). Patients were aged 63 ± 15 years with 182 patients on haemodialysis and 46 on peritoneal dialysis. Over 24 months following cessation of cinacalcet, we observed 26 parathyroidectomies, 3 episodes of calciphylaxis, 8 fractures and 50 deaths. Eight patients recommenced cinacalcet, meeting criteria under a special access scheme. Biochemical changes from baseline to 12 months after cessation included increased levels of serum PTH from 54 (interquartile range 27-90) pmol/L to 85 (interquartile range 41-139) pmol/L (P < 0.0001), serum calcium from 2.3 ± 0.2 mmol/L to 2.5 ± 0.1 mmol/L (P < 0.0001) and alkaline phosphatase from 123 (92-176) IU/L to 143 (102-197) IU/L (P < 0.0001)., Conclusion: Significant increases in serum PTH, calcium and alkaline phosphatase occurred over a 12-month period following withdrawal of cinacalcet. Longer-term follow up will determine if these biochemical and therapeutic changes are associated with altered rates of parathyroidectomies and cardiovascular mortality and morbidity., (© 2018 Royal Australasian College of Physicians.)

Background: Inadequate patient knowledge about transplantation can result in low patient satisfaction and contribute to poor clinical outcomes. The purpose of this patient-oriented research project was to develop an educational intervention for patients awaiting kidney transplantation., Methods: An educational intervention was developed by patients and health care providers, experts in medication adherence, video education, motivational psychology, and cultural education. Project objectives were defined and content was guided by a series of studies conducted with stakeholders. A review process was undertaken with additional patients, external health care providers and ninth grade high school students and edits were applied accordingly., Results: A set of six educational videos, ranging in length from 3 to 24 min, was created to describe the transplant process. The videos are patient friendly in design, and incorporate animations to explain complex information to accommodate low health literacy, and patient testimonials align the content with principles of adult learning theory. Feedback from external patient reviews [n = 8], external care providers [n = 13] and students [n = 26], indicate that the mini-series is informative and useful., Conclusion: Patient involvement significantly influenced the development of a video series about kidney transplantation., Practice Implications: Patient engagement is integral for developing high quality and relevant educational interventions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Context: Poor knowledge about immunosuppressive (IS) medications remains a major problem for patients in the posttransplant setting. Therefore, more effective educational strategies in the pretransplant setting are being considered as a possible method to improve knowledge and readiness for the challenges of posttransplant care. However, the most effective/relevant content of a pretransplant educational program is yet to be determined., Objective: To identify pretransplant education topics from the posttransplant patient perspective., Design: A focus group meeting was conducted among 7 high-functioning, stable adult kidney transplant recipients recruited from the Saskatchewan Transplant Program. Demographic information including age, gender, occupation, background/ethnicity, and time since transplant were recorded. A moderator, assistant moderator, and research assistant facilitated the 90-minute focus group meeting using a predetermined semistructured interview guide. The session was audio recorded and transcribed verbatim. Nvivo software was used to code the data and identify emerging themes exploring views of participants relating to the educational information required for pretransplant patients., Results: Patients were satisfied with the education they had received. Ideas were classified into the following major themes-patient satisfaction, transplant waitlist, surgery, medications, posttransplant complications, lifestyle and monitoring, knowledge acquisition, illusion of control, and life changes posttransplant. Knowledge gaps were identified in all areas of the transplantation process and were not exclusive to IS medications., Conclusion: Misconceptions regarding transplantation were identified by a group of high-functioning, stable adult recipients who were satisfied with their clinical care. Future educational strategies should aim to address the entire transplantation process and not be limited to medications.

