Biomarkers of Kidney Secretory Function for Discriminating Risk of Hyperkalemia

鉴别高钾血症风险的肾脏分泌功能生物标志物

• 批准号: 10727192
• 负责人: Nicholas Wettersten
• 金额: $ 12.31万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727192
• 关键词: Address; Albuminuria; Aldosterone; Ancillary Study; Biological Markers; Blood; Blood specimen; Cardiomyopathies; Cessation of life; Chronic Kidney Failure; Cities; Clinical Markers; Creatinine; Data; Development; Distal; Distal convoluted renal tubule structure; Dose; Drug Interactions; EFRAC; Electrolytes; Evaluation Studies; Excretory function; Face; Fibrosis; Frequencies; General Population; Glomerular Filtration Rate; Goals; Health; Heart Arrest; Heart failure; Homeostasis; Hospitalization; Incidence; Individual; International; Intervention Trial; Investigation; Kansas; Kidney; Kidney Diseases; Life; Link; Measures; Medical; Methods; Monitoring Clinical Trials; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Organ; Participant; Patients; Pharmaceutical Preparations; Placebos; Positioning Attribute; Potassium; Questionnaires; Randomized; Renal tubule structure; Research; Resources; Risk; Risk Factors; Serum; Spironolactone; Spottings; Subgroup; Symptoms; Toxin; Tubular formation; Urine; Work; appropriate dose; arm; biomarker identification; biomarker panel; blood pressure intervention; cardiovascular risk factor; clinical practice; clinical risk; clinical trial enrollment; cohort; design; follow-up; glomerular filtration; high risk; hyperkalemia; improved; individual patient; innovation; insight; kidney biopsy; mortality risk; novel; novel marker; preservation; prospective; randomized, clinical trials; risk minimization; risk mitigation; risk stratification; tool

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.

项目概要 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 患有心力衰竭 (HF) 和慢性肾脏疾病以及使用某些药物的个体中的血压升高， 如螺内酯。目前识别高钾血症风险增加的个体的方法是 简陋的。钾主要由肾脏通过肾小球滤过和肾小管排出。 分泌，但目前在评估高钾血症风险时仅考虑肾小球滤过。小说 肾小管分泌的生物标志物与肾小管纤维化密切相关，我们最近发现 证明较低的分泌评分（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，例如螺内酯，可通过以下方式消除： 分泌。肾小管分泌生物标志物与药物的清除有关 依赖肾脏分泌消除。螺内酯治疗射血保留性心力衰竭 Fraction (TOPCAT) 试验是一项多中心国际临床试验，入组了 3445 名 HFpEF 患者 将参与者随机分配到螺内酯组和安慰剂组。在 TOPCAT 中，高钾血症发生率为 18.7% 螺内酯组为 9.1%，安慰剂组为 9.1%。在这项 TOPCAT 辅助研究中，我们将测量肾脏 肾小管分泌生物标志物的具体目的是：1）确定是否有一组新的肾小管分泌 生物标志物在 TOPCAT 中识别出高钾血症风险较高的心力衰竭患者，并且 2) 确定肾小管是否 分泌生物标志物与心力衰竭症状和利尿钠肽的改善相关 TOPCAT 中 HF 患者螺内酯治疗的水平。这项研究的结果将提供 在开始之前对个体进行高钾血症风险分层的创新方法的证据 引发高钾血症的药物，并导致新的研究方向，其中我们移动分泌 生物标志物从研究到临床实践，最终目标是利益最大化，同时 最大限度地减少分泌药物的药物剂量和药物间相互作用的风险。