Authors' Reply: Refining the Map of Diuretic Resistance in Acute Heart Failure

We thank Kazory and Koratala for their interest and comments1 on the implications of the Loop diuretic intensification Or adjuvant Thiazide in Mechanisms of Diuretic Resistance study, published in JASN.2 Although we agree with Kazory and Koratala1 that the field would benefit from a more refined approach to diuretic resistance phenotyping, we respectfully disagree that the study findings were negative. Both diuretic escalation strategies significantly improved natriuresis in an objectively diuretic resistance cohort, with an adjuvant thiazide strategy showing clear superiority. However, the mechanisms underlying the improved natriuresis were not as hypothesized. Patients with diuretic resistance primarily in the loop of Henle had significantly worse natriuretic response with loop intensification compared with adjuvant thiazide, and those with a predominant distal mechanism of resistance did not respond preferentially to a thiazide. These significant observations challenge the conventional wisdom on the diuretic resistance mechanisms in acute heart failure, which are based on animal models. A valid criticism of our approach to defining diuretic resistance mechanistic subtypes using the median change in fractional excretion of lithium (FELi) was raised, and we agree that diuretic resistance mechanisms likely exist as a continuum rather than distinct categories. Kazory and Koratala1 suggested that using more extreme delta FELi values to categorize resistance mechanisms could improve classification and potentially affect our observations. To investigate this important question, we categorized resistance in the loop as the bottom quartile of delta FELi after the screening intravenous loop diuretic, and resistance in the distal tubules as the top quartile in a sensitivity analysis. The outcome of change in 6-hour natriuresis in this sensitivity analysis did not materially differ from the primary analysis for those randomized to loop intensification (loop resistance 23±35 mmol versus distal tubule resistance 81±83 mmol; P = 0.02) nor adjuvant thiazide (loop resistance 92±28 mmol versus distal tubule resistance 86±77 mmol; P = 0.82). These findings reinforce our conclusions that diuretic resistance mechanisms in human acute heart failure are different and more complicated than that previously suggested by animal models.