Background: Several educational interventions have been designed to improve patient knowledge before and after kidney transplantation. However, evaluation of such interventions has been difficult because validated instruments to measure knowledge-based outcomes in this population have not been developed., Objective: To create a tool to measure patient knowledge of kidney transplantation and to evaluate its validity., Methods: The Kidney Transplant Understanding Tool (K-TUT) was created using a stepwise iterative process. Experts in the field and transplant recipients were consulted to establish content validity. The K-TUT consists of 9 true/false and 13 multiple-choice questions, and scores are based on the number correct answers [YES/NO format] of 69 items. The questionnaire was piloted in a study that also measured health literacy (via the Short Test of Functional Health Literacy) in transplant candidates, whereas the main survey was mailed to transplant recipients. Test-retest was performed, and completed surveys were analyzed for internal consistency, construct validity, floor and ceiling effects, and reproducibility., Results: Surveys were offered to 106 pretransplant patients and 235 in the posttransplant period, and response rates were 38.7% (41/106) and 63.4% (149/235), respectively. The mean corrected scores were 53.1 ± 8.5 (77%) and 56.2 ± 6.3 (81%), respectively. Test-retest was performed over 20% of both cohorts and percent agreement ranged between 70% and 100% in the pretransplant group and 66% and 100% in the posttransplant group. Cronbach α ranged from 0.794 to 0.875 in all cohorts indicating favorable internal consistency. Increased health literacy in the pretransplant group was significantly associated with increased knowledge ( r = 0.52; P < 0.001), suggestive of construct validity, and the absence of floor and ceiling effects was positive. The majority of transplant recipients (98/148, 67%) believed the questionnaire adequately assessed transplant knowledge, about a quarter (36/148, 24.3%) were "unsure," and 85% (126/148) agreed that no questions should be removed., Conclusions: Although more study is warranted to further assess psychometric properties, the K-TUT appears to be a promising tool to measure transplant knowledge., Competing Interests: The authors declare no conflicts of interest.

Background: The Framingham risk score (FRS) and cardiovascular risk calculator for renal transplant recipients (CRCRTR-MACE) quantify cardiovascular risk in renal transplant recipients (RTR). In contrast to the FRS, the CRCRTR-MACE includes serum creatinine as a variable in the risk prediction equation., Objective: To determine the influence of impaired renal function on performances of the two equations., Methods: A chart review of 270 RTR transplanted from 1979 to 2012. High risk was defined at scores ≥20%. Standard statistical analyses included multivariate analysis (MVA), stepwise analysis, and odds ratio to estimate contributions of risk factors., Results: Mean transplant duration was 9.51 ± 6.65 yr. Mean eGFR was 59.19 ± 28.26 mL/min/1.73 m(2) . FRS and CRCRTR-MACE scores of least 20% were present in 9.3% and 24.8%, respectively, while 7.2% and 11.2% of RTR with eGFR ≥60 mL/min/1.73 m(2) were high risk, respectively. Mean age, blood pressure, TC:HDL ratio, smoking, and diabetes were evenly distributed in patients with varying eGFR. FRS scores remained similar at wide eGFR range (≤30 mL/min/1.73 m(2) -≥90 mL/min/1.73 m(2) ), while CRCRTR-MACE scores significantly increased as eGFR decreased., Conclusions: CRCRTR-MACE identified more patients at high cardiovascular risk, even in those with more favorable renal function, suggesting a fundamental difference between the two calculators beyond renal function., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Evidence for a protective effect of N-acetylcysteine (NAC) on acute and chronic kidney disease is equivocal, and controversy persists about whether NAC affects creatinine level independently of actual kidney function. Study objectives are to investigate whether NAC affects serum creatinine level independently of alterations in other measures of kidney function., Study Design: Double-blind randomized controlled trial., Setting & Participants: Patients with stage 3 chronic kidney disease (n = 60), Canada, 2007-2008., Intervention: Participants were randomly allocated to receive 4 doses of oral NAC (each 1,200 mg) or placebo, administered at 12-hour intervals., Outcome: The primary outcome was change in serum creatinine level between baseline and 4 hours after the last treatment dose. In addition, changes in other parameters of kidney function were measured between baseline and 4, 24, or 48 hours after the last treatment dose., Measurements: Serum creatinine, cystatin C, 24-hour urine protein and creatinine excretion, and creatinine clearance., Results: 60 patients, mean age of 70 years, 75% men, 50% had diabetes, with mean creatinine clearance of 43.7 ± 18.8 (SD) mL/min were enrolled. Between baseline and 4 hours posttreatment, serum creatinine level decreased by 0.044 ± 0.15 mg/dL in the NAC group and 0.040 ± 0.18 mg/dL in the placebo group (95% CI for difference, -0.09 to 0.08; P = 0.9). No significant differences between groups were observed for change in serum creatinine, cystatin C, urine protein, urine creatinine, or creatinine clearance values at any time., Limitations: Blinding patients to orally administered liquid NAC is difficult and it is possible that patients receiving NAC were not sufficiently blinded. Effects of NAC beyond 48 hours of treatment were not evaluated., Conclusions: In this randomized controlled trial, NAC had no short-term effect on creatinine level and did not decrease urine protein excretion within 48 hours of treatment., (Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone., Design, Setting, Participants, & Measurements: A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo., Results: Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly., Conclusions: With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.

