Frailty is associated with increased risk of cirrhosis disease progression and death.

BACKGROUND AND AIMS: The Liver Frailty Index (LFI) is a well-studied tool that evaluates frailty in patients with cirrhosis. Consisting of grip strength, chair stands, and balance testing, the LFI has been associated with increased mortality in patients awaiting liver transplant. We aimed to extend our understanding of frailty in cirrhosis by exploring the relationship between the LFI and the risk of (1) cirrhosis progression, (2) mortality, and (3) unplanned hospitalizations, in both compensated and decompensated disease. APPROACH AND RESULTS: Adult patients with cirrhosis from four centers in North America and one in India were included. Frailty was measured at baseline using the LFI and categorized as robust (LFI < 3.2), prefrail (LFI 3.2-4.5), and frail (LFI > 4.5). Progression of cirrhosis was defined by an increase in clinical stage, ranging from 1 to 5, from baseline using the D'Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate regression models, with transplant as a competing risk. In total, 822 patients with cirrhosis were included. Average Model for End-Stage Liver Disease (MELD) score was 15.5 ± 6.0. In patients with compensated cirrhosis, being frail versus robust was associated with increased risk of progression to the next cirrhosis stage or to death (HR, 2.45; 95% CI, 1.14-5.29) and with an increased risk of unplanned hospitalizations (2.32; 95% CI, 1.13-4.79), after adjusting for age, sex, and MELD score. Similar HRs were observed in patients with decompensated cirrhosis. CONCLUSIONS: Frailty was an independent predictor of cirrhosis progression or death and unplanned hospitalization across patients with compensated and decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.

Metabolic acidosis is undertreated and underdiagnosed: a retrospective cohort study.

BACKGROUND: Guidelines recommend treatment of metabolic acidosis (MA) in patients with chronic kidney disease (CKD), but the diagnosis and treatment rates in real-world settings are unknown. We investigated the frequency of MA treatment and diagnosis in patients with CKD. METHODS: In this retrospective cohort study, we examined administrative health data from two US databases [Optum's de-identified Integrated Claims + Clinical Electronic Health Record Database (US EMR cohort; 1 January 2007 to 30 June 2019) and Symphony Health Solutions IDV® (US claims cohort; 1 May 2016 to 30 April 2019)] and population-level databases from Manitoba, Canada (1 April 2006 to 31 March 2018). Patients who met laboratory criteria indicative of CKD and chronic MA were included: two consecutive estimated glomerular filtration results <60 mL/min/1.73 m2 and two serum bicarbonate results 12 to <22 mEq/L over 28-365 days. Outcomes included treatment of MA (defined as a prescription for oral sodium bicarbonate) and a diagnosis of MA (defined using administrative records). Outcomes were assessed over a 3-year period (1 year pre-index, 2 years post-index). RESULTS: A total of 96 184 patients were included: US EMR, 6179; Manitoba, 3223; US Claims, 86 782. Sodium bicarbonate treatment was prescribed for 17.6%, 8.7% and 15.3% of patients, and a diagnosis was found for 44.7%, 20.9% and 20.9% of patients, for the US EMR, Manitoba and US Claims cohorts, respectively. CONCLUSIONS: This analysis of 96 184 patients with laboratory-confirmed MA from three independent cohorts of patients with CKD and MA highlights an important diagnosis and treatment gap for this disease-modifying complication.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33 048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. RESULTS: There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). CONCLUSION: Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Patient views regarding cannabis use in chronic kidney disease and kidney failure: a survey study.

BACKGROUND: Cannabis is frequently used recreationally and medicinally, including for symptom management in patients with kidney disease. METHODS: We elicited the views of Canadian adults with kidney disease regarding their cannabis use. Participants were asked whether they would try cannabis for anxiety, depression, restless legs, itchiness, fatigue, chronic pain, decreased appetite, nausea/vomiting, sleep, cramps and other symptoms. The degree to which respondents considered cannabis for each symptom was assessed with a modified Likert scale ranging from 1 to 5 (1, definitely would not; 5, definitely would). Multilevel multivariable linear regression was used to identify respondent characteristics associated with considering cannabis for symptom control. RESULTS: Of 320 respondents, 290 (90.6%) were from in-person recruitment (27.3% response rate) and 30 (9.4%) responses were from online recruitment. A total of 160/320 respondents (50.2%) had previously used cannabis, including smoking [140 (87.5%)], oils [69 (43.1%)] and edibles [92 (57.5%)]. The most common reasons for previous cannabis use were recreation [84/160 (52.5%)], pain alleviation [63/160 (39.4%)] and sleep enhancement [56/160 (35.0%)]. Only 33.8% of previous cannabis users thought their physicians were aware of their cannabis use. More than 50% of respondents probably would or definitely would try cannabis for symptom control for all 10 symptoms. Characteristics independently associated with interest in trying cannabis for symptom control included symptom type (pain, sleep, restless legs), online respondent {ß = 0.7 [95% confidence interval (CI) 0.1-1.4]} and previous cannabis use [ß = 1.2 (95% CI 0.9-1.5)]. CONCLUSIONS: Many patients with kidney disease use cannabis and there is interest in trying cannabis for symptom control.

