Does Thiazolidinedione Therapy Improve Endothelial Function and Preserve Renal Function

Does Chronic Thiazolidinedione Therapy Improve Endothelial Function and Preserve Renal Function in Non-Diabetic Patients With Chronic Kidney Disease?

The hypothesis of the current proposal is that chronic pioglitazone therapy will result in improved endothelial function, decreased inflammation, and preservation of renal function in patients with CKD but without diabetes.

Despite continued improvements in the outcomes of patients with cardiovascular disease, similar improvements have not been seen in patients with chronic kidney disease (CKD). CKD constitutes one of the highest risk populations for cardiovascular disease. When the creatinine clearance is ≤ 60 ml/min the risk for cardiovascular events is greater than that of diabetes. However, few studies have focused on the prevention or treatment of coronary artery disease (CAD) in CKD patients. The development of endothelial dysfunction and increased inflammation appear to be critical in the development of atherosclerosis and cardiovascular disease. The broad long-term objective of this grant proposal is to determine unique therapies to reduce endothelial dysfunction and inflammation, and thereby help to prevent cardiovascular disease and preserve renal function in patients with CKD. Thiazolidinediones such as pioglitazone appear to improve endothelial function and decrease inflammation, an effect that may be present in patients with or without diabetes. To address this hypothesis the following Specific Aims are proposed: To determine the effects of chronic pioglitazone therapy on endothelial function in non-diabetic patients with CKD (creatinine clearance ≤ 60 ml/ min, but not on dialysis) To determine the effects chronic pioglitazone therapy on inflammation and oxidative stress in non-diabetic patients with CKD To determine the effects chronic pioglitazone therapy on progression of renal disease in non-diabetic patients with CKD

0.4 mg sublingual nitroglycerin tablet was given to all patients without a contraindication to check the brachial reactivity.

Brachial arterial reactivity was measured by ultrasound. A blood pressure cuff was placed around the right forearm. Using the ultrasound probe of the ultrasound, 2-dimensional images clearly defining the anterior and posterior intimal wall of the brachial artery were collected. Flow velocities were then measured using pulsed wave Doppler. The blood pressure cuff previously placed around the patient's right forearm was inflated to 200 mmHg. The cuff remained inflated for 5 minutes as the patient remained motionless and quiet. Prior to deflation, the patient was asked to remain still as flow velocities and 2-dimensional images were obtained immediately following cuff deflation. Then a 0.4 mg sublingual nitroglycerin tablet was given to all patients without a contraindication and all measurements were repeated.

Inclusion Criteria: Age over 18 years. Creatinine clearance ≤ 60 ml/min by the Cockcroft-Gault equation Patients not anticipated to go on dialysis or have renal transplantation in the next 6 months Ability to provide informed consent Life expectancy greater than 12 months Exclusion Criteria: Diabetes mellitus or a fasting blood glucose ≥ 110 mg/dL Acute renal failure Class 3 or 4 heart failure Liver failure, ascites, or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) two times the upper limit of normal Hemoglobin less than 9 mg/dL Multiple myeloma Premenopausal women not using at least 1 form of birth control Pregnant or nursing women Prisoners Known allergy to pioglitazone