Exercise in Obese Diabetic Patients With Chronic Kidney Disease

Patients with type 2 diabetes, obesity, and chronic kidney disease (CKD) are generally
physically inactive, have a high mortality rate, and may benefit from an exercise program.
However, there have been no randomized controlled trials to determine the benefits of
exercise training in this population. This study seeks to substantiate the hypothesis that
increasing energy expenditure by exercise training in the obese diabetic patient with CKD
will result in the following benefits:

1. Renal benefits, including reduction in proteinuria and stabilization of glomerular
filtration rate (GFR)

2. Cardiovascular benefits, including decreased blood pressure, decreased heart rate, and
increased exercise tolerance.

3. Improved glucose control (lower glycated hemoglobin), lipid control (decreased
cholesterol with improved atherogenic profile)

4. Improved body composition (weight loss, increased lean body mass and decreased fat
mass).

5. Decreased inflammation (assessed by high-sensitivity C-reactive protein), endothelial
dysfunction (assessed by flow-mediated dilatation), and oxidative stress (assessed by
reduced glutathione).

6. Increased health-related quality of life.

In preparation for this proposal, the investigators performed a 24-week randomized controlled
feasibility study comparing aerobic exercise plus optimal medical management to medical
management alone in patients with type 2 diabetes, obesity (BMI > 30 kg/m2), and stage 2-4
CKD (eGFR 15-90 mL/min/1.73m2) with persistent proteinuria of > 200 mg/g. Subjects randomized
to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised
home exercise. The primary outcome variable was change in proteinuria. Exercise training
resulted in a significant improvement in exercise duration during stress testing which
persisted until 24 weeks. This was accompanied by significant decreases in resting systolic
blood pressure and 24-hour proteinuria at 24 weeks. No changes were seen in the control
group. The investigators concluded that exercise training in obese diabetic patients with CKD
is feasible and results in a demonstrable training effect (increased exercise duration and
decreased resting blood pressure). Moreover, it may decrease proteinuria and thus have a
renoprotective effect.

The investigators now propose a larger-scale randomized controlled trial to determine the
effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative
stress in diabetic patients with CKD. This will be a 52-week randomized study based on the
investigators' pilot study design with some modifications. As opposed to the 6-week training
period and 18-week home exercise period utilized in the pilot study, subjects randomized to
exercise will undergo 12 weeks of intensive exercise training in the exercise laboratory
followed by 40 weeks of supervised home exercise training (total duration of study 1 year).
Moreover, due to recent recommendations that resistance training be incorporated into
exercise training regimens in type 2 diabetic patients, the investigators will incorporate
resistance (strength) training in this proposal. The primary outcome variable will be change
in proteinuria at 12 and 52 weeks. Secondary outcome variables will be change in albuminuria
and estimated glomerular filtration rate (eGFR) at 12 and 52 weeks. In addition, the
investigators will measure blood pressure (BP), glycated hemoglobin, lipid profile,
C-reactive protein (CRP) levels, body weight and composition, endothelial dysfunction (by
flow-mediated dilatation), and Quality of Life (QoL) evaluations. The Index of Coexistent
Diseases (ICED) to measure comorbidities to determine if comorbid conditions had any
influence on the outcomes of the study. The Center for Epidemiologic Studies Depression Scale
(CES-D) will also be used to determine the influence of depression (covariate) on study
outcomes and adherence with the study objectives.

This study will directly address the effects of a structured exercise program in a patient
population at high risk for cardiovascular complications. The investigators will specifically
address the novel idea that exercise will not only improve cardiovascular fitness but will
also ameliorate the renal complications resulting from diabetes.

Inclusion Criteria:

- Diabetes mellitus

- CKD Stages 2-4

- BMI > 30

- Persistent proteinuria (urine protein/creatinine > 200 mg/g for > 3 mo)

- On treatment with ACE inhibitor or ARB

- On treatment with aspirin

- On treatment with statin (if LDL > 100)

Exclusion Criteria:

- Symptomatic neuropathy/retinopathy

- Positive stress test due to coronary arterial disease

- Symptomatic cardiovascular disease

- Congestive heart failure (New York Heart Association Class III or IV)

- Chronic obstructive pulmonary disease (FEV1 < 50% predicted and/or requires
supplemental oxygen support during exercise)

- Complaints of angina during the stress test

- Cerebrovascular disease/cognitive impairment

- Renal transplant

- Inability to walk on the treadmill

- Any unforeseen illness or disability that would preclude exercise testing or training

- Participation in a formal exercise program within the previous 12 weeks