Hyperkalemia-Related Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based therapies that slow the progression of chronic kidney disease (CKD) but can cause hyperkalemia. We aimed to evaluate the association of discontinuing RAAS inhibitors after an episode of hyperkalemia and clinical outcomes in patients with CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults in Manitoba (7,200) and Ontario (n = 71,290), Canada, with an episode of de novo RAAS inhibitor-related hyperkalemia (serum potassium ≥ 5.5 mmol/L) and CKD. EXPOSURE: RAAS inhibitor prescription. OUTCOME: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular (CV) mortality, fatal and nonfatal CV events, dialysis initiation, and a negative control outcome (cataract surgery). ANALYTICAL APPROACH: Cox proportional hazards models examined the association of RAAS inhibitor continuation (vs discontinuation) and outcomes using intention to treat approach. Sensitivity analyses included time-dependent, dose-dependent, and propensity-matched analyses. RESULTS: The mean potassium and mean estimated glomerular filtration rate were 5.8 mEq/L and 41 mL/min/1.73 m2, respectively, in Manitoba; and 5.7 mEq/L and 41 mL/min/1.73 m2, respectively, in Ontario. RAAS inhibitor discontinuation was associated with a higher risk of all-cause mortality (Manitoba: HR, 1.32 [95% CI, 1.22-1.41]; Ontario: HR, 1.47 [95% CI, 1.41-1.52]) and CV mortality (Manitoba: HR, 1.28 [95% CI, 1.13-1.44]; and Ontario: HR, 1.32 [95% CI, 1.25-1.39]). RAAS inhibitor discontinuation was associated with an increased risk of dialysis initiation in both cohorts (Manitoba: HR, 1.65 [95% CI, 1.41-1.85]; Ontario: HR, 1.11 [95% CI, 1.08-1.16]). LIMITATIONS: Retrospective study and residual confounding. CONCLUSIONS: RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD. Strategies to maintain RAAS inhibitor treatment after an episode of hyperkalemia may improve clinical outcomes in the CKD population.

Opioids and the Risk of Motor Vehicle Collision: A Systematic Review.

Background: Opioid analgesics are among the most commonly prescribed medications, but questions remain regarding their impact on the day-to-day functioning of patients including driving. We set out to perform a systematic review on the risk of motor vehicle collision (MVC) associated with prescription opioid exposure. Method: We searched Medline, PubMed, EMBASE, Scopus, and TRID from January 1990 to August 31, 2021 for primary studies assessing prescribed opioid use and MVCs. Results: We identified 14 observational studies that met inclusion criteria. Among those, 8 studies found an increased risk of MVC among those participants who had a concomitant opioid prescription at the time of the MVC and 3 found no significant increase of culpability of fatal MVC. The 3 studies that evaluated the presence of a dose-response relationship between the dose of opioids taken and the effects on MVC risk reported the existence of a dose-response relationship. Due to the heterogeneity of the different studies, a quantitative meta-analysis to sum evidence was deemed unfeasible. Our review supports increasing evidence on the association between motor vehicle collisions and prescribed opioids. This research would guide policies regarding driving legislation worldwide. Conclusion: Our review indicates that opioid prescriptions are likely associated with an increased risk of MVCs. Further studies are warranted to strengthen this finding, and investigate additional factors such as individual opioid medications, opioid doses and dose adjustments, and opioid tolerance for their effect on MVC risk.

Health-Related Quality of Life: A Rapid Predictor of Hospitalization in Patients With Cirrhosis.

