Effects of Neprilysin Inhibition With ARNI (LCZ 696) on the Cardiorenal and Humoral Response to Acute Saline Volume Expansion in DM With and Without PDD

6.1 Visit 1 Consent Visit: Possible study participants will meet with study coordinator to review consent form. After enrollment into the study, a 6-minute walk will be performed (minimum required distance: 450 meters). Diet instructions will be given by a dietician about a no added salt diet, 120 mEq Na/day, which will be maintained throughout the study period. Comprehensive metabolic panel (including albumin, bilirubin, calcium, bicarbonate, chloride, creatinine, glucose, alkaline phosphatase, potassium, total protein, sodium, AST, ALT and BUN)and complete blood count with differential will be obtained. Brief physical exam or nursing assessment will be performed by a qualified Study Team Member. Visit 2 will be scheduled at least one week out from consent visit to accommodate diet compliance, unless participant is already compliant with salt intake parameter. Instructions for completing a 24-hour urine collection, and container for Study Visit 2, will be given.

Subjects who are taking angiotensin converting enzyme inhibitors (ACEI) will be switched over to an equivalent dose of Valsartan or Losartan, which will be maintained for 3 days beyond the end of the study period. This is due to the FDA recommendation that patients on ACEI should have a 36 hour washout period before administering ARNI due to the increased risk of angioedema.

6.2 Visit 2 Participants will start a twenty-four hour urine collection one day prior to the active study day for assessment of baseline sodium excretion, creatinine clearance and urine protein analysis.

Subjects will be admitted to the Clinical Research Translational Unit (CRTU). On the active study day, subjects will withhold their usual dose of medications and will be placed in the supine position for 1 hour. During the first 15 minutes, two standard intravenous (IV) catheters will be placed (one in each arm). One catheter will be used for infusion and the other (in the contralateral arm) for blood sampling. A bladder ultrasound will be completed after the participant's first void after admitting to assess for urine retention. Subjects will be asked to drink 10ml/Kg of water to insure sufficient urinary flow. A priming dose (calculated according to body size) of Iothalamate, to measure glomerular filtration rate (GFR), is infused, followed by a constant rate IV sustaining dose (calculated according to estimated kidney function) of Iothalamate. The subjects will be asked to empty their bladder spontaneously every thirty minutes (if subjects are unable to void every thirty minutes, a urinary catheter will be used upon consent). Throughout the study, at the end of each 30-minute clearance period, subjects will be asked to drink an amount of water equivalent to the sum of the blood losses and the urinary flow.

After an equilibration period of 45 minutes, a 30-minute baseline renal clearance will be carried out. Urinary samples for determination of volume, urinary sodium excretion (UNaV), cGMP, and Iothalamate will be obtained at the end of the clearance period. Venous blood samples for Iothalamate, sodium, ANP, BNP, cGMP, soluble neprilysin, renin, angiotensin II and aldosterone will be obtained at the middle of the clearance period. Blood pressure will be measured at 20-minute intervals by using an automatic blood pressure cuff, and heart rate will be continuously monitored by electrocardiography. Echocardiography will be performed during these baseline clearances to determine left atrial (LA) and LV volumes and systolic and diastolic function.