UCSF

Rationale & objective

Heart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.

Study design

Observational cohort.

Setting & population

Euvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.

Predictors

Plasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.

Outcomes

Sodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.

Analytical approach

Robust linear regression models estimated the associations of each RAAS intermediate with outcomes.

Results

The analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = -0.41 [-0.76, -0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = -0.48 [-0.83, -0.14] and β = -0.51 [-0.95, -0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.

Limitations

Small sample size; highly selected participants; associations may not be causal.

Conclusions

Among multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.