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Chronic kidney disease (CKD) is associated with a pro-oxidative and pro-inflammatory state, and this is thought to contribute to a decrease in vascular function leading to greater cardiovascular disease (CVD) risk. Curcumin supplementation has been shown to reduce oxidative stress and improve endothelial function at rest in healthy older humans, although the magnitude of this effect remains unknown during exercise in CKD. The primary aim of this proposal is to determine whether exercising blood flow and vasoconstrictor responsiveness are improved as a result of acute oral supplementation with curcumin in patients with CKD. We hypothesize that: 1) acute curcumin supplementation will increase steady state exercise blood flow, and 2) reduce vasoconstriction induced by an acute sympathetic stimulus (cold pressor test) CKD.

Active muscles require an optimal amount of local blood flow to meet the functional and metabolic demand of the exercising muscle. It is well known that maximal aerobic work capacity and exercise tolerance are reduced in CKD, contributing to functional impairment and loss of independence. A multitude of factors may be responsible for this outcome including reduced blood flow to active muscle beds brought on by greater levels of oxidative stress in CKD. Aging and some individuals with disease (coronary artery disease, hypertension, diabetes) exhibit elevated resting sympathetic nerve activity (SNA), leading to greater vasoconstriction and pressor responses during exercise. However, the magnitude of this effect remains unknown in CKD. Importantly, there are a lack of interventions aimed at improving blood flow and reduce sympathetic mediated vasoconstriction in patients with CKD.

Recent evidence in aging humans suggest that curcumin supplementation improves vascular function by reducing oxidative stress. However, it remains unknown whether acute curcumin supplementation can be regarded as an effective therapeutic strategy aimed at modulating exercise vasodilation and sympathetic mediated vasoconstriction in CKD. Understanding the mechanisms that impair vascular function within exercising muscle is important when understanding implications for systemic blood pressure regulation, cardiovascular disease and functional work capacity in CKD. Therefore, identifying a low cost, non-pharmaceutical intervention and its potential impact on improving vascular function in CKD is a priority in preventative cardiovascular disease medicine.

The present proposal aims to examine the effect of sympathetic vasoconstriction on the differential changes in exercising blood flow in response to acute oral supplementation with curcumin in patients with CKD.

Inclusion Criteria for CKD subjects:

Age 45-80 years old CKD stage III and IV (estimated glomerular filtration rate: 15-60 mL/min/1.73m2) BMI <40 kg/m2-1 Able to give informed consent

Exclusion Criteria for CKD subjects will include answering yes to the following questions:

• Active participation in another study?
• Dialysis?
• End stage renal disease or kidney failure?
• Kidney transplant?
• Sever liver disease or transplant?
• Diabetes?
• Angina (i.e., chest discomfort/pain/pressure upon exertion)
• Severe congestive heart failure?
• Pacemaker/defibrillator?
• Heart arrhythmia (i.e. Atrial fibrillation/flutter)?
• Pregnant, breastfeeding, or unwilling to use adequate birth control?
• Active infection or antibiotic therapy?
• Immunosuppressive therapy within the last 3 months?
• History of stroke?
• Have you had a heart attack in the last 3 months?
• Have you taken curcumin in last 3 months?
• Current use of Hormone Replacement Therapy (if female)?
• Current smoker?
• Anemic (Hemoglobin count <9)?

Inclusion Criteria for healthy middle-age and older subjects:

Age 45-80 years old BMI <40 kg/m2 1 Able to give informed consent

Exclusion Criteria for health older subjects will include answering yes to the following questions:

• Chronic kidney disease?
• Hypertension?
• Asthma?
• Heart disease?
• Clinical depression?
• Autonomic disorders?
• Sleep apnea?
• Sever liver disease or transplant?
• Diabetes?
• Heart attack?
• Angina (i.e., chest discomfort/pain/pressure upon exertion)
• Severe systolic or congestive heart failure?
• Heart angioplasty/stent or bypass surgery?
• Heart valve surgery/replacement or valve disease?
• Pacemaker/defibrillator?
• Heart arrhythmia (i.e. Atrial fibrillation/flutter)?
• Pregnant, breastfeeding, or unwilling to use adequate birth control?
• Active infection or antibiotic therapy?
• Immunosuppressive therapy within the last 3 months?
• Have you taken curcumin in last 3 months?
• Current use of Hormone Replacement Therapy (if female)?
• Current smoker?
• Anemic (Hemoglobin count <9)?

Patient, providers, and the investigative team will all be blinded to the randomization.