Biomarkers of Kidney Secretory Function for Discriminating Risk of Hyperkalemia

项目摘要 高钾血症是一种常见且可能危及生命的电解质紊乱。高钾血症的风险是 在心力衰竭（HF）和慢性肾病患者中以及使用某些药物时， 例如螺内酯。目前鉴定高钾血症风险增加的个体的方法是 基本的钾主要由肾脏通过肾小球滤过和肾小管滤过排出。 分泌，但目前只有肾小球滤过被认为是评估高钾血症的风险。小说 肾小管分泌物的生物标志物与肾小管纤维化密切相关，我们最近 表明较低的分泌评分，即分泌生物标志物的综合评分，与 发生高钾血症的风险较高。许多药物，如螺内酯，通过 分泌物肾小管分泌生物标志物与药物清除相关 依靠肾脏分泌来消除。螺内酯治疗保留射血功能心力衰竭 分数（TOPCAT）试验是一项多中心国际临床试验，入组了3445例HFpEF患者， 将参与者随机分为螺内酯组和安慰剂组。在TOPCAT中，高钾血症发生率为18.7%， 在本TOPCAT辅助研究中，我们将测量肾脏 小管分泌生物标志物，其具体目的是：1）确定一组新的小管分泌生物标志物， 在TOPCAT中，生物标志物识别高钾血症风险较高的HF患者，和2）确定肾小管是否 分泌生物标志物与心力衰竭症状和利钠肽的改善相关 TOPCAT中HF患者接受螺内酯治疗后的血药浓度。这项研究的结果将提供 在开始治疗前对高钾血症风险个体进行风险分层的创新方法的证据 引起高钾血症的药物，并导致一个新的调查路线，其中我们移动分泌 生物标志物从研究到临床实践，最终目标是最大限度地提高效益， 最大限度地降低药物剂量和分泌药物的药物-药物相互作用的风险。

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.