Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
Condition: Proteinuric Kidney Disease; Diabetic Nephropathy; Hypertensive Nephrosclerosis; IgA Nephropathy; Focal Segmental Glomerulosclerosis; Glomerulopathy (Obesity-associated); Glomerulonephritis, Membranous
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Glomerulonephritis, IGA; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Glomerulonephritis, Membranous; Nephrosclerosis
Intervention: Aliskiren; Valsartan
Intervention MeSH terms: Valsartan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Hypothesis: Aldosterone breakthrough will occur at a far lower frequency during renin
      inhibition (0-10% over 9 months), alone or in combination with an ARB, compared to
      conventional ARB therapy (35-45% over 9 months). The investigators hypothesize that
      aldosterone breakthrough occurs due to accumulation of active precursor substances, most
      notably angiotensin II, produced in response to conventional RAAS blockade with ACEinhibitors
      and ARBs. The investigators believe that direct renin inhibition (DRI) should minimize this
      accumulation and therefore significantly lower or possibly eliminate the breakthrough effect.

      Interruption of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting
      enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), alone and in
      combination, has become a leading therapy to slow the progression of chronic heart and kidney
      disease. Both types of drugs inhibit the formation of aldosterone, a hormone, which has been
      shown to have harmful effects on patients with chronic heart and kidney disorders. This
      treatment is effective but not perfect since, even after an initial improvement, many
      patients become worse over the long term. This may be due to an unexpected increase in
      aldosterone, a phenomenon called "aldosterone breakthrough."

      The purpose of this study is to find out whether the use of a direct renin inhibitor (DRI)
      alone, or in combination with an angiotensin receptor blocker (ARB), will lessen the
      occurrence of aldosterone breakthrough since direct renin inhibitors inhibit the formation of
      aldosterone at a very early step. This study will compare the effectiveness of adding Diovan
      (valsartan) or Tekturna (aliskiren) or a combination of Diovan and Tekturna to the usual
      antihypertensive treatment. The investigators will follow blood pressure, aldosterone levels,
      and urinary protein levels over 9 months to evaluate which of these therapies is most
      effective for treating hypertension in patients with proteinuric kidney disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Proteinuria > 300 mg/day

          -  Normal to mildly reduced kidney function (eGFR > 45 ml/min/1.73m2)

          -  Systolic blood pressure >130 mm Hg

          -  Diastolic blood pressure >70 mm Hg

          -  Diagnoses of diabetic nephropathy, hypertensive nephrosclerosis, IgA nephropathy,
             focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis,
             membranous nephropathy, fibrillary glomerulonephritis, or obesity-associated
             glomerulopathy

        Exclusion Criteria:

          -  Concomitant use of cyclosporine (which can interact with aliskiren)

          -  Inability to undergo 6 week washout period if already on RAAS-blocking drug(s)
             (includes renin inhibitor, ACE-inhibitor, ARB, and mineralocorticoid receptor blocker)

          -  eGFR < 45 ml/min/1.73m2

          -  Urine protein excretion < 300 mg/day

          -  Serum K > 5.0 mEq/l

          -  Systolic blood pressure > 170 mm Hg or < 130 mm Hg after washout period

          -  Diastolic blood pressure > 110 mm Hg or < 70 mm Hg after washout period

          -  Congestive heart failure NYHA class III and IV

          -  History of any cardiovascular events (stroke, TIA, MI, unstable angina, CABG, PCI, CHF
             hospitalization) in 3 months prior to study visit 1

          -  2nd or 3rd degree heart block without a pacemaker or other uncontrolled arrhythmia

          -  Clinically significant valvular disease

          -  Known renal artery stenosis

          -  Any surgical or medical condition that might significantly alter the pharmacokinetics
             of the study drugs (n.b. bariatric surgery > 6 months prior to visit 1 is not an
             exclusion)

          -  History or evidence of drug or alcohol abuse within the last 12 months

          -  Any concurrent life threatening condition with a life expectancy less than 2 years

          -  Pregnant or nursing (lactating) women

          -  Women of child-bearing potential unless postmenopausal for at least 1 year, surgically
             sterile, or using effective methods of contraception as defined by local health
             authorities