Metformin in Kidney Disease

Chronic kidney disease (CKD) is a major global health problem associated with substantial costs and resource utilization. Currently, CKD affects more than 500 million people worldwide. Patients with CKD have unacceptably high mortality rates due to cardiovascular (CV) causes, which are not entirely explained by traditional CV risk factors. The mortality rates in advanced CKD are six times higher compared to the Medicare population, with CVD accounting for the overwhelming majority of deaths. Insulin resistance (IR) is common in CKD patients and may represent a central link between CKD and the increased CVD risk observed in this population. Insulin resistance may increase CV risk by impairing and worsening endothelial function, increasing reactive oxygen species, and exacerbating systemic inflammation-hence, insulin resistance is considered a "non-traditional CV risk factor" in CKD.

Obesity (defined by a body mass index \[BMI\] of at least 30 kg/m2) is a major public health problem-the upward trend in obesity prevalence across regions and continents is a worldwide concern. Obesity increases the risk for cardiovascular disease and death. In the general population, obesity hastens death by 9.4 years. Obesity is an independent risk factor for CKD. Besides its contribution to the development of diabetes and hypertension, increased fat mass may also have a direct impact on kidney function.

In spite of the increasing prevalence of both obesity and CKD, the impact of obesity in the CKD population is not known, especially in terms of the exaggerated metabolic disturbances associated with their coexistence. It is highly likely that these two conditions have profound interactions that exaggerate the severity of the metabolic derangements when they coexist, particularly in regards to adipokine dysregulation, the risk of "insulin resistance", and downstream effects on vascular health. The current proposal will attempt to characterize the relative and combined impact of both obesity and CKD on metabolic disturbances, which may aid in risk stratification and identifying specific targets for intervention.

The ultimate goal of this proposal is to understand the relative and combined impact of obesity and CKD on the generation and maintenance of insulin resistance and their impact on cardiovascular health.

Specific Aim 2: To study the effects of metformin, an AMPK activator, on metabolic disturbances associated with obesity and moderate CKD.

S.A.2.a: To test if metformin will improve LAR in obese patients with moderate CKD compared to placebo.

S.A.2.b: To test if metformin will improve markers of systemic inflammation, oxidative stress, endothelial dysfunction in obese patients with moderate CKD compared to placebo.

S.A.2.c: To test if metformin will improve atherosclerosis markers and reduce clinical CVD events in obese patients with moderate CKD compared to placebo.

Hypothesis: The investigators hypothesize that the administration of metformin in obese CKD patients will significantly improve the adipokine profiles-particularly through a reduction in LAR. Additionally, that it will improve systemic inflammation, oxidative stress and endothelial function, which may or may not be mediated by changes in adipokines. Finally, the investigators hypothesize that improvements in these markers of vascular health will translate into reduced arterial stiffness and less clinical CV events


Eligibility Criteria:
Inclusion Criteria:

* Age 18 years old;
* Ability to give informed consent;
* Life expectancy greater than 6 months;
* Estimated GFR 30-59 ml/min/1.73m\^2;
* Overweight (BMI \>=25 to \< 30 kg/m\^2) or obese (BMI \>=30 kg/m\^2); or normal (BMI \>=18.5 to \<25 kg/m\^2) if pre-diabetic or insulin resistant.

Exclusion Criteria:

* Pregnancy or breast feeding;
* Presence or history of Diabetes Mellitus type I or II
* History of metformin use or any insulin sensitizer or any drug for the treatment of metabolic syndrome over the last one year;
* Any acute kidney injury episode in the last 4 months due to the risk of recurrent AKI;
* Proteinuria of \> 5 g in 24 hours determined by a 24 hour urine collection or PCR \> 4.5;
* Uncontrolled hypertension with systolic blood pressure 160 mmHg and diastolic blood pressure 100 mmHg;
* Patients with new changes to their antihypertensive regimen over the last 1 month;
* Severe, unstable, or active inflammatory disease; active infection including seropositive HIV, Hepatitis B or C; active connective tissue disorder; or moderate to severe liver disease;
* Decompensated heart failure;
* Recent hospitalization or surgical procedure within 1 month prior to the study for any cause;
* Current active malignancy or cancer history in the prior 5 years (excluding squamous cell and basal cell skin cancers);
* Known intolerance to the study drug;
* Patient receiving oral or injected steroids
* Use of any investigational product or device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments;