Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease
Condition: Renal Insufficiency, Chronic
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency
Intervention: ISMN; Vitamin C
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Chronic Kidney Diseases; Chronic Kidney Insufficiency; Chronic Renal Diseases; Chronic Renal Insufficiency; Kidney Insufficiency, Chronic; Cardiac Failure; Congestive Heart Failure; Heart Decompensation; Heart Failure, Congestive; Myocardial Failure

Summary:

      Heart failure (HF) is an epidemic and is a major burden on the US healthcare system. The most
      common cardiovascular endpoint is HF. Thus, novel interventions to prevent HF in chronic
      kidney disease (CKD) are highly desirable. This study will assess: the variability in the
      response to isosorbide mononitrate (ISMN) therapy; the degree of change in central
      hemodynamics and cardiac endpoints through analysis of changes in left ventricle (LV) mass,
      diffuse myocardial fibrosis, and myocardial systolic and diastolic function.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Chronic kidney disease stage 3

          -  Elevated left ventricular mass index or LV posterior wall thickness >1.4 cm documented
             in a clinically indicated echocardiographic or MRI examination within the previous 24
             months or electrocardiographic LV hypertrophy

          -  Stable medical therapy as defined by no addition, removal or change in dosage >100% of
             Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers,
             beta-blockers, or calcium channel blockers for > 30 days

          -  Current therapy with an ACE inhibitor, hydralazine or a statin, all of which have been
             shown to reduce nitrate tolerance

        Exclusion Criteria:

          -  A clinically- indicated stress test demonstrating significant myocardial ischemia
             within 1 year of enrollment, not followed by coronary revascularization

          -  Rhythm other than sinus (i.e., atrial fibrillation)

          -  Non-cardiac condition limiting life expectancy to <1 year

          -  Current or anticipated future need for long acting organic nitrate therapy

          -  Severe aortic or mitral valve disease

          -  Hypertrophic cardiomyopathy

          -  Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid)

          -  Pericardial disease

          -  Primary pulmonary arteriopathy

          -  History of myocardial infarction, unstable angina, percutaneous transluminal coronary
             angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days, or
             requirement for either PTCA or CABG at the time of consent

          -  Resting heart rate (HR) >100 bpm

          -  A reduced LV ejection fraction (EF<50%)

          -  Known severe liver disease (AST >3x normal, alkaline phosphatase or bilirubin >2x
             normal)

          -  Allergy to ISMN

          -  Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or
             tadalafil

          -  Therapy with rosiglitazone

          -  Current pregnancy or a positive urine pregnancy test; women who become pregnant during
             the study will be discontinued from the trial

          -  Therapy with warfarin

          -  History of kidney stones

          -  History of glucose-6-phosphate dehydrogenase (G6PD) deficiency

          -  Systolic blood pressure <110 mmHg or diastolic blood pressure <40 mmHg;

          -  Contraindications to a cardiac MRI: (a) Central nervous system aneurysm clips; (b)
             Implanted neural stimulators; (c) Implanted cardiac pacemaker or defibrillator; (d)
             Cochlear implant; (e) Ocular foreign body (e.g. metal shavings); (f) Other implanted
             medical devices: (e.g. drug infusion ports); (g) Insulin pump; (h) Metal shrapnel or
             bullet; (i) Claustrophobia; (j) Extreme obesity rendering the patient unable to fit
             into narrow-bore scanners; (k) Unwillingness of the patient to undergo a cardiac MRI.