PROJECT SUMMARY Hyperkalemia is a common and potentially life-threatening electrolyte disturbance. The risk of hyperkalemia is higher in individuals with heart failure (HF) and chronic kidney disease and with the use of certain medications, such as spironolactone. Current methods to identify individuals at increased risk of hyperkalemia are rudimentary. Potassium is primarily eliminated by the kidneys through glomerular filtration and tubular secretion, but currently only glomerular filtration is considered when evaluating risk for hyperkalemia. Novel biomarkers of kidney tubular secretion have been strongly linked with tubule fibrosis and we have recently demonstrated that a lower secretion score, a composite score from secretion biomarkers, is associated with a higher risk of incident hyperkalemia. Many medications, such as spironolactone, are eliminated through secretion. Kidney tubule secretion biomarkers have been associated with the clearance of medications dependent on kidney secretion for elimination. The Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT) trial is a multicenter international clinical trial that enrolled 3445 patients with HFpEF and randomized participants to spironolactone versus placebo. In TOPCAT, rates of hyperkalemia were 18.7% in spironolactone arm and 9.1% in the placebo arm. In this TOPCAT ancillary study, we will measure kidney tubule secretion biomarkers with the specific aims to: 1) determine if a novel panel of tubular secretion biomarkers identifies HF patients at higher risk for hyperkalemia in TOPCAT, and 2) determine if tubule secretion biomarkers are associated with improvements in heart failure symptoms and natriuretic peptide levels from spironolactone therapy among HF patients in TOPCAT. The results of this study will provide evidence for an innovative method to risk stratify individuals for risk of hyperkalemia prior to starting hyperkalemia provoking medications, and lead to a new line of investigation wherein we move secretion biomarkers from research towards clinical practice with the ultimate goal of maximizing benefits while minimizing risks of drug dosing and drug-drug interactions for secreted drugs.