OBJECTIVES: Patients with cirrhosis experience a worsened quality of life; this may be quantified by the use of health-related QoL (HRQoL) constructs, such as the chronic liver disease questionnaire (CLDQ) and EuroQoL Group-visual analog scale (EQ-VAS). In this multicenter prospective study, we aimed to evaluate HRQoL as a predictor of unplanned hospital admission/early mortality, identify HRQoL domains most affected in cirrhosis, and identify predictors of low HRQoL in patients with cirrhosis. METHODS: Multivariable logistic regression was used to determine independent association of HRQoL with primary outcome and identify predictors of low HRQoL. HRQoL was also compared with population norms. RESULTS: In this cohort of 402 patients with cirrhosis, mean model for end-stage liver disease was 12.5 (4.9). More than 50% of the cohort had low HRQoL, considerably lower than population norms. HRQoL (measured by either CLDQ or EQ-VAS) was independently associated with the primary outcome of short-term unplanned hospitalization/mortality. Every 1-point increase in the CLDQ and every 10-point increase in the EQ-VAS reduced the risk of reaching this outcome by 30% and 13%, respectively. Patients with cirrhosis had lower HRQoL scores than population norms across all domains of the CLDQ. Younger age, female sex, current smoker, lower serum albumin, frailty, and ascites were independently associated with low CLDQ. DISCUSSION: Patients with cirrhosis experience poor HRQoL. HRQoL is independently associated with increased mortality/unplanned hospitalizations in patients with cirrhosis and could be an easy-to-use prognostic screen that patients could complete in the waiting room before their appointment.

Acute Kidney Injury Events in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Sodium/glucose cotransporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease and prevent heart failure events. However, SGLT2 inhibitors may increase the risk for acute kidney injury (AKI). Our objective was to assess whether SGLT2 inhibitor use, compared with all other glucose-lowering drugs (oGLDs), is associated with increased rates of AKI. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults in Manitoba, Canada, with type 2 diabetes mellitus followed up from June 2014 until March 2017. EXPOSURES: Initial SGLT2 inhibitor or oGLD use ascertained through a province-wide outpatient prescription database. OUTCOME: The primary outcome was incident AKI, identified either by an increase in serum creatinine level and/or hospital discharge codes for AKI while taking glucose-lowering drugs (on-treatment approach). ANALYTICAL APPROACH: A propensity score analysis was used to assemble groups of incident users of SGLT2 inhibitors and a 1:1 matched set of oGLD users. The rate of AKI was compared across matched groups using cause-specific hazards models. Sensitivity analyses considered exposure to be constant throughout follow-up after initiation of the drug treatment (intention-to-treat approach) or incorporated recurrent exposures (new user design). RESULTS: Comparing 4,778 incident users of SGLT2 inhibitors with 4,778 incident users of oGLDs, there were no differences observed in the primary outcome (HR, 0.64; 95% CI, 0.40-1.03; P = 0.06) using an on-treatment approach. In neither set of sensitivity analyses were SGLT2 inhibitors associated with increased risk for AKI. LIMITATIONS: Drug choice may have been related to AKI risk, laboratory data were obtained from clinical care, and changes in adverse event reporting may have followed the US Food and Drug Administration warning. There were insufficient data to compare individual SGLT2 inhibitors. CONCLUSIONS: Compared with oGLDs, SGLT2 inhibitors were not observed to be associated with increased risk for AKI in a clinical population-based cohort.

The Fracture Risk Assessment Tool (FRAX®) predicts fracture risk in patients with chronic kidney disease.

The Fracture Risk Assessment Tool (FRAX®) was developed to predict fracture risk in the general population, but its applicability to patients with chronic kidney disease (CKD) is unknown. Using the Manitoba Bone Mineral Density (BMD) Database, we identified adults not receiving dialysis with available serum creatinine measurements and bone densitometry within 1 year. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Incident major osteoporotic fractures and hip fractures were ascertained from population-based health care databases. The performance of FRAX, derived without and with BMD, was studied in relation to CKD stage. Among 10,099 subjects (mean age 64 ± 13 years, 13.0% male), 2,154 had eGFR 30-60 mL/min/1.73 m2 (CKD stage 3) and 590 had eGFR <30 mL/min/1.73 m2 (CKD stages 4-5). During a 5-year observation period, 772 individuals experienced a major osteoporotic fracture and 226 had a hip fracture. FRAX predicted risk for major osteoporotic fracture and hip fracture in all eGFR strata. For every standard deviation increase in FRAX score derived with BMD, the hazard ratio (HR) for hip fracture was 4.54 (95% confidence interval [CI] 3.57-5.77) in individuals with eGFR ≥ 60 mL/min/1.73m2, 4.52 (95% CI 3.15-6.49) in individuals with eGFR 30-60 mL/min/1.73m2, and 3.10 (95% CI 1.80-5.33) in individuals with eGFR <30 mL/min/1.73m2. The relationship between FRAX and major osteoporotic fracture was stronger in those with CKD compared to those with preserved eGFR. These findings support the use of FRAX to risk stratify patients with non-dialysis CKD for major osteoporotic fractures and hip fractures.

