L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD

Study Overview
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Brief Summary
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Cardiovascular disease is the primary cause of death in patients with end stage renal disease (ESRD). New research suggests that the high risk of death may be partly due to high levels of fibrosis and a loss of small blood vessels in the heart of patients with dialysis-dependent ESRD. This study is designed to compare the effects of two different drugs, spironolactone and L-arginine, with placebo on structure and function of the heart in individuals with dialysis-dependent ESRD.

Detailed Description
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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.

Official Title
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A Randomized, Controlled Trial of L-arginine and Spironolactone in Dialysis-dependant End Stage Renal Disease

Conditions
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End Stage Renal Disease, Hemodialysis

Intervention / Treatment
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* Drug: Spironolactone
* Dietary Supplement: L-arginine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spironolactone + Placebo<br>Spironolactone 25 mg by mouth daily + Placebo L-arginine-liquid formulation by mouth 3 times daily | Drug: Spironolactone<br> <br> * Other names: Aldactone;Drug: Placebo<br> <br> |
| Placebo Comparator: Double Placebo<br>Placebo spironolactone-1 tablet by mouth daily + Placebo L-arginine liquid formulation by mouth 3 times daily | Drug: Placebo<br> <br> |
| Experimental: Spironolactone + L-arginine<br>Spironolactone 25 mg daily + L-arginine 3 grams orally 3 times daily | Drug: Spironolactone<br> <br> * Other names: Aldactone;Dietary Supplement: L-arginine<br> <br> |
| Experimental: L-arginine + Placebo<br>L-arginine 3 grams by mouth 3 times daily + Placebo spironolactone 1 tablet by mouth daily | Dietary Supplement: L-arginine<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in coronary Flow Reserve (PET) | Coronary flow reserve will be measured using rest and stress 13N ammonia myocardial positron emission tomography (PET) at baseline and 9 months | Between baseline and 9 months | 
| Change in left ventricular diastolic function | Left ventricular diastolic function will be measured using mitral annular E' on tissue doppler index echocardiography at baseline and 9 months | Between baseline and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association between coronary flow reserve (CFR) and tissue doppler index (E') |  | Baseline | 
| Change in resting myocardial blood flow |  | Between baseline and 9 months | 
| Change in left ventricular mass index |  | Between baseline and 9 months | 
| Change in coronary vascular resistance |  | Between 0 and 9 months | 
| Association between change in coronary flow reserve (CFR) and change in diastolic function-tissue doppler index (E') |  | Between baseline and 9 months | 
| Change in early diastolic function (E') |  | Between baseline and 2 weeks | 
| Combined cardiovascular safety | Combined rate of death, myocardial infarction, stroke, or hospitalization | Up to 9 months | 
| Cardiovascular death |  | Up to 9 months | 
| Hyperkalemia | Hyperkalemia requiring extra dialysis, adjustment in dialysate potassium, or discontinuation of therapy | Up to 9 months | 
| Hypotension | Symptomatic or intradialytic hypotension up to 9 months | Up to 9 months | 
| Change in early coronary flow reserve |  | Between baseline and 2 weeks | 
| Change in hyperemic myocardial blood flow |  | Between baseline and 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dialysis, ESRD, Cardiovascular disease, spironolactone, L-arginine, myocardial perfusion, coronary flow reserve, diastolic function