Mechanisms of Diuretic Resistance in Heart Failure (MsDR)

The protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide infused over 1 hour and measuring peak Fractional Excretion of Sodium (FENa), 1-hour post completion of infusion. Upon meeting FENa inclusion criteria (<5% for diuretic resistance and >10% for diuretic responsive), participants may proceed to the subsequent study procedures. Participants will begin a study diet provided by the metabolic kitchen five days prior to the first study visit with randomized treatment (Day 0). Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.

Total sodium output in response to a loop diuretic differs based on Glomerular Filtration Rate (GFR). However, a diuretic responsive participant with normal or severely reduced GFR each will achieve a similar peak FENa of approximately 20% with high dose diuretic. In a cohort of 109 hospitalized diuretic resistance (DR) HF patients that received 12.5mg bumetanide, a peak FENa <5% occurred in 66% patients. The mean FENa in this group was 2.6 ± 1.3 %, thus FENa <5% is common and a clinically relevant threshold for DR, and thus was chosen as the threshold to define diuretic resistance for the proposed study.

Participants will be asked to follow the study diet as the design seeks to decrease the variability of diuretic response introduced by variations in dietary sodium intake. For the current study, a four-gram sodium, low acid (0.8 g/kg protein) diet will be utilized. Four grams was chosen since, in prior experience, this is the average pre-study sodium intake of outpatient HF study participants and thus will facilitate rapid transition into balance.

Inclusion Criteria:

• Clinical diagnosis of HF
• No plan for titration/change of heart failure medical or device therapies during the study period.
• Absence of non-elective hospitalizations in the previous 3 months.
• At optimal volume status by symptoms, exam, and dry weight
• Age > 18 years
• Additional inclusion criteria for diuretic resistant cohort determined at the diuretic challenge visit: Peak FENa < 5% following 10mg IV bumetanide challenge
• Additional inclusion criteria for diuretic responsive cohort determined at the diuretic challenge visit: Peak FENa > 10% following 10mg IV bumetanide challenge

Exclusion Criteria:

• GFR <20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies
• Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
• History of flash pulmonary edema requiring hospitalization and treatment with biphasic positive airway pressure or mechanical ventilation or a "brittle" volume sensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e. amyloid cardiomyopathy, etc).
• Hemoglobin < 8 g/dL
• Pregnant or breastfeeding
• Inability to give written informed consent or comply with study protocol or follow-up visits
• Chronic Urinary retention limiting ability to perform timed urine collection procedures