Mechanisms of Diuretic Resistance and Diuretic Response in the LOT-MDR Mechanistic Randomized Controlled Trial: A Prespecified Analysis

Background: The LOT-MDR trial compared diuretic escalation strategies in acute heart failure (AHF) and diuretic resistance (DR). In a prespecified analysis, we hypothesized DR in the loop of Henle (DR-Loop) would respond favorably to loop intensification and DR in the distal nephron (DR-Distal) would respond best to adjuvant thiazide. Methods: Hospitalized AHF patients (N=100) with DR (<100mmol Na excretion to screening IV loop diuretic) were randomized to 2.5X IV loop diuretic dose intensification or IV chlorothiazide added to the same loop dose. At screening, DR was categorized as DR-Loop, an increase in fractional excretion of lithium (FELi, measuring Na exiting the loop of Henle) below the population median value 4.4%, or DR-Distal (increased FELi above the median). Results: Loop intensification significantly increased urine loop diuretic delivery [median 203% (IQR 147%, 259%)]. A ceiling effect of loop intensification was not observed for natriuresis nor FELi up to 400mg IV furosemide equivalents. The increase in diuretic delivery and relative increase in FELi did not differ by DR mechanism (p=0.77 and p=0.99 respectively). However, loop intensification paradoxically produced less augmentation in natriuresis (p=0.004) in DR-Loop compared to DR-Distal, due to a larger absolute augmentation of FENa and FELi in DR-Distal. The improvement in natriuresis with adjuvant thiazide was not superior in patients with DR-Distal compared to DR-Loop (p=0.54). Conclusion: Contrary to the hypotheses, treating DR-Loop with loop diuretic intensification and treating DR-Distal with adjuvant thiazide did not preferentially improve natriuresis. Subtherapeutic diuretic delivery is not the primary mechanism for DR-Loop, and transport through NCC is not the primary compensatory mechanism in DR-Distal. Funding: NIDDK Support