Sirolimus is a member of a novel class of immunosuppressant drug that potently suppresses T cell proliferation and expansion by inhibition of the Target of Rapamycin Complex 1 (TORC1) protein kinase. Sirolimus also has anti-proliferative effects on intrinsic cells of the kidney, and increasing evidence suggests that it may have a therapeutic role in non-transplant renal diseases. In the normal kidney, sirolimus is considered to be non-nephrotoxic. In the diseased kidney, sirolimus may be beneficial or detrimental, depending on the type of renal injury. In polycystic kidney disease, TORC1 activation mediates renal tubular epithelial cell (TEC) proliferation and cyst growth in animals, and Phase III clinical trials are underway to determine the effect of sirolimus in attenuating disease progression in humans. In contrast, in acute kidney injury, sirolimus transiently impairs proximal TEC regeneration and delays renal recovery. In animal models of lupus nephritis and diabetic kidney disease, sirolimus prevents disease progression. However, the efficacy of sirolimus in human glomerulonephritis as well as in diabetic chronic kidney disease remains unclear, as it paradoxically exacerbates renal dysfunction when the baseline glomerular filtration rate is low (< 40 ml/min/1.73 m(2)) and there is heavy proteinuria (> 300 mg/day). This may, in part, be due to inhibition of compensatory glomerular capillary repair through the suppression of endothelial cell proliferation and angiogenic growth factor production by podocytes. Therefore, at present, polycystic kidney disease is the most promising therapeutic application for sirolimus in non-transplant renal diseases, and further studies are needed to clarify its role in other situations.

Chronic kidney disease mineral and bone disorder (CKD-MBD) describes the laboratory, bone and vascular abnormalities that exist in patients with CKD stages 3-5D and that may persist after transplantation. Persisting abnormalities of bone turnover and abnormal mineralization, together with bone mineral density (BMD) loss from glucocorticoids, may all predispose to a loss of structural integrity and increased fracture risk in kidney and kidney pancreas recipients. Vitamin D, calcitriol, calcitonin and bisphosphonates have all been used to preserve BMD following transplantation, despite a lack of safety data and the potential for some of these drugs to cause harm. A limited number of post-transplant studies utilizing these drugs have not yet documented improved fracture prevention or fracture-related mortality and have not considered allocation based on risk factors for fracture or markers of bone turnover. Targeted allocation of the available therapies based on a stratification of risk appears warranted. This might be achieved using an algorithm incorporating BMD, X-ray evaluation, laboratory investigations including bone turnover markers and the assessment of standard fracture risk factors at the time of and soon after transplantation. This approach, which is similar to protocols used in the general population, may result in more effective management of patients and fewer adverse effects such as adynamic bone disease. Although BMD is a surrogate for fracture risk in the general population it is not validated in this transplant population. Consequently, such an approach should be confirmed by studies that include bone biopsy data and an evaluation of patient level outcomes.