Surgical frailty assessment: a missed opportunity.

BACKGROUND: Preoperative frailty predicts adverse postoperative outcomes. Despite the advantages of incorporating frailty assessment into surgical settings, there is limited research on surgical healthcare professionals' use of frailty assessment for perioperative care. METHODS: Healthcare professionals caring for patients enrolled at a Canadian teaching hospital were surveyed to assess their perceptions of frailty, as well as attitudes towards and practices for frail patients. The survey contained open-ended and 5-point Likert scale questions. Responses were compared across professions using independent sample t-tests and correlations between survey items were analyzed. RESULTS: Nurses and allied health professionals were more likely than surgeons to think frailty should play a role in planning a patient's care (nurses vs. surgeons p = 0.008, allied health vs. surgeons p = 0.014). Very few respondents (17.5%) reported that they 'always used' a frailty assessment tool. Results from qualitative data analysis identified four main barriers to frailty assessment: institutional, healthcare system, professional knowledge, and patient/family barriers. CONCLUSION: Across all disciplines, the lack of knowledge about frailty issues was a prominent barrier to the use of frailty assessments in practice, despite clinicians' understanding that frailty affects their patients' outcomes. Confidence in frailty assessment tool use through education and addressing barriers to implementation may increase use and improve patient care. Healthcare professionals agree that frailty assessments should play a role in perioperative care. However, few perform them in practice. Lack of knowledge about frailty is a key barrier in the use of frailty assessments and the majority of respondents agreed that they would benefit from further training.

Is current preoperative frailty assessment adequate?

SUMMARY: Preoperative frailty predicts adverse postoperative outcomes. Recommendations for preoperative assessment of elderly patients include performing a frailty assessment. Despite the advantages of incorporating frailty assessment into surgical settings, there is limited research on surgical health care professionals' perception and use of frailty assessment for perioperative care. We surveyed local health care employees to assess their attitudes toward and practices for frail patients. Nurses and allied health professionals were more likely than surgeons to agree frailty should play a role in planning a patient's care. Lack of knowledge about frailty issues was a prominent barrier to the use of frailty assessments in practice, despite clinicians understanding that frailty affects their patients' outcomes. Results of this survey suggest further training in frailty issues and the use of frailty assessment instruments is necessary and could improve the uptake of such tools for perioperative care planning.

Impact of a Medical Fitness Model on Incident Major Adverse Cardiovascular Events: A Prospective Cohort Study of 11 000 Members.

BACKGROUND: Cardiovascular disease remains the leading cause of disease burden and death in the world. The medical fitness model may be an alternative public health strategy to address cardiovascular risk factors with medical integrated programming. METHODS AND RESULTS: We performed a retrospective cohort study between January 1, 2005, and December 31, 2015. Adults (aged ≥18 years) who did not have a prior major adverse cardiovascular event were included. Controls were assigned a pseudo-index date at random on the basis of the frequency distribution of start dates in the medical fitness facility group. Multivariate Cox proportional hazards regression models were adjusted for age, sex, socioeconomic status, comorbidities, and year of index date. We stratified the medical fitness facility group into low-frequency attenders (≤1 weekly visit) and regular-frequency attenders (>1 weekly visit). Our primary outcome was a hospitalization for nonfatal myocardial infarction and stroke, heart failure, or cardiovascular death. We included 11 319 medical fitness facility members and 507 400 controls in our study. Compared with controls, members had a lower hazard risk of a major adverse cardiovascular event-plus (hazard ratio [HR], 0.88 [95% CI, 0.81-0.96]). Higher weekly attendance was associated with a lower hazard risk of a major adverse cardiovascular event-plus compared with controls, but the effect was not significant for lower weekly attendance (low-frequency attenders: HR, 0.94 [95% CI, 0.85-1.04]; regular-frequency attenders: HR, 0.77 [95% CI, 0.67-0.89]). CONCLUSIONS: Medical fitness facility membership and attendance at least once per week may lower the risk of a major adverse cardiovascular event-plus. The medical fitness model should be considered as a public health intervention, especially for individuals at risk for cardiovascular disease.

The impact of dialysate flow rate on haemodialysis adequacy: a systematic review and meta-analysis.

Background: Patients with kidney failure treated with maintenance haemodialysis (HD) require appropriate small molecule clearance. Historically, a component of measuring 'dialysis adequacy' has been quantified using urea kinetic modelling that is dependent on the HD prescription. However, the impact of dialysate flow rate on urea clearance remains poorly described in vivo and its influence on other patient-important outcomes of adequacy is uncertain. Methods: We searched Embase, MEDLINE and the Cochrane Library from inception until April 2022 for randomized controlled trials and observational trials comparing a higher dialysate flow rate (800 ml/min) and lower dialysate flow rate (300 ml/min) with a standard dialysis flow rate (500 ml/min) in adults (age ≥18 years) treated with maintenance HD (>90 consecutive days). We conducted a random effects meta-analysis to estimate the pooled mean difference in dialysis adequacy as measured by Kt/V or urea reduction ratio (URR). Results: A total of 3118 studies were identified. Of those, nine met eligibility criteria and four were included in the meta-analysis. A higher dialysate flow rate (800 ml/min) increased single-pool Kt/V by 0.08 [95% confidence interval (CI) 0.05-0.10, P < .00001] and URR by 3.38 (95% CI 1.97-4.78, P < .00001) compared with a dialysate flow rate of 500 ml/min. Clinically relevant outcomes including symptoms, cognition, physical function and mortality were lacking and studies were generally at a moderate risk of bias due to issues with randomization sequence generation, allocation concealment and blinding. Conclusion: A higher dialysate flow increased urea-based markers of dialysis adequacy. Additional high-quality research is needed to determine the clinical, economic and environmental impacts of higher dialysate flow rates.

Randomized Controlled Trial of the Effect of an Exercise Rehabilitation Program on Symptom Burden in Maintenance Hemodialysis: A Clinical Research Protocol.

Background: People receiving hemodialysis experience high symptom burden that contributes to low functional status and poor health-related quality of life. Management of symptoms is a priority for individuals receiving hemodialysis but limited effective treatments exist. There is emerging evidence that exercise programming can improve several common dialysis-related symptoms. Objective: The primary aim of this study is to evaluate the effect of an exercise rehabilitation program on symptom burden in individuals receiving maintenance hemodialysis. Design: Multicenter, randomized controlled, 1:1 parallel, open label, prospective blinded end point trial. Setting: Three facility-based hemodialysis units in Winnipeg, Manitoba, Canada. Participants: Adults aged 18 years or older with end-stage kidney disease receiving facility-based maintenance hemodialysis for more than 3 months, with at least 1 dialysis-related symptom as indicated by the Dialysis Symptom Index (DSI) severity score >0 (n = 150). Intervention: Supervised 26-week exercise rehabilitation program and 60 minutes of cycling during hemodialysis thrice weekly. Exercise intensity and duration were supervised and individualized by the kinesiologist as per participant baseline physical function with gradual progression over the course of the intervention. Control: Usual hemodialysis care (no exercise program). Measurements: Our primary outcome is change in symptom burden at 12 weeks as measured by the DSI severity score. Secondary outcomes include change in modified DSI severity score (includes 10 symptoms most plausible to improve with exercise), change in DSI severity score at 26 and 52 weeks; time to recover post-hemodialysis; health-related quality of life measured using EuroQol (EQ)-5D-5L; physical activity behavior measured by self-report (Godin-Shepherd questionnaire) and triaxial accelerometry; exercise capacity (shuttle walk test); frailty (Fried); self-efficacy for exercise; and 1-year hospitalization and mortality. Methods: Change in primary outcome will be compared between groups by independent 2-tailed t test or Mann-Whitney U test depending on data distribution and using generalized linear mixed models, with study time point as a random effect and adjusted for baseline DSI score. Similarly, change in secondary outcomes will be compared between groups over time using appropriate parametric and nonparametric statistical tests depending on data type and distribution. Limitations: The COVID-19 pandemic restrictions on clinical research at our institution delayed completion of target recruitment and prevented collection of accelerometry and physical function outcome data for 15 months until restrictions were lifted. Conclusions: The application of an exercise rehabilitation program to improve symptom burden in individuals on hemodialysis may ameliorate common symptoms observed in individuals on hemodialysis and result in improved quality of life and reduced disability and morbidity over the long term. Importantly, this pragmatic study, with a standardized exercise intervention that is adaptable to baseline physical function, addresses an important gap in both clinical care of hemodialysis patients and our current knowledge.

Contexte: Les personnes sous hémodialyse éprouvent un grand nombre de symptômes qui contribuent à un faible état fonctionnel et à une mauvaise qualité de vie liée à la santé. La prise en charge des symptômes est une priorité pour les personnes sous hémodialyse, mais les traitements efficaces sont limités. De nouvelles preuves montrent que l'adoption d'un programme d'exercice permettrait d'améliorer plusieurs symptômes courants liés à la dialyse. Objectifs: Le principal objectif de cette étude est d'évaluer l'effet d'un programme de rééducation par l'exercice sur le fardeau des symptômes chez les personnes recevant une hémodialyse d'entretien. Conception: Essai clinique prospectif randomisé-contrôlé, en aveugle, en parallèle 1:1 et ouvert, multicentrique. Cadre: Trois unités d'hémodialyse de Winnipeg, au Manitoba (Canada). Sujets: Des adultes atteints d'insuffisance rénale terminale qui reçoivent des traitements d'hémodialyse d'entretien en centre depuis plus de trois mois et qui présentent au moins un symptôme lié à la dialyse, tel qu'indiqué par un score de gravité de l'indice des symptômes de la dialyse (Dialysis Symptom Index) supérieur à zéro (n = 150). Intervention: Programme supervisé de rééducation par l'exercice d'une durée de 26 semaines et 60 minutes de vélo trois fois par semaine pendant l'hémodialyse. L'intensité et la durée de l'exercice ont été supervisées par un kinésiologue qui les a ensuite personnalisées en fonction de la forme physique initiale du participant en prévoyant une progression graduelle tout au long de l'intervention. Groupe témoin: Soins habituels d'hémodialyse (sans programme d'exercice). Mesures: Notre principal critère de jugement est un changement dans le fardeau lié aux symptômes après 12 semaines, tel que mesuré par le score de gravité de l'indice des symptômes de dialyse (ISD). Les critères d'évaluation secondaires comprennent un changement du score modifié de gravité de l'ISD (portant sur 10 symptômes les plus plausibles de s'améliorer avec l'exercice), la modification du score de gravité de l'ISD après 26 et 52 semaines, le temps de récupération après l'hémodialyse, la qualité de vie liée à la santé mesurée par le questionnaire EQ5D-5L, le comportement lié à l'activité physique mesuré par autoévaluation (questionnaire Godin-Shepherd) et par accéléromètre triaxial, la capacité d'effort (test de marche navette), la fragilité (Fried), le sentiment d'efficacité autodéclaré face à l'exercice, ainsi que les hospitalisations et la mortalité à un an. Méthodologie: Les changements pour le principal critère de jugement seront comparés entre les groupes par un test t bilatéral indépendant ou un test U de Mann-Whitney en fonction de la distribution des données, ainsi qu'à l'aide de modèles linéaires mixtes généralisés avec un point temporel de l'étude comme effet aléatoire et corrigé en fonction du score ISD initial. Les changements dans les résultats secondaires seront comparés entre les groupes au fil du temps à l'aide des tests statistiques paramétriques et non paramétriques appropriés selon le type de données et la distribution. Limites: Les restrictions liées à la pandémie de COVID-19 dans notre établissement ont retardé le recrutement des cibles et empêché pendant 15 mois la collecte de données sur les résultats mesurés par l'accéléromètre et les mesures de la fonction physique, soit jusqu'à ce que les restrictions soient levées. Conclusion: L'adoption d'un programme de rééducation par l'exercice visant à réduire le fardeau lié aux symptômes chez les personnes sous hémodialyse peut améliorer les symptômes courants observés dans cette population et se traduire par une amélioration de la qualité de vie et une réduction de l'invalidité et de la morbidité à long terme. Il convient de noter que cet essai pragmatique, avec son intervention d'exercice standardisée adaptable à la condition physique initiale de la personne, comble une lacune importante dans les soins cliniques des patients sous hémodialyse et dans nos connaissances actuelles.

Ticagrelor as Compared to Clopidogrel Following Percutaneous Coronary Intervention for Acute Coronary Syndrome.

Dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 inhibitor has become a mainstay of therapy after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Although higher-potency P2Y12 inhibitors are preferred over clopidogrel in major society guidelines, recent evidence has questioned the extent of the benefit. It is important to evaluate the relative efficacy and safety of P2Y12 inhibitors in a real-world setting. This is a retrospective cohort study of all patients who underwent PCI for ACS in a Canadian province from January 1, 2015 to March 31, 2020. Baseline characteristics, including co-morbidities, medications, and bleeding risk, were obtained. Propensity matching was used to compare patients who received ticagrelor versus clopidogrel. The primary outcome was occurrence of major adverse cardiovascular events (MACEs) at 12 months, defined as death, nonfatal myocardial infarction, or unplanned revascularization. Secondary outcomes included all-cause mortality, major bleeding, stroke, and all-cause hospitalization. A total of 6,665 patients were included; 2,108 received clopidogrel and 4,214 received ticagrelor. Patients who received clopidogrel were older, had more co-morbidities, including cardiovascular risk factors, and had a higher bleeding risk. In 1.925 propensity score-matched pairs, ticagrelor was associated with a significantly lower risk of MACE (hazard ratio 0.79, 0.67 to 0.93, p <0.01) and hospitalization (hazard ratio 0.85, 0.77 to 0.95, p <0.01). No difference was observed in the risk of major bleeding. A statistically nonsignificant trend toward reduced risk of all-cause mortality was noted. In conclusion, in a real-world high-risk cohort, ticagrelor was associated with decreased risk of MACE and all-cause hospitalization compared with clopidogrel after PCI for ACS.

Magnitude of the Potential Screening Gap for Fabry Disease in Manitoba: A Population-Based Retrospective Cohort Study.

Background: Fabry disease is a rare disorder caused by the deficient activity of α-galactosidase A (GLA) that often leads to organ damage. Fabry disease can be treated with enzyme replacement or pharmacological therapy, but due to its rarity and nonspecific manifestations, it often goes undiagnosed. Mass screening for Fabry disease is impractical; however, a targeted screening program for high-risk individuals may uncover previously unknown cases. Objective: Our objective was to use population-level administrative health databases to identify patients at high risk of Fabry disease. Design: Retrospective cohort study. Setting: Population-level health administrative databases housed at the Manitoba Centre for Health Policy. Patients: All residents of Manitoba, Canada, between 1998 and 2018. Measurements: We ascertained the evidence of GLA testing in a cohort of patients at high risk of Fabry disease. Methods: Individuals without a hospitalization or prescription indicative of Fabry disease were included if they had evidence of 1 of 4 high-risk conditions for Fabry disease: (1) ischemic stroke <45 years of age, (2) idiopathic hypertrophic cardiomyopathy, (3) proteinuric chronic kidney disease or kidney failure of unknown cause, or (4) peripheral neuropathy. Patients were excluded if they had known contributing factors to these high-risk conditions. Those who remained and had no prior GLA testing were assigned a 0% to 4.2% probability of having Fabry disease depending on their high-risk condition and sex. Results: After applying exclusion criteria, 1386 individuals were identified as having at least 1 high-risk clinical condition for Fabry disease in Manitoba. There were 416 GLA tests conducted during the study period, and of those, 22 were conducted in individuals with at least 1 high-risk condition. This leaves a screening gap of 1364 individuals with a high-risk clinical condition for Fabry disease in Manitoba who have not been tested. At the end of the study period, 932 of those individuals were still alive and residing in Manitoba, and if screened today, we expect between 3 and 18 would test positive for Fabry disease. Limitations: The algorithms we used to identify our patients have not been validated elsewhere. Diagnoses of Fabry disease, idiopathic hypertrophic cardiomyopathy, and peripheral neuropathy were only available via hospitalizations and not physician claims. We were only able to capture GLA testing processed through public laboratories. Patients identified to be at high risk of Fabry disease by the algorithm did not undergo GLA testing due to a clinical rationale that we were unable to capture. Conclusions: Administrative health databases may be a useful tool to identify patients at higher risk of Fabry disease or other rare conditions. Further directions include designing a program to screen high-risk individuals for Fabry disease as identified by our administrative data algorithms.

