Background and objectives Patients with ESKD are sedentary. When patient-identified barriers to exercise are addressed, recruitment and retention in exercise trials remain low, suggesting that the trial design may not resonate with them. Therefore, we conducted a survey of patients on dialysis to assess perceived benefits and barriers to exercise and discover preferred outcomes and exercise type by dialysis modality and age in anticipation of designing future randomized, controlled trials.Design, setting, participants, & measurements English-and French-speaking patients with ESKD treated with hemodialysis or peritoneal dialysis were recruited from two tertiary care hospitals in Ottawa and Montreal, Canada. Summary descriptive statistics were used to describe patient responses; then, they were separated by dialysis modality and age category. ResultsThe survey was completed by 423 participants. Current activity levels were similar across modalities (P=0.35); 78% of younger patients walked at least 10 minutes at a time on 3 or more days compared with only 58% of older patients (P=0.001). The two most desired benefits of exercise were improved energy (18%) and strength (14%). The third priority differed, such that improved sleep, maintenance of independence, and longevity were selected by patients on peritoneal dialysis, patients on in-center hemodialysis, and patients on home hemodialysis, respectively. Older patients were most interested in improvements in energy, strength, and maintenance of independence, whereas younger patients were interested in improving energy, longevity, and transplant candidacy. Only 25% of patients were able to exercise without difficulty; the major barriers for the remaining patients were feeling patients were feeling too tired (55%), short of breath (50%), and too weak (49%). If patients were to exercise, they wanted to exercise at home (73%) using a combination of aerobic and resistance training (41%), regardless of modality or age category. ConclusionsThe majority of patients undergoing maintenance dialysis in two tertiary hospitals in Ottawa and Montreal report similar desired outcomes and barriers, with greater differences by age category than modality.

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes.

Background: Frailty is a clinical phenotype of decreased physiologic reserve that is associated with increased morbidity and mortality. The most meaningful way to assess frailty in patients with end-stage kidney disease (ESKD) is unknown. Objective: To assess the prevalence of frailty in ESKD patients using the easy-to-administer FRAIL scale and, to determine its association with mortality, transplantation, and hospitalization. Design: A cohort study was used. Setting: The Ottawa Hospital, Ottawa, Ontario, Canada, was the setting of this study. Patients: All eligible adult ESKD patients treated with dialysis from August to November 2017 at The Ottawa Hospital were invited to participate. Measurements: The FRAIL scale. Methods: Eligible patients completed an exercise survey with FRAIL questions embedded within the instrument. Number of comorbid illnesses was determined from the electronic medical record and weight loss was calculated from target weight in the patients’ dialysis prescription. Mortality, transplant status, and hospitalizations were ascertained from the electronic medical record 18 months later; differences by frailty status were evaluated using descriptive statistics. Kaplan-Meier and Cox regression models were used to examine the association between frailty and transplant. Results: Of 476 ESKD patients screened, 261 participated; 101 receiving peritoneal dialysis, 135 intermittent hemodialysis, and 25 home hemodialysis. Thirty-nine, 145, and 77 were frail, pre-frail, and not frail, respectively. Employment status, ethnicity, and comorbid illnesses differed significantly by frailty status, but mortality did not. In univariate analysis, frail patients were less likely to be listed for ( P = .05) and to receive a kidney transplant ( P = .02). However, after adjusting for age and modality, frailty was not statistically associated with a decreased likelihood of transplant (Hazard Ratio: 0.15; confidence interval [CI], 0.02-1.15; P = .068). The results were similar when accounting for the competing risk of death ( P = .060). Frail patients were more likely to be hospitalized ( P = .01) and spend more time in the hospital ( P = .04). Limitations: Single-center design with a relatively short follow-up and small sample size limiting the number of variables that could be assessed in analysis. We also excluded patients who were unable to communicate in English or French and those patients with physical limitations such as amputations, potentially affecting generalizability. Conclusions: Frail ESKD patients as identified by the FRAIL scale are less likely to receive a renal transplant; this association diminished statistically after adjusting for age and modality and when accounting for the competing risk of death. Frail patients were at increased risk of hospitalization. Further study with larger patient numbers and longer follow-up is needed to determine the usefulness of the FRAIL scale in predicting adverse outcomes. Trial registration: Not required as this was an observational study.