Hypertension and Kidney Function After Living Kidney Donation.

Importance: Recent guidelines call for better evidence on health outcomes after living kidney donation. Objective: To determine the risk of hypertension in normotensive adults who donated a kidney compared with nondonors of similar baseline health. Their rates of estimated glomerular filtration rate (eGFR) decline and risk of albuminuria were also compared. Design, Setting, and Participants: Prospective cohort study of 924 standard-criteria living kidney donors enrolled before surgery and a concurrent sample of 396 nondonors. Recruitment occurred from 2004 to 2014 from 17 transplant centers (12 in Canada and 5 in Australia); follow-up occurred until November 2021. Donors and nondonors had the same annual schedule of follow-up assessments. Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. Exposure: Living kidney donation. Main Outcomes and Measures: Hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure [DBP] ≥90 mm Hg, or antihypertensive medication), annualized change in eGFR (starting 12 months after donation/simulated donation date in nondonors), and albuminuria (albumin to creatinine ratio ≥3 mg/mmol [≥30 mg/g]). Results: Among the 924 donors, 66% were female; they had a mean age of 47 years and a mean eGFR of 100 mL/min/1.73 m2. Donors were more likely than nondonors to have a family history of kidney failure (464/922 [50%] vs 89/394 [23%], respectively). After statistical weighting, the sample of nondonors increased to 928 and baseline characteristics were similar between the 2 groups. During a median follow-up of 7.3 years (IQR, 6.0-9.0), in weighted analysis, hypertension occurred in 161 of 924 donors (17%) and 158 of 928 nondonors (17%) (weighted hazard ratio, 1.11 [95% CI, 0.75-1.66]). The longitudinal change in mean blood pressure was similar in donors and nondonors. After the initial drop in donors' eGFR after nephrectomy (mean, 32 mL/min/1.73 m2), donors had a 1.4-mL/min/1.73 m2 (95% CI, 1.2-1.5) per year lesser decline in eGFR than nondonors. However, more donors than nondonors had an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up (438/924 [47%] vs 49/928 [5%]). Albuminuria occurred in 132 of 905 donors (15%) and 95 of 904 nondonors (11%) (weighted hazard ratio, 1.46 [95% CI, 0.97-2.21]); the weighted between-group difference in the albumin to creatinine ratio was 1.02 (95% CI, 0.88-1.19). Conclusions and Relevance: In this cohort study of living kidney donors and nondonors with the same follow-up schedule, the risks of hypertension and albuminuria were not significantly different. After the initial drop in eGFR from nephrectomy, donors had a slower mean rate of eGFR decline than nondonors but were more likely to have an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT00936078.

A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

Impact of Hepatitis C Virus Cure on Depressive Symptoms in the Human Immunodeficiency Virus-Hepatitis C Virus Coinfected Population in Canada.

BACKGROUND: Depression is common in people with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), with biological and psychosocial mechanisms at play. Direct acting antivirals (DAA) result in high rates of sustained virologic response (SVR), with minimal side-effects. We assessed the impact of SVR on presence of depressive symptoms in the HIV-HCV coinfected population in Canada during the second-generation DAA era (2013-2020). METHODS: We used data from the Canadian CoInfection Cohort (CCC), a multicenter prospective cohort of people with a HIV and HCV coinfection, and its associated sub-study on food security. Because depression screening was performed only in the sub-study, we predicted Center for Epidemiologic Studies Depression Scale-10 classes in the CCC using a random forest classifier and corrected for misclassification. We included participants who achieved SVR and fit a segmented modified Poisson model using an interrupted time series design, adjusting for time-varying confounders. RESULTS: We included 470 participants; 58% had predicted depressive symptoms at baseline. The median follow-up was 2.4 years (interquartile range [IQR]: 1.0-4.5.) pre-SVR and 1.4 years (IQR: 0.6-2.5) post-SVR. The pre-SVR trend suggested depressive symptoms changed little over time, with no immediate level change at SVR. However, post-SVR trends showed a reduction of 5% per year (risk ratio: 0.95 (95% confidence interval [CI]: .94-.96)) in the prevalence of depressive symptoms. CONCLUSIONS: In the DAA era, predicted depressive symptoms declined over time following SVR. These improvements reflect possible changes in biological pathways and/or better general health. If such improvements in depression symptoms are durable, this provides an additional reason for treatment and early cure of HCV.

The Living Kidney Donor Safety Study: Protocol of a Prospective Cohort Study.

