Pioglitazone to Reduce Sympathetic Overactivity in CKD Patients

Chronic Kidney Disease (CKD) is a major health problem affecting more than 26 million
Americans. Notably, more patients with CKD die of cardiovascular complications than progress
to dialysis. An overactive sympathetic nervous system is a well known cardiovascular risk
factor present in CKD. The increase in sympathetic nerve activity (SNA) may not only
contribute to hypertension, but also accelerates the progression of end organ damage that is
independent of any rise in blood pressure. Indeed, elevated SNA is associated with poor
prognosis and increased risk of cardiovascular morbidity and mortality. Thus, the sympathetic
nervous system constitutes a primary novel drug target needed for improving cardiovascular
outcomes in CKD patients. However, limited effort has been directed at identifying the
mechanisms driving sympathetic overactivity in CKD and importantly, SNA remains high in these
patients despite standard drug therapy including angiotensin converting enzyme inhibitors and
angiotensin II receptor blockers. Thus, a better understanding of the mechanism(s) of the
elevated SNA would enable us to devise more effective countermeasures and help reduce the
subsequent morbidity and mortality among CKD patients. A potential signal driving SNA
involves accumulation of the endogenous nitric oxide synthase inhibitor asymmetric
dimethylarginine (ADMA). ADMA is elevated in CKD and is a strong, independent predictor of
future cardiovascular events in these patients. Much of the work with ADMA has been
correlational in nature with a focus on the well-known vascular endothelial properties of
nitric oxide. However, increasing functional evidence indicates that nitric oxide is also a
key signaling molecule involved in the tonic restraint of sympathetic outflow from the
brainstem. Indeed, the investigators have recently demonstrated that systemic experimental
inhibition of nitric oxide synthase causes sympathetic activation in healthy humans. In the
current study, the investigators will target the pathophysiological nitric oxide synthase
inhibition caused by elevated ADMA concentrations in CKD and its role in mediating
sympathetic overactivity. Recent work has reported that thiazolidinediones, such as
pioglitazone, reduce ADMA likely by upregulating dimethylarginine dimethylamino-hydrolase
(DDAH), the enzyme responsible for the breakdown of ADMA. Indeed, analysis of the DDAH gene
revealed the presence of a thiazolidinedione binding site, implying that thiazolidinediones
can directly regulate DDAH expression and subsequently ADMA levels. Thus, thiazolidinediones
may provide a promising therapy in CKD. Indeed, in a recent study, CKD patients treated with
pioglitazone were less likely to reach the composite end points of cardiovascular morbidity
and mortality. Importantly, this effect was independent of the level of renal impairment
suggesting protective effects even in moderate CKD. However, the mechanisms for these
improvements remain unclear. In this study, the investigators hypothesize that these
favorable cardiovascular effects are through a lowering of ADMA and SNA. Thus, the ability of
pioglitazone to reduce ADMA and SNA in CKD patients will be tested.

Inclusion Criteria:

- CKD patients classified as Stage 3 and 4 of National Kidney Foundation Classification
with estimated glomerular filtration rate (GFR) between 15 and 59 mL/min/1.73 m2
according to the Modification of Diet in Renal Disease (MDRD) formula based on serum
creatinine, age, gender, and race.

- Men and women 35 to 70 years of age

Exclusion Criteria:

- Allergy to Glitazones

- Myocardial infarction

- Heart failure

- Angina

- History of kidney stones

- Liver disease (abnormal liver enzymes)

- Anemia (hemoglobin <8 g/dl)

- Cancer with current treatment

- Previous organ transplantation

- Immunosuppressant therapy

- Human immunodeficiency virus infection

- Pregnancy or lactating

- Current tobacco use

- Dilantin and oral contraceptive usage due to potential drug interaction with
glitazones

- Self-identified history of hypoglycemia