Epithelial Sodium Channel (ENaC) as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

Epithelial Sodium Channel (ENaC) as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

The purpose of this study is to determine with the administration of amiloride, observe an enhanced natriuresis, reduction in blood pressure and weight compared to the administration of hydrochlorothiazide in Type 2 Diabetics.

Renal sodium retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome. There is abundant evidence that this occurs even in the absence of activation of hormones that are known to activate renal Na transporters. Proteinuria not only reflects glomerular damage, but also functions as a risk factor for cardiovascular disease, stroke, end stage renal disease and is associated with extracellular volume expansion and high BP. In the natural course of Type II diabetes, microalbuminuria and elevations in blood pressure are thought to occur at around the same time. Blood pressure in microalbuminuric diabetics is more sensitive to dietary salt intake than in normoalbuminuric patients despite both groups having similar aldosterone and plasma renin activity levels. Proteolytic processing of ENaC subunits might provide the primary defect in renal sodium handling in these microalbuminuric individuals. However, proteinuria is not consistently identified as a risk factor for incipient elevation in blood pressure and in some studies elevated blood pressure predicts the advent of microalbuminuria. Analyses of normotensive normoalbuminuric subjects in previous studies have found that higher urinary albumin levels in the normal range predicted incident hypertension. A similar finding was seen in a non-diabetic cohort. These studies suggest that these disparate results may be related to the cut off that defined microalbuminuria. Another possible explanation is that an ENaC activator, like plasmin, contributes to the generation of incident hypertension in some individuals. Levels of albuminuria may not necessarily be reflective of ENaC activator levels and may vary from individual to individual. Perhaps urinary plasmin and plasminogen provides a more robust biomarker for those individuals who may develop hypertension. Recent evidence suggests that in some individuals with glomerular damage, proteases not normally found in urine enter the urinary space and aberrantly cleave ENaC. In this setting, filtered plasminogen (inactive precursor) is converted to plasmin (active protease) by urokinase that is expressed in tubular epithelial lumen. The proteolytic activation of ENaC would generate a primary defect in renal sodium handling, a mechanism that may be a particularly important factor leading to increases in extracellular fluid volume and BP that accompany nephrotic syndrome. While previous studies have examined the role of amiloride in low-renin hypertension, and as an additional agent the conventional treatment of hypertension, no human trials have tested whether ENaC inhibitors impact blood pressure and volume status in the setting of proteinuria. Over a ten year period, millions of diabetics, 5.3% of Type II diabetics and 28% of Type I diabetics develop macroscopic proteinuria.

Amiloride 10 mg taken every day for two weeks, along with adherence to specified diet. On day 14 titrate dose up to Amiloride 20 mg, take every day for two weeks after completion of two week intake of Amiloride 10 mg, along with adherence to specified diet.

HCTZ 12.5 mg taken every day for two weeks, along with adherence to specified diet. On day 14 titrate dose up to HCTZ 25 mg taken every day for two weeks after completion of two week intake of HCTZ 12.5 mg, along with adherence to specified diet

Change in clinic systolic BP. This BP measure will be the average of three serial BP measurements taken one minute apart after 5 minutes of sitting quietly.

To demonstrate effect size on relevant hypertension outcomes such as volume status and urinary sodium excretion. Also assess the fractional excretion of sodium (FENa) and chloride (FECI). Endpoint will be the 24 hour urine excretion.

Inclusion Criteria: Age 18 to 80 yrs at randomization History of Type 2 Diabetes Presence of systolic hypertension or pre-hypertension (average systolic blood pressure (SBP) ≥120 mmHg and <180 mmHg.) Urinary protein/creatinine ratio >300 mg/g creatinine at screening Hemoglobin A1C<8% Willing and able to give informed consent Exclusion Criteria: Average SBP of ≥180 mmHg or diastolic blood pressure (DBP) of ≥110 mmHg Current symptomatic heart failure, history of New York Heart Association Class III or IV congestive heart failure, or left ventricular (LV) ejection fraction (by any method) <25%; these patients may be harmed with withdrawal of diuretics Serum potassium level <3.5 or >5.0 at screening History of hyperkalemia in the last two years (serum K>5.5) Contraindication to use of hydrochlorothiazide or amiloride Unstable angina pectoris or acute myocardial infarction (MI) in last 3 months Known secondary causes of hypertension (HTN) (screening for these conditions will not be required) Estimated glomerular filtration rate (GFR) <60 mL/min/1.73m², as determined by validated estimating equations On or expected to be on immunosuppressive therapy Any history of solid organ transplantation Significant dementia Other factors likely to limit adherence during trial (eg. alcohol or substance abuse, plan to move in next year, history of non-adherence to medications, appointments and medical care, reluctance of close family members to participate in trial, lack of support from primary healthcare provider) Participation in another investigational trial within 4 weeks of the screening visit Arm Circumference too large or too small to allow accurate blood pressure measurement Pregnancy or currently trying to become pregnant (although this is unlikely because of age limit Incarceration

Passero CJ, Hughey RP, Kleyman TR. New role for plasmin in sodium homeostasis. Curr Opin Nephrol Hypertens. 2010 Jan;19(1):13-9. doi: 10.1097/MNH.0b013e3283330fb2.