Background: Living kidney donation is considered generally safe in healthy individuals; however, there is a need to better understand the long-term effects of donation on blood pressure and kidney function. Objectives: To determine the risk of hypertension in healthy, normotensive adults who donate a kidney compared with healthy, normotensive non-donors with similar indicators of baseline health. We will also compare the 2 groups on the rate of decline in kidney function, the risk of albuminuria, and changes in health-related quality of life. Design Participants and Setting: Prospective cohort study of 1042 living kidney donors recruited before surgery from 17 transplant centers (12 in Canada and 5 in Australia) between 2004 and 2014. Non-donor participants (n = 396) included relatives or friends of the donor, or donor candidates who were ineligible to donate due to blood group or cross-match incompatibility. Follow-up will continue until 2021, and the main analysis will be performed in 2022. The anticipated median (25th, 75th percentile, maximum) follow-up time after donation is 7 years (6, 8, 15). Measurements: Donors and non-donors completed the same schedule of measurements at baseline and follow-up (non-donors were assigned a simulated nephrectomy date). Annual measurements were obtained for blood pressure, estimated glomerular filtration rate (eGFR), albuminuria, patient-reported health-related quality of life, and general health. Outcomes: Incident hypertension (a systolic/diastolic blood pressure ≥ 140/90 mm Hg or receipt of anti-hypertensive medication) will be adjudicated by a physician blinded to the participant's donation status. We will assess the rate of change in eGFR starting from 12 months after the nephrectomy date and the proportion who develop an albumin-to-creatinine ratio ≥3 mg/mmol (≥30 mg/g) in follow-up. Health-related quality of life will be assessed using the 36-item RAND health survey and the Beck Anxiety and Depression inventories. Limitations: Donation-attributable hypertension may not manifest until decades after donation. Conclusion: This prospective cohort study will estimate the attributable risk of hypertension and other health outcomes after living kidney donation.

Contexte: Chez les personnes en bonne santé, faire don d'un rein est généralement considéré comme sûr. Il convient toutefois de mieux comprendre les effets à long terme de ce don sur la pression artérielle et la fonction rénale. Objectifs: Déterminer le risque d'hypertension chez les adultes sains et normotendus qui donnent un rein par rapport à des non-donneurs sains et normotendus ayant des indicateurs de santé de base similaires. Nous comparerons également le taux de réduction de la fonction rénale, le risque d'albuminurie et les changements dans la qualité de vie liée à la santé entre les deux groupes. Cadre type d'étude et participants: Étude de cohorte rétrospective menée sur 1 042 donneurs de rein vivants, recrutés avant la chirurgie dans 17 centres de transplantation (12 au Canada et 5 en Australie) entre 2004 et 2014. Le groupe des non-donneurs (n=396) était constitué de parents ou amis du donneur, ou de candidats donneurs non admissibles à faire un don en raison d'une incompatibilité de groupe sanguin ou lors du test de compatibilité croisée. Le suivi s'est poursuivi jusqu'en 2021 et l'analyse principale sera effectuée en 2022. Le temps de suivi médian prévu (25e percentile, 75e percentile, maximum) après le don est de 7 ans (6, 8, 15 ans). Mesures: Les donneurs et les non-donneurs ont complété le même calendrier de mesures à l'inclusion et pendant le suivi (une date simulée de néphrectomie a été attribuée aux non-donneurs). Des mesures annuelles de pression artérielle, de débit de filtration glomérulaire estimé (DFGe), d'albuminurie, de qualité de vie liée à la santé autodéclarée et de santé générale ont été obtenues. Issues principales: L'hypertension incidente (pression artérielle systolique/diastolique ≥ 140/90 mm Hg ou prise d'un médicament antihypertenseur) sera jugée par un médecin aveugle au statut de don du participant. Nous évaluerons le taux de variation du DFGe à partir de 12 mois après la date de la néphrectomie et la proportion de participants qui développeront un rapport albumine/créatinine ≥ 3 mg/mmol (≥ 30 mg/g) pendant le suivi. La qualité de vie liée à la santé sera évaluée à l'aide du questionnaire de santé RAND de 36 questions et de l'Inventaire d'anxiété et de dépression de Beck. Limites: L'hypertension attribuable au don pourrait ne pas se manifester avant des décennies après le don. Conclusion: Cette étude de cohorte prospective permettra d'estimer le risque d'hypertension attribuable au don et d'autres effets sur la santé du donneur après un don de rein.