Background and Objectives: Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo., Design, Setting, Participants, & Measurements: Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test., Results: Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group (n = 22 [11 pairs]; mean difference 0.63). Interim analysis at 4 wk also showed no significant difference between mesna and placebo (n = 32 [16 pairs]; placebo 26.3 micromol/L, mesna 24.5 micromol/L; mean difference 1.88). Multivariable adjustments for baseline characteristics did not alter the analysis. Plasma mesna seemed to reach steady-state concentrations by 4 wk., Conclusions: It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.

Background: N-acetylcysteine (NAC) is commonly administered to high-risk individuals to attenuate the risk of contrast-induced nephropathy in spite of the debate regarding its efficacy. In several studies serum creatinine decreased after exposure to NAC and contrast dye. The mechanism by which NAC attenuates the decline in renal function is not known. Studies in subjects with normal renal function suggest NAC may have an effect on tubular secretion., Aim: The aim of this study was to determine the effect of NAC on renal function, measured by serum creatinine and Cystatin C, in patients with stage 3 chronic kidney disease., Method: Serum creatinine and Cystatin C were measured prior to, 4, 24 and 48 h after the administration of 600 mg oral NAC in 30 patients. The protocol was repeated with the addition of 1200 mg oral cimetidine administered 3 h before NAC., Results: Serum creatinine was not significantly different from baseline (186 +/- 65 micromol/L) to 4 h (185 +/- 62 micromol/L), 24 h (187 +/- 64 micromol/L) or 48 h (184 +/- 61 micromol/L) post NAC, nor were Cystatin C levels. Co-administration of cimetidine resulted in a significant rise in serum creatinine with no change in Cystatin C levels., Conclusion: This study failed to detect a change in serum creatinine or Cystatin C after a single dose of NAC in participants with stage 3 chronic kidney disease. Further randomized trials of multiple doses and longer follow up are needed to confirm these results.

Several studies have reported improved outcomes with daily hemodialysis (DHD), but the strength of this evidence has not been evaluated. The published evidence on DHD was synthesized and its quality rated to inform need and sample size calculations for a randomized trial. Citations were identified in MEDLINE and EMBASE using validated search strategies. Dialysis journals that were not indexed and bibliographies of relevant articles were hand-searched. Two authors reviewed all citations. Articles that reported original data on five or more adults who were receiving DHD (1.5 to 3 h, 5 to 7 d/wk) for > or = 3 mo were included. Twenty-five articles reporting 14 unique populations with 268 patients (five to 72 per study) met inclusion criteria. Of the 14 cohorts, 13 were studied with an observational design, 10 were studied prospectively, and four had parallel control groups. Mean age ranged form 41 to 64 yr, mean time on dialysis was 2 to 11 yr, 0 to 28% of patients had diabetes, > 90% had arteriovenous fistulae, and > 50% were dialyzed at home. Most data were described at < or = 12 mo of follow-up. Outcomes included quality of life, cardiovascular disease, erythropoiesis, nutritional status, hospitalizations, and vascular access failures. Reporting was too heterogeneous to allow pooling of data. Ten of 11 studies suggested improvements in blood pressure; findings for other outcomes varied. Discontinuation of DHD occurred in 0 to 57% in-center and 0 to 15% home patients. Studies of DHD are limited by small sample size, nonideal control groups, selection and dropout biases, and paucity of data on potential risks. Randomized trials with adequate statistical power are required to establish the efficacy and the safety of DHD.

