Association of Proximal Tubule Secretion With Hyperkalemia Risk, Treatment Response, and Outcomes in Heart Failure With Preserved Ejection Fraction

Rationale & Objective: Endogenous biomarkers reflecting impaired kidney tubular secretion are associated with risk of hyperkalemia in patients with hypertension and chronic kidney disease. Whether these biomarkers are associated with risk of hyperkalemia, therapeutic response, and adverse cardiovascular and kidney events in heart failure (HF) patients receiving mineralocorticoid receptor antagonists is unknown. Study Design: An observational cohort study. Setting & Participants: Individuals with HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT study. Predictors: Summary secretion score incorporating urine-to-plasma ratios of 9 secretion markers measured in paired samples at baseline. Outcomes: Change in serum potassium during follow-up, measures of treatment response assessed by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and N-terminal pro-B-type natriuretic peptide over 12 months, and adverse cardiovascular and kidney events. Analytic Approach: Linear mixed-effects models, Cox proportional hazards models, and linear regression adjusting for risk factors, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. Results: Among 372 TOPCAT participants, 179 (48%) were randomized to spironolactone, 45% were women, the mean age was 70 ± 10 years and estimated glomerular filtration rate was 66 ± 18 mL/min/1.73 m². In adjusted models, higher secretion score was not associated with changes in serum potassium, change in KCCQ ≥5 points, change in N-terminal pro-B-type natriuretic peptide, adverse cardiovascular or kidney events. In adjusted models, a higher secretion score was associated with lower KCCQ at 12 months (change −3.5, 95% CI, −6.6 to −0.4) in the spironolactone arm, but not in the placebo arm. Limitations: Low number of events, confounding from Eastern Europe participants who may have not had HFpEF or taken prescribed therapies. Conclusions: Biomarkers of tubular secretion are not associated with risk of hyperkalemia, treatment response, or cardiovascular and kidney events in individuals with HFpEF. Plain-language Summary: People with chronic kidney disease and hypertension with reduced proximal tubule secretion capacity have a greater risk of hyperkalemia. Whether similar associations are seen in individuals with heart failure is unknown. We studied 372 participants with heart failure with preserved ejection fraction enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist study. Using blood and urine specimens collected at the time of enrollment, we measured nine biomarkers of proximal tubule secretion capacity and combined them into a composite secretion score. We then evaluated whether this score was associated with potassium changes, response to treatment, and cardiac and kidney events. In this population, proximal tubule secretion capacity was not associated with any of these outcomes.