L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD

We hypothesize that that abnormalities in aldosterone and nitric oxide (NO) homeostasis
contribute to the progression of microvascular disease and myocardial fibrosis in ESRD and
that agents designed to restore normal aldosterone and NO homeostasis will improve
microvascular and diastolic cardiac function in the heart of individuals with dialysis
dependent ESRD. We will test 2 specific agents: The mineralocorticoid receptor blocker
spironolactone; and L-arginine, an agent which improves NO bioavailability. Two specific
aims will be addressed using a prospective, double-blinded, 2x2 factorial trial in dialysis
dependent patients with ESRD. Subjects will be randomized to placebo, spironolactone plus
placebo, L-arginine plus placebo, or combination spironolactone and L-arginine therapy.
Diastolic cardiac function will be assessed using tissue Doppler index (TDI) determined
mitral annular velocities (E') on LV echocardiography, and microvascular supply will be
assessed using CFR—the ratio of hyperemic to resting myocardial blood flow—measured by
positron emission tomography (PET) scans at baseline, 2 weeks and after 9 months of
randomized therapy.

This randomized trial of spironolactone and L-arginine will provide important data about the
contributions of aldosterone and NO to the pathogenesis of cardiovascular disease in ESRD,
will demonstrate the therapeutic potential of L-arginine and spironolactone as as targeted
cardiovascular therapies for use in ESRD, and will provide important insights into the
underlying pathophysiology of cardiovascular disease in ESRD. The results generated will
provide the data needed to design large-scale trials testing whether spironolactone or
L-arginine can improve mortality or cardiovascular outcomes in ESRD.

Inclusion Criteria:

- Chronic dialysis therapy for End Stage Renal Disease

- Age 21-85

Exclusion Criteria:

- Hyperkalemia requiring unscheduled dialysis within 3 months

- Pre-dialysis potassium ≥6.5 meq/L within 3 months

- Hypotension defined as SBP <100

- Recurrent intra-dialytic hypotension defined as recurrent cramping, light-headedness,
or hypotension requiring infusion of saline or other intervention or otherwise
limiting ability to achieve dry weight. Or SBP <80

- History of myocardial infarction

- History of coronary artery bypass surgery

- Non revascularized coronary disease >90%

- Mitral valve repair or replacement

- Severe mitral valve disease

- Renal transplant expected within 9 months

- Expected survival < 9 months

- Pregnant

- Prisoners

- Unable to provide consent

- Allergy to spironolactone or L-arginine

- Digitalis use

- 1st or 2nd degree heart block