Background: Patients admitted to Lions Gate Hospital, North Vancouver, British Columbia, with a primary diagnosis of community-acquired pneumonia (CAP) have a mean length of stay (LOS) of 9.1 days compared with 7.9 days for peer group hospitals. This difference of 1.2 days results in an annual potential savings of 406 bed days and warranted an investigation into the management of CAP., Objective: To characterize and provide recommendations for the management of CAP., Methods: A retrospective chart review of patients admitted with a primary diagnosis of CAP between May 1, 2000 and August 31, 2000., Results: Fifty-one patients were included in the study, with a mean LOS of 9.9 days and a median LOS of five days. Based on pneumonia severity index scores calculated for each patient, eight patients (16%) were admitted inappropriately. Initial empirical antibiotic choices were consistent with the Canadian CAP guidelines in 27 patients (53%), with inconsistencies arising mainly because cephalosporin or azithromycin monotherapy regimens were prescribed. Step-down from intravenous to oral antibiotics occurred in approximately 20 patients (39%). An additional 12 patients (24%) could have undergone step-down, and step-down was not applicable in 19 patients (37%). The potential annual cost avoidance from implementing admission criteria based on a pneumonia severity index score, applying step-down criteria and promoting early discharge criteria was estimated to be $220,000., Conclusions: Considerable variability exists in the treatment of CAP. A CAP preprinted order sheet was developed to address the issues identified in the present study and provide consistency in the management of CAP at Lions Gate Hospital.

Background: Patent foramen ovale (PFO) is found in up to 50% of patients less than 55 years of age who have had a stroke. Therapeutic options include no therapy, antiplatelet therapy, warfarin and surgical closure of the PFO., Objectives: To determine the relative and attributable risks of PFO for recurrent cerebral ischemic events in young patients with stroke or transient ischemic attacks. The predictors of recurrent cerebral ischemic events and the effects of different therapies on recurrence rates were sought., Design: Follow-up of a retrospective cohort of patients with cryptogenic stroke or transient ischemic attacks identified from an echocardiography database., Setting: University-based regional neurology referral centre., Patients: Consecutive group of 90 patients less than 60 years of age who underwent transesophageal echocardiography following a cryptogenic transient ischemic attack (TIA) or stroke (cerebrovascular accident [CVA]) between 1991 and 1997., Interventions: Structured telephone interviews and chart reviews., Results: Fifty-two patients had a PFO, and 38 patients did not have a PFO. During a mean follow-up of 46 months, 19 recurrent cerebral ischemic events (12 TIA and seven CVA) occurred in 14 patients with PFO, and eight recurrent events (three TIA and five CVA) occurred in six patients without PFO. The recurrence rates were 12% and 5%/patient/year in the PFO and control groups, respectively, for a crude recurrence rate ratio of 2.39 (95% CI 1.01 to 6.32, P < 0.03). The attributable risk of PFO in recurrent neurological events was 7%/patient/year. In a Cox regression model, predictors of recurrent neurological events were presence of PFO (hazard ratio 5.27, 95% CI 1.58 to 17.6, P < 0.007), history of migraine (hazard ratio 4.54, 95% CI 1.11 to 18.52, P < 0.035), hypertension requiring therapy (hazard ratio 3.5, 95% CI 1.33 to 9.01, P < 0.01), and antiplatelet or no therapy instead of warfarin therapy (hazard ratio 2.88, 95% CI 1.11 to 8.7, P < 0.04). Fourteen patients underwent surgical closure of PFO; there were no neurological recurrences during a mean follow-up of 43 months (crude incidence rate difference 12%/patient/year, 95% CI 6.6 to 17.9, P < 0.02)., Conclusions: Patients with PFO had a significantly higher rate of recurrent cerebral ischemic events than those without PFO. Surgical PFO closure prevented any recurrences during a mean follow-up of 43 months. Warfarin was better than antiplatelet therapy or no therapy in preventing recurrences.