Contexte: La maladie de Fabry est un trouble rare causé par une activité déficiente de α-galactosidase A (GLA) qui conduit fréquemment à des dommages aux organes. La maladie de Fabry peut être traitée par remplacement enzymatique ou par traitement pharmacologique, mais elle passe souvent inaperçue en raison de sa rareté et de ses manifestations non spécifiques. Le dépistage de masse de la maladie de Fabry est irréalisable, mais un programme de dépistage ciblé pour les personnes présentant un risque élevé pourrait révéler des cas auparavant inconnus. Objectif: Notre objectif était d'utiliser les bases de données administratives sur la santé des populations pour recenser les patients présentant un risque élevé de maladie de Fabry. Conception: Étude de cohorte rétrospective. Cadre: Les bases de données administratives sur la santé des populations hébergées au Manitoba Centre for Health Policy. Sujets: Tous les résidents du Manitoba (Canada) entre 1998 et 2018. Mesures: Nous avons examiné les preuves d'un dosage de la GLA dans une cohorte de patients présentant un risque élevé de maladie de Fabry. Méthodologie: Les individus sans hospitalisation ou ordonnance indicative de la maladie de Fabry ont été inclus s'ils présentaient une des quatre affections suivantes, jugées à haut risque pour la maladie de Fabry: 1) accident vasculaire cérébral ischémique avant 45 ans; 2) cardiomyopathie hypertrophique idiopathique; 3) insuffisance rénale chronique protéinurique ou insuffisance rénale de cause inconnue; 4) neuropathie périphérique. Les patients ont été exclus s'ils présentaient des facteurs de contribution connus à ces maladies à haut risque. Les personnes restantes qui n'avaient pas de preuves d'un dosage antérieur de la GLA ont reçu une probabilité de 0 à 4,2 % d'avoir la maladie de Fabry, selon leur maladie à risque élevé et leur sexe. Résultats: Après l'application des critères d'exclusion, 1 386 personnes ont été identifiées au Manitoba comme ayant au moins une affection clinique présentant un risque élevé pour la maladie de Fabry. Pendant la période de l'étude, 416 dosages de GLA ont été effectués, dont 22 chez des individus présentant au moins une affection à risque élevé; soit un déficit de dépistage pour 1 364 Manitobains présentant un risque élevé de maladie de Fabry à qui aucun dosage n'avait été fait. À la fin de la période de l'étude, 932 de ces personnes étaient encore vivantes et résidaient toujours au Manitoba. Si ces individus étaient dépistés aujourd'hui, on pourrait s'attendre à obtenir entre 3 et 18 dosages positifs pour la maladie de Fabry. Limites: Les algorithmes que nous avons utilisés pour identifier nos sujets n'avaient pas été validés ailleurs. Les diagnostics de maladie de Fabry, de cardiomyopathie hypertrophique idiopathique et de neuropathie périphérique n'étaient disponibles que par une hospitalisation et non par demande d'un médecin. Seuls les dosages de la GLA effectués par des laboratoires publics ont pu être saisis. Les patients répertoriés par l'algorithme comme présentant un risque élevé de maladie de Fabry n'avaient pas subi de dosage de la GLA en raison d'une justification clinique qu'il nous a été impossible de saisir. Conclusion: Les bases de données administratives sur la santé peuvent s'avérer un bon outil pour recenser les patients présentant un risque plus élevé de développer la maladie de Fabry ou d'autres maladies rares. Les orientations futures comprennent la conception d'un programme de dépistage des individus présentant un risque élevé pour la maladie de Fabry, tels que recensés par nos algorithmes de données administratives.

Association of serum bicarbonate with the development of kidney stones in patients with chronic kidney disease: a retrospective cohort study.

Background: Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. Methods: We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22 mmol/L (metabolic acidosis) or 22 to <30 mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up. Results: A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0% vs 9.5%, P < .0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development. Conclusions: Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.

A chair-stand time of greater than 15 seconds is associated with an increased risk of death and hospitalization in cirrhosis.

Background: Frailty is a clinical state of increased vulnerability and is common in patients with cirrhosis. The liver frailty index (LFI) is a validated tool to evaluate frailty in cirrhosis, comprising of grip strength, chair stands, and balance tests. The chair-stand test is an easy to conduct frailty subcomponent that does not require specialized equipment and may be valuable to predict adverse clinical outcomes in cirrhosis. The objective of this study was to determine if the chair-stand test is an independent predictor of mortality and hospitalization in cirrhosis. Methods: A retrospective review of 787 patients with cirrhosis was conducted. Chair-stand times were collected at baseline in person and divided into three groups: <10 seconds (n = 276), 10-15 seconds (n = 290), and >15 seconds (n = 221). Fine-Gray proportional hazards regression models were used to evaluate the association between chair-stand times and the outcomes of mortality and non-elective hospitalization. Results: The hazard of mortality (HR 3.21, 95% CI 2.16%-4.78%, p <0.001) and non-elective hospitalization (HR 2.24, 95% CI 1.73%-2.91%, p <0.001) was increased in group 3 in comparison to group 1. A chair-stand test time >15 seconds had increased all-cause mortality (HR 2.78, 95% CI 2.01%-3.83%, p <0.001) and non-elective hospitalizations (HR 1.84, 95% CI 1.48%-2.29%, p <0.001) compared to <15 seconds. Conclusions: A chair-stand test time of >15 seconds is independently associated with mortality and non-elective hospitalizations. This test holds promise as a rapid prognostication tool in cirrhosis. Future work will include external validation and virtual assessment in this population.