Tailoring care for frail and lonely older people with HIV in Canada: a cross-sectional study.

BACKGROUND: 40-60% of people with HIV report experiencing loneliness, and 5-29% of PWH are frail (depending on the definition used). The risk of death in individuals who are frail and lonely, or frail and socially isolated has recently been estimated to be 1·8 times that in individuals who are not frail, lonely, or socially isolated. The aim of the present study was to determine the prevalence of loneliness, and other vulnerabilities related to ageing, in frail older adults with HIV. METHODS: We assessed frailty with the Clinical Frailty Scale (CFS) in a cross-sectional, convenience sample of people with HIV aged 50 years or older in Southern Alberta, Canada. All Southern Alberta Clinic patients aged 50 years or older who attended a virtual or in-person clinic visit between March and October, 2020, and who underwent frailty screening were included in the present analyses. Individuals scoring 4 or higher on the CFS then completed a structured questionnaire to provide information on additional co-factors, including loneliness (Three-item Loneliness Scale), falls, impaired gait and balance, polypharmacy, unintentional weight loss, food insecurity, and subjective cognitive concerns. Age, sex, nadir CD4 cell count, duration of known HIV infection, ethnicity, and risk category were evaluated for associations with frailty. We used t tests to compare means and Pearson χ2 tests to compare proportions. Patients gave written informed consent for use of data. The use of data was approved by the University of Calgary Conjoint Heath Research Ethics Board. FINDINGS: We assessed frailty in 292 older people with HIV. The mean age was 59 years (range 50-86 years) and 45 (16%) were women. On the basis of a score of 4 or greater on the CFS, 40 (14%) participants were identified as frail. Frail individuals tended to be older than those who were not frail (mean age 61·9 years, SD 8·5 versus 58·4 years, SD 6·3; t test difference 3·5, 95% CI 1·3-5·7; p=0·0011). However, there was no association between frailty status and sex, nadir CD4 cell count, duration of known HIV infection, or self-reported ethnicity. Frail individuals were more likely to report injection drug use as a component of their risk for acquisition than were non-frail individuals. Of the frail participants, 15 (42%) reported loneliness, 15 (42%) had fallen in the past year, and 18 (50%) reported impaired gait or balance. One-fifth (8) reported unintentional weight loss and 12 (33%) experienced food insecurity. Nearly 40% (14) reported subjective memory concerns. INTERPRETATION: In this sample of ageing people with HIV, frailty and loneliness were prevalent. Given the increased risk of death when frailty and loneliness are both present, upstream and targeted interventions are urgently needed. These might include measures to address loneliness, risk of falls, weight loss, food insecurity, and memory concerns. FUNDING: Canadian Foundation for Healthcare Improvement, Advancing Frailty Care in the Community.

Comparative outcomes for mature T-cell and NK/T-cell lymphomas in people with and without HIV and to AIDS-defining lymphomas.

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.

Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients: Long-term Outcomes of a Randomized Clinical Trial.

Importance: The complications of corticosteroids make the inclusion of these drugs in immunosuppressive protocols for kidney transplant patients undesirable. However, cessation of corticosteroids is associated with a higher risk of short-term rejection, and the long-term outcomes of patients withdrawn from corticosteroids remain uncertain. Objective: To compare long-term kidney transplant outcomes of patients randomized to continue or withdraw corticosteroids. Design, Setting, and Participants: This prospective multicenter randomized double-blind placebo-controlled trial was conducted between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment until June 8, 2018. The study included 28 kidney transplant centers in the United States, including 386 low- to moderate-immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week after transplant. Analyses were intention to treat. Analysis began September 2018 and ended June 2019. Interventions: Patients were randomized to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant. Main Outcomes and Measures: Kidney allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant. Results: Of 385 patients, 191 were assigned to withdraw from corticosteroids (mean [SD] age, 46.5 [12.1] years), and 194 patients were assigned to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years after transplant. The adjusted hazard ratios of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10; P = .19) and for allograft failure censored for patient death was 0.78 (95% CI, 0.52-1.19; P = .25) and did not differ between the patients assigned to withdraw from corticosteroids vs assigned to continued corticosteroids. Results were consistent in a per-protocol analysis among 223 patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years after transplant. The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs. Conclusions and Relevance: Long-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low- to moderate-immune risk kidney transplant recipients.

