Physical Activity in Renal Disease (PAIRED): The Effect on Hypertension

Background and importance: Hypertension is highly prevalent among Canadians with non-dialysis dependent chronic kidney disease (CKD). It is a modifiable risk factor for both cardiovascular (CV) events and CKD progression. Exercise is an effective strategy for blood pressure (BP) reduction in the general population but in people with CKD, hypertension is mediated by different causes (i.e. vascular stiffness, volume expansion) and it is unclear whether exercise will reduce BP in this population. Consequently, exercise resources are not offered in the routine multidisciplinary care of people with CKD and the prevalence of sedentary behaviour remains double that of the general population. The role of exercise in CKD management is also an important question for patients. From CIHR-supported workshops with patients, the role of lifestyle, such as exercise in CKD was a top research priority.

Research aims: i.To determine the effect of exercise on mean ambulatory systolic blood pressure (SBP) in people with CKD compared to usual care. The investigators hypothesize that exercise training will significantly reduce BP compared to control. ii.To inform the design of a larger, multi-center trial evaluating the effect of exercise on the risk of CKD progression.

Methods: A 160 participant, single center randomized trial of adults from Alberta Kidney Care North CKD clinics, Edmonton, Albert, Canada. Participants with an estimated glomerular filtration rate (eGFR) of 15-44 ml/min per 1.73m2 and SBP \>130 mmHg will be randomized, stratified by eGFR (\<30 versus ≥ 30) to an exercise intervention or usual care. The main outcome is the difference in 24-hour ambulatory SBP after eight weeks of exercise training between groups. Secondary outcomes include: BPs at eight and 24 weeks, dose of anti-hypertensives, aortic stiffness, CV-risk markers, CV fitness, 7-day accelerometry, quality of life, safety, and in an exploratory analysis, eGFR and proteinuria. The intervention is thrice weekly moderate intensity aerobic exercise supplemented with isometric resistance exercise, targeting 150 minutes per week and delivered over 24-weeks. Phase 1: one supervised weekly sessions and home-based sessions (eight weeks). Phase 2: home-based sessions (16 weeks). To detect a clinically important BP reduction of 5 mmHg between groups requires 128 patients (two sample t-test, alpha 0.05, beta 0.2, common standard deviation of 10 mmHg). Assuming 20% dropout requires 160 patients. For the primary outcome, the investigators will use a mixed linear regression model in which BP is regressed on group, baseline SBP and eGFR, and time point.

Expected outcomes: The findings from this study will address a significant knowledge gap in hypertension management in CKD, inform care-delivery and the design of a larger study on CKD progression. This proposal aligns with priorities for both patients and decision makers: to identify the role of exercise in CKD management and to reshape the delivery of renal care so that it is more consistent with patient values and preferences.


Eligibility Criteria:
Inclusion Criteria:

* Resting SBP \>120 mmHg systolic on screening BP clinic measurements (with an electronic sphygmomanometer, mean of three readings after first reading is discarded) and at least one previous SBP measurement above 120 mmHg on a separate occasion within the past six months (home or clinic measurement).
* Stable on blood pressure medications for the past eight weeks
* eGFR 15-44 ml/min per 1.73m2 eGFR between 15-44 ml/min per 1.73m2 within the last three months and one additional value in this rage in the last 12 months.
* Independent ambulation with or without an assistive device for at least three consecutive minutes
* Cognition and English language sufficient enough to understand written information, provide consent, and comply with the testing and interventions
* Approval of the attending nephrologist
* No significant exercise-induced arrhythmia or new ischemia on submaximal incremental exercise testing (final screening step)

Exclusion Criteria:

* Resting SBP \>160 mmHg or DBP \> 110 mmHg on screening BP clinic measurement (Note: the individual may be re-screened 8 weeks after medication adjustment)
* Arm circumference greater than 54 centimeters (size limit of large ABPM cuff)
* Recent (\<6 weeks) or planned (\<6 months) major cardiovascular events or procedures
* Any known contraindication to exercise (American College of Sports Medicine Guidelines)

Acute myocardial infarction (3-5 days) or unstable angina; Uncontrolled symptomatic arrhythmias; Active endocarditis; Acute myocarditis or pericarditis; Symptomatic severe aortic stenosis; Acute pulmonary embolism or deep vein thrombosis; Suspected dissecting aneurysm; Uncontrolled asthma; Uncontrolled pulmonary edema; Room air desaturation to \<85%; Acute non-cardiopulmonary disorder that may affect exercise performance (infection, orthopedic problem); Mental impairment leading to inability to cooperate; Uncontrolled hypertension (as above)

* Pregnant or planning to become pregnant
* Transplant
* Life expectancy or predicted time to renal replacement therapy \<9 months (attending physician judgment)
* Planned move or hospital admission within the next 9 months
* Currently enrolled in an interventional clinical trial; currently enrolled in a structured exercise program or performing regular exercise training \> 2 day/week in the last 3 months
* Taking other medications known to affect blood pressure (prednisone cyclosporine) and expected adjustment in the next 9 months
* Significant barrier to participation in a home exercise program or an insurmountable barrier to attend in-center training sessions.