Chronic exposure of cells to cognate agonists has been established to cause homologous desensitization of G protein-coupled receptors. In this work, we show that exposure of adult rat cardiomyocytes to isoproterenol (ISO) for 24 h led to the desensitization of beta-adrenoceptor (beta-AR) coupled adenylyl cyclase (AC) activity, which was associated with an increased inhibition of AC by M2-muscarinic receptor (MR) agonist, carbachol (Cch), and a decreased inhibition of AC by A1-adenosine receptor (AdR) agonist, N6-phenylisopropyladenosine (R-PIA). Chronic exposure of cells to Cch caused the desensitization of M2-MR-coupled AC, decreased the inhibitory action of R-PIA on AC and increased ISO-stimulated AC, while chronic exposure to R-PIA caused the desensitization of A1-AdR-coupled AC and modestly increased ISO-stimulated AC without any significant effect on Cch inhibition of the enzyme. Thus, chronic exposure of cardiomyocytes revealed for the first time a more complex and differential nature of cross-talk among the three major G-coupled receptors in modulating AC.

To evaluate the effects of the in vivo endotoxin treatment of the rat on (1) the contractile responses in the subsequently isolated papillary muscle to adrenergic and cholinergic agonists and (2) the biochemical parameters (cyclic GMP, nitric oxide synthesis, protein phosphorylation and ADP-ribosyslation) in the subsequently isolated cardiomyocytes. Following the in vivo endotoxin treatment (4 mg/kg i.p., 18 h), contractile responses to increasing amounts of isoprenaline or to increasing amounts of oxotremorine in the presence of a fixed amount of isoprenaline were determined in isolated papillary strips. Activities of nitric oxide synthase, guanylyl cyclase, as well as phosphorylation of phospholamban and troponin-inhibitory subunit, and pertussis toxin-catalyzed and endogenous ADP-ribosylations were determined in the intact cardiomyocytes and subcellular fractions. The increase in the force of contraction by isoprenaline was reduced, while its inhibition by oxotremorine was greater in the endotoxin-treated papillary strips. The activities of both nitric oxide synthase, primarily of the inducible form of the enzyme, and cytosolic guanylyl cyclase were higher while the phosphorylations of both phospholamban and troponin-inhibitory subunit were of lesser magnitude in the cardiomyocytes following the in vivo endotoxin treatment. Pertussis toxin-catalyzed ADP-ribosylation of the 41 kDa polypeptide, which is the alpha subunit of Gi, was also decreased. The results of the present study support the postulate that alterations in both the cyclic AMP and cyclic GMP signalling cascade contribute to the myocardial dysfunction caused by endotoxin and cytokines.

The main objective of this study was to characterize the alpha 1-adrenoceptors expressed in adult rat brown adipocytes. For this purpose, membrane fractions were prepared from brown adipose tissue as well as from isolated brown adipocytes. The following are major findings: (i) BAT membranes were considerably enriched in alpha 1-adrenoceptors (specific [3H]prazosin binding, Bmax, 79.49 +/- 16.77 fmol/mg protein; KD, 0.24 +/- 0.04 nM); (ii) among the cells that comprise brown adipose tissue, brown adipocytes were enriched in alpha 1-adrenoceptors; (iii) > 95% of total alpha 1-adrenoceptors were resistant to inactivation by 20 microM chloroethylclonidine, which readily and essentially completely inactivated alpha 1B-adrenoceptors in rat liver membranes; (iv) brown adipose tissue membrane alpha 1-adrenoceptors showed high affinity towards 5-methyl urapidil (KD 7.23 +/- 2.49 nM) and WB 4101 (KD 0.66 +/- 0.30 nM) and low affinity towards BMY 7378 (KD 0.34 +/- 0.03 microM); essentially similar affinities for these drugs were seen for membranes prepared from brown adipocytes; and (v) EBDA/LIGAND analysis of 5-methyl urapidil, WB 4101, and BMY 7378 competition curves revealed the presence of a single binding site for these drugs. Recent work has documented that 5-methyl urapidil and WB 4101 interact with high affinity with alpha 1A-adrenoceptors, while BMY 7378 interacts with high affinity with alpha 1D-adrenoceptors. Taken together, these findings are consistent with the view that alpha 1-adrenoceptors expressed in adult rat BAT are mainly of the alpha 1A subtype.