End Stage Renal Disease, Hemodialysis
Conditions
Keywords
Dialysis, ESRD, Cardiovascular disease, spironolactone, L-arginine, myocardial perfusion, coronary flow reserve, diastolic function
Brief summary
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
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.
Interventions
DRUGSpironolactone
DIETARY_SUPPLEMENTL-arginine
DRUGPlacebo
Sponsors
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Joslin Diabetes Center
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in coronary Flow Reserve (PET) | Between baseline and 9 months | Coronary flow reserve will be measured using rest and stress 13N ammonia myocardial positron emission tomography (PET) at baseline and 9 months |
| Change in left ventricular diastolic function | Between baseline and 9 months | Left ventricular diastolic function will be measured using mitral annular E' on tissue doppler index echocardiography at baseline and 9 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 9 months | Combined rate of death, myocardial infarction, stroke, or hospitalization |
| Association between coronary flow reserve (CFR) and tissue doppler index (E') | Baseline | — |
| Hyperkalemia | Up to 9 months | Hyperkalemia requiring extra dialysis, adjustment in dialysate potassium, or discontinuation of therapy |
| Hypotension | Up to 9 months | Symptomatic or intradialytic hypotension 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 | — |
| Cardiovascular death | Up to 9 months | — |
| Change in resting myocardial blood flow | Between baseline and 9 months | — |
Countries
United States
Outcome results
None listed