Gross Chromosomal Rearrangements in Kluyveromyces marxianus Revealed by Illumina and Oxford Nanopore Sequencing.

Kluyveromyces marxianus (K. marxianus) is an increasingly popular industrially relevant yeast. It is known to possess a highly efficient non-homologous end joining (NHEJ) pathway that promotes random integration of non-homologous DNA fragments into its genome. The nature of the integration events was traditionally analyzed by Southern blot hybridization. However, the precise DNA sequence at the insertion sites were not fully explored. We transformed a PCR product of the Saccharomyces cerevisiae URA3 gene (ScURA3) into an uracil auxotroph K. marxianus otherwise wildtype strain and picked 24 stable Ura+ transformants for sequencing analysis. We took advantage of rapid advances in DNA sequencing technologies and developed a method using a combination of Illumina MiSeq and Oxford Nanopore sequencing. This approach enables us to uncover the gross chromosomal rearrangements (GCRs) that are associated with the ScURA3 random integration. Moreover, it will shine a light on understanding DNA repair mechanisms in eukaryotes, which could potentially provide insights for cancer research.

The Orthopaedic Political Action Committee: Growth and Influence Over 20 Years.

The Political Action Committee (PAC) of the American Association of Orthopaedic Surgeons, also known as the OrthoPAC, is one of the most powerful and well-respected healthcare PACs in Washington, DC. Since its inception in 1999, the OrthoPAC has advocated at the federal level for orthopaedic patients and orthopaedic surgery as a profession. This manuscript will familiarize the reader with PACs, the history and structure of the OrthoPAC, important accomplishments of the OrthoPAC, current legislative positions, and leadership/organization. We also review the various ways that orthopaedic surgeons can engage in advocacy for musculoskeletal care.

Eliminating Structural Barriers: The Impact of Unrestricted Access on Hepatitis C Treatment Uptake Among People Living With Human Immunodeficiency Virus.

BACKGROUND: High costs of direct-acting antivirals (DAAs) have led health-care insurers to limit access worldwide. Using a natural experiment, we evaluated the impact of removing fibrosis stage restrictions on hepatitis C (HCV) treatment initiation rates among people living with human immunodeficiency virus (HIV), and then examined who was left to be treated. METHODS: Using data from the Canadian HIV-HCV Coinfection Cohort, we applied a difference-in-differences approach. Changes in treatment initiation rates following the removal of fibrosis stage restrictions were assessed using a negative binomial regression with generalized estimating equations. The policy change was then specifically assessed among people who inject drugs (PWID). We then identified the characteristics of participants who remained to be treated using a modified Poisson regression. RESULTS: Between 2010-2018, there were a total of 585 HCV initiations among 1130 eligible participants. After removing fibrosis stage restrictions, DAA initiations increased by 1.8-fold (95% confidence interval [CI] 1.3-2.4) controlling for time-invariant differences and secular trends. Among PWID the impact appeared even stronger, with an adjusted incidence rate ratio of 3.6 (95% CI 1.8-7.4). However, this increased treatment uptake was not sustained. At 1 year following universal access, treatment rates declined to 0.8 (95% CI .5-1.1). Marginalized participants (PWID and those of indigenous ethnicity) and those disengaged from care were more likely to remain HCV RNA positive. CONCLUSIONS: After the removal of fibrosis restrictions, HCV treatment initiations nearly doubled immediately, but this treatment rate was not sustained. To meet the World Health Organization elimination targets, the minimization of structural barriers and adoption of tailored interventions are needed to engage and treat all vulnerable populations.

Screening for Asymptomatic Coronary Artery Disease in Waitlisted Kidney Transplant Candidates: A Cost-Utility Analysis.

RATIONALE & OBJECTIVE: On account of the high prevalence of cardiovascular disease in patients with kidney failure, clinical practice guidelines recommend regular screening for asymptomatic coronary artery disease (CAD) in patients on the kidney transplant waitlist. To date, the cost-effectiveness of such screening has not been evaluated. A Canadian-Australasian randomized controlled trial of screening kidney transplant candidates for CAD (CARSK) is currently is being conducted to answer this question. We conducted a cost-utility analysis to determine, before completion of the trial, the cost-effectiveness of no further screening versus regular screening for asymptomatic CAD and to evaluate potential influential variables that may affect results of the economic evaluation. STUDY DESIGN: A modeled cost-utility analysis. SETTING & POPULATION: A theoretical cohort of adult Australian and New Zealand kidney transplant candidates on the waitlist. INTERVENTION: No further screening for asymptomatic CAD versus regular protocolized screening (annual or second yearly) for CAD after kidney transplant waitlisting. OUTCOMES: Incremental cost-effectiveness ratio, reported as cost per quality-adjusted life-year (QALY). MODEL, PERSPECTIVES, & TIMEFRAME: Markov microsimulation model, health system perspective and over a lifetime horizon. RESULTS: In the base case, the incremental cost-effectiveness ratio of no further screening was $11,122 per QALY gained when compared with regular screening. No further screening increased survival by 0.49 life-year or 0.35 QALY. One-way sensitivity analyses identified the costs of transplantation in the first year and CAD prevalence as the most influential variables. Probabilistic sensitivity analyses showed that 94% of the simulations were cost-effective below a willingness-to-pay threshold of $50,000 per QALY gained. LIMITATIONS: Rates of cardiovascular events in waitlisted candidates and transplant recipients are limited in the contemporary era. The results may not be generalizable to populations outside Australia and New Zealand. CONCLUSIONS: No further screening for CAD after waitlisting is likely to be cost-effective and may improve survival. Precision around CAD prevalence estimates and health care resource use will reduce existing uncertainty.

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.

Access to Kidney Transplantation after a Failed First Kidney Transplant and Associations with Patient and Allograft Survival: An Analysis of National Data to Inform Allocation Policy.

BACKGROUND AND OBJECTIVES: Patients who have failed a transplant are at increased risk of repeat transplant failure. We determined access to transplantation and transplant outcomes in patients with and without a history of transplant failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational study of national data, the proportion of waitlisted patients and deceased donor transplant recipients with transplant failure was determined before and after the new kidney allocation system. Among patients initiating maintenance dialysis between May 1995 and December 2014, the likelihood of deceased donor transplantation was determined in patients with (n=27,459) and without (n=1,426,677) a history of transplant failure. Among transplant recipients, allograft survival, the duration of additional kidney replacement therapy required within 10 years of transplantation, and the association of transplantation versus dialysis with mortality was determined in patients with and without a history of transplant failure. RESULTS: The proportion of waitlist candidates (mean 14%) and transplant recipients (mean 12%) with transplant failure did not increase after the new kidney allocation system. Among patients initiating maintenance dialysis, transplant-failure patients had a higher likelihood of transplantation (hazard ratio [HR], 1.16; 95% confidence interval [95% CI], 1.12 to 1.20; P<0.001). Among transplant recipients, transplant-failure patients had a higher likelihood of death-censored transplant failure (HR, 1.44; 95% CI, 1.34 to 1.54; P<0.001) and a greater need for additional kidney replacement therapy required within 10 years after transplantation (mean, 9.0; 95% CI, 5.4 to 12.6 versus mean, 2.1; 95% CI, 1.5 to 2.7 months). The association of transplantation versus dialysis with mortality was clinically similar in waitlisted patients with (HR, 0.32; 95% CI, 0.29 to 0.35; P<0.001) and without transplant failure (HR, 0.40; 95% CI, 0.39 to 0.41; P<0.001). CONCLUSIONS: Transplant-failure patients initiating maintenance dialysis have a higher likelihood of transplantation than transplant-naïve patients. Despite inferior death-censored transplant survival, transplantation was associated with a similar reduction in the risk of death compared with treatment with dialysis in patients with and without a prior history of transplant failure.

Canadian-Australasian Randomised trial of screening kidney transplant candidates for coronary artery disease-A trial protocol for the CARSK study.

Transplantation is the preferred treatment for patients with kidney failure, but the need exceeds the supply of transplantable kidneys, and patients routinely wait >5 years on dialysis for a transplant. Coronary artery disease (CAD) is common in kidney failure and can exclude patients from transplantation or result in death before or after transplantation. Screening asymptomatic patients for CAD using noninvasive tests prior to wait-listing and at regular intervals (ie, annually) after wait-listing until transplantation is the established standard of care and is justified by the need to avoid adverse patient outcomes and loss of organs. Patients with abnormal screening tests undergo coronary angiography, and those with critical stenoses are revascularized. Screening is potentially harmful because patients may be excluded or delayed from transplantation, and complications after revascularization are more frequent in this population. CARSK will test the hypothesis that eliminating screening tests for occult CAD after wait-listing is not inferior to regular screening for the prevention of major adverse cardiac events defined as the composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, and hospitalization for unstable angina. Secondary outcomes include the transplant rate, safety measures, and the cost-effectiveness of screening. Enrolment of 3,306 patients over 3 years is required, with patients followed for up to 5 years during wait-listing and for 1 year after transplantation. By validating or refuting the use of screening tests during wait-listing, CARSK will ensure judicious use of health resources and optimal patient outcomes.

