Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease

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.

This is a randomized, open-label, three-arm study comparing Diovan (valsartan, an ARB), Tekturna (aliskiren, a DRI), and the combination of valsartan + aliskiren (i.e. ARB + DRI). One hundred twenty subjects (40 per arm) will be treated with Tekturna, Diovan, or a combination of both drugs for 9 months on top of their usual antihypertensive treatment. Changes in urinary aldosterone excretion will be monitored during therapy to measure the incidence of aldosterone breakthrough, defined as any sustained positive change from baseline urinary aldosterone excretion by the completion of the 9-month study period. This frequency measure will be compared during ARB, DRI, and ARB + DRI therapy. Changes in urinary protein excretion will also be monitored alongside the urinary aldosterone levels to determine whether aldosterone breakthrough is associated with refractory proteinuria. This is an innovative study that will be the first to (1) examine aldosterone breakthrough during DRI therapy, and (2) explore whether addition of a DRI to an ARB protects against aldosterone breakthrough. In addition, this will be the first study to examine whether DRI therapy (alone or in combination with ARB) is effective therapy for hypertension in patients with non-diabetic 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