Effect of Serum Chloride Concentrations on Diuretic Effect in the TRANSFORM-Mechanism Mechanistic Study

Background: Chloride, a regulator of multiple sodium transport pathways and renin secretion, has been associated with diuretic resistance previously in cross sectional studies. In the TRANSFORM-Mechanism study we found no meaningful pharmacokinetic or pharmacodynamic advantages of torsemide versus furosemide. After establishing dose equivalency, the torsemide group had a 2-fold higher dose than the furosemide group, leading to a randomized exposure that can alter chloride levels. In a post-hoc analysis, we evaluated the change in serum chloride with randomized assignment to torsemide vs. furosemide and chloride’s association with renin, estimated glomerular filtration rate (eGFR), and diuretic efficiency (DE). Methods: TRANSFORM-Mechanism randomized (N=88) heart failure patients to oral torsemide or furosemide and intensively characterized diuretic response after the first dose of randomized therapy, and again after 30 days of chronic dosing. Results: Serum chloride increased in both groups from baseline to 30 days but increased more with furosemide (1.0±3.4 mEq/L) than torsemide (0.2±4.6 mEq/L) (p=0.003). Increase in serum chloride concentration between visits was associated with a decrease in serum renin concentration (r=-0.323, p=0.007). Increase in serum chloride concentration between visits was also associated with increased eGFR (r=0.317, p=0.013) and increased DE defined as natriuretic response normalized to diuretic dose (r=0.391, p=0.001). Conclusion: Regardless of randomized diuretic or prescribed dose, increase in serum chloride concentration between study visits was associated with decreased serum renin concentration and increased eGFR and DE. Funding: NIDDK Support