Determinants of Liver Complications Among HIV/Hepatitis B Virus-Coinfected Patients.

BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown. SETTING: North American AIDS Cohort Collaboration on Research and Design. METHODS: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL). RESULTS: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]. CONCLUSIONS: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Trends in cause-specific mortality in HIV-hepatitis C coinfection following hepatitis C treatment scale-up.

OBJECTIVE: Hepatitis C virus (HCV) treatment may reduce liver-related mortality but with competing risks, other causes of mortality may undermine benefits. We examined changes in cause-specific mortality among HIV-HCV coinfected patients before and after scale-up of HCV treatment. DESIGN: Prospective multicentre HIV-HCV cohort study in Canada. METHODS: Cause-specific deaths, classified using a modified 'Coding of Cause of Death in HIV' protocol, were determined for two time periods, 2003-2012 and 2013-2017, stratified by age (20-49; 50-80 years). Comparison of trends between periods was performed using Poisson regression. To account for competing risks, multinomial regression was used to estimate the cause-specific hazard ratios of time and age on cause of death, from which end-stage liver disease (ESLD)-specific 5-year cumulative incidence functions were estimated. RESULTS: Overall, 1634 participants contributed 8248 person-years of follow-up; 273 (17%) died. Drug overdose was the most common cause of death overall, followed by ESLD and smoking-related deaths. In 2013-2017, ESLD was surpassed by drug overdose and smoking-related deaths among those aged 20-49 and 50-80, respectively. After accounting for competing risks, comparing 2003-2012 to 2013-2017, ESLD deaths declined (adjusted hazards ratio: 0.18, 95% confidence interval 0.05-0.62). However, both early and late period cumulative incidence functions demonstrated increased risk of death from ESLD for patients with poor HIV control and advanced fibrosis. CONCLUSION: The gains made in overall mortality with HCV therapy may be thwarted if modifiable harms are not addressed. Although ESLD-related deaths have decreased over time, treatment should be further expanded, prioritizing those with advanced fibrosis.

Evaluation of laboratory disturbance risk when adding low-dose cotrimoxazole for PJP prophylaxis to regimens of high-grade glioma patients taking RAAS inhibitors.

BACKGROUND: Cotrimoxazole is associated with the development of hyponatremia, hyperkalemia and elevated serum creatinine, especially when combined with inhibitors of the renin-angiotensin-aldosterone system (RAAS). Pneumocystis jirovecii pneumonia (PJP) prophylaxis is the standard of care for high-grade glioma (HGG) patients receiving temozolomide concurrently with radiotherapy, low-dose cotrimoxazole being the preferred agent. Many of these patients are also taking renin-angiotensin-aldosterone system inhibitors, however the risk of significant laboratory disturbance in these patients remains undescribed. OBJECTIVE: We evaluated whether high-grade glioma patients taking renin-angiotensin-aldosterone system inhibitors receiving low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis are at additional risk of laboratory disturbances in comparison with their non-renin-angiotensin-aldosterone system counterparts. METHODS: We conducted a retrospective chart review of adult neuro-oncology patients treated for WHO Grade III or IV glioma between 2013 and 2016. Patient serum Na, K, creatinine, and eGFR were compared (renin-angiotensin-aldosterone system vs. non-renin-angiotensin-aldosterone system) using the chi-square test. Binary logistic regression analysis was then performed to account for differences between cohorts. RESULTS: Of 63 patients (35 non-renin-angiotensin-aldosterone system, 28 renin-angiotensin-aldosterone system), patients in the renin-angiotensin-aldosterone system cohort were more likely to experience a laboratory disturbance (odds ratio=3.17, p = 0.03). Overall, these disturbances were moderate, but were slightly more common and slightly more severe in the renin-angiotensin-aldosterone system cohort. CONCLUSION: Adding low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis to the regimens of patients with high-grade glioma taking renin-angiotensin-aldosterone system inhibitors increases the risk of laboratory disturbances. While these are generally moderate, some patients are at risk of significant electrolyte abnormalities requiring intervention.