Mechanisms of Muscle Blood Flow Dysregulation and Exercise Intolerance in Chronic Kidney Disease

Progressive muscle weakness and premature fatigue are characterize the condition of chronic
kidney disease (CKD) which can be very debilitating. Mechanisms underlying exercise
intolerance in CKD is not completely understood. Previous studies have demonstrated impaired
skeletal muscle vasodilation during exercise in CKD patients, which may contribute to
exercise intolerance. Normally, there is blunting of sympathetic mediated vasoconstriction in
exercising muscle to allow for steady blood supply to exercising muscles. This phenomenon is
called functional sympatholysis. Functional sympatholysis is impaired by increases in
reactive oxygen specie and may be impaired in CKD.

Experiments will be performed on 2 groups of subjects 1) Normal kidney function (eGFR>90) 2)
Stage 2-3 CKD (eGFR 30-89). VAsoactive medications will be held for 72 hours before study.
All participants will attend a baseline study visit, which will include a physical
examination, a medical history review, vital sign measurements, and blood collection. Muscle
nerve activity and muscle oxygenation will be measured while the subjects perform hand grip
exercise at 30% maximum voluntary contraction with and without lower body negative pressure
(- 20 mmHg). Muscle blood flow will be measured before and after hand grip exercises. CKD
subjects will then be randomized to exercise training (to squeeze a tennis ball repeatedly
for at least 30 min/day) or no exercise training for 28 days. Procedures in baseline visit
will be repeated followed by cross over to alternate group for 28 days followed by repeat of
baseline procedures. Blood flow, muscle oxygenation and muscle nerve activity will be
compared between CKD and normal subjects as well as before and after exercise training for
CKD subjects.

Inclusion Criteria:

- Normotensive adults

- CKD 2-3

Exclusion Criteria:

- Blood Pressure ≥140/90

- eGFR >60ml/min/1.73 m2 or eGFR <30ml/min/1.73 m2

- Any evidence of cardiopulmonary disease, left ventricular hypertrophy or systolic
dysfunction by echocardiography.

- Diabetes mellitus or other systemic illness

- Pregnancy

- Any history of substance abuse or current cigarette use

- Any history of psychiatric illness

- History of malignancy