Human Cardiorenal Syndrome

人类心肾综合症

• 批准号: 9102339
• 负责人: HORNG H CHEN
• 金额: $ 39.01万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102339
• 关键词: Acute; Address; Amino Acids; Angiotensin Receptor; Annexin A1; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Apoptotic; Biological; Biological Markers; Brain natriuretic peptide; C-terminal; Cell Death Signaling Process; Cell Proliferation Regulation; Cells; Cessation of life; Chronic; Clinic; Clinical; Clinical Research; Clinical Sciences; Data; Development; Diuretics; Dose; Enalapril; Functional disorder; Funding; Furosemide; Goals; Grant; Guanosine Monophosphate; Heart failure; Hospitalization; Human; Hypotension; Incidence; Injury; Kidney; Lead; Measures; Messenger RNA; Methods; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Neprilysin; Outcome; Pathway interactions; Patients; Peptides; Phagocytosis; Physiological; Property; Proteomics; Proximal Kidney Tubules; RNA Splicing; Renal function; Renin-Angiotensin-Aldosterone System; Reporting; Research; Rosa; Second Messenger Systems; Specimen; Syndrome; Systolic heart failure; Testing; Time; Translational Research; United States National Institutes of Health; Urine; activator 1 protein; base; blood pressure reduction; design; human study; improved; inhibitor/antagonist; innovation; novel; novel diagnostics; novel therapeutics; patient population; prognostic value; public health relevance; saluretic; second messenger

 DESCRIPTION (provided by applicant): The broad objective of this renewal is to advance our understanding of pathophysiological mechanisms of human cardiorenal syndrome (CRS) as defined by the presence of systolic heart failure and renal dysfunction with the goal of developing novel therapeutics and diagnostics for the patients. In the first funding cycle, we investigated the biological interaction between diuretic therapy, the renin-angiotensin- aldosterone-system (RAAS) and cyclic 3′-5′-guanosine monophosphate (cGMP) pathway in human CRS. Specifically, we accomplished the following: 1) Demonstrated that short term (3 weeks) reduction of furosemide dose was well tolerated in patients with chronic systolic heart failure (HF) and improved renal function only in those with renal dysfunction; 2) Utilizing urine proteomics methods, we discovered that Annexin A1 is a potential urine biomarker of CRS; 3) Preliminary data from our grant on the potential renal specific actions low dose nesiritide lead to the design and completion of the ROSE-AHF study carried out within the NHLBI Heart Failure Clinical Research Network. The ROSE-AHF study demonstrated that low dose nesiritide was not renal specific with an increased incidence of hypotension and did not enhance renal function in patients with acute HF and renal dysfunction. Hence, emphasizing the need for a renal specific therapy for human CRS. Specific Aim 1 will determine the efficacy of a novel renal specific peptide, ANX-042, which was designed based on alternatively spliced B-type natriuretic peptide (BNP) discovered by the applicant and colleagues in enhancing GFR without significant hypotension in human CRS. We have identified an alternatively spliced mRNA for B-type natriuretic peptide (ASBNP) that includes a unique and distinct longer carboxyl-terminus. Based on this mRNA, we biodesigned a truncated peptide form (ANX-042) containing the first 13 amino acids of its C-terminal. In experimental heart failure, ANX-042 has potent diuretic and natriuretic actions without the vasodilatory hypotensive properties. In a recently completed First-in-Human study, we have demonstrated that ANX-042 is safe and that it activates its second messenger cGMP at doses that did not result in symptomatic reduction of blood pressure in healthy humans. Our objective is to determine, for the first time, if ANX-042 will enhance renal function without hypotension in patients with systolic HF and renal dysfunction. Specific Aim 2 will test the hypothesis that urine Annexin A1 (AnxA1) is a biomarker of renal injury in acute HF with renal dysfunction with prognostic value. AnxA1 acts as an important endogenous anti- inflammatory molecule and also participates in regulation of cell proliferation and cell death signaling and promotes efficient phagocytosis of apoptotic cells. We found that urine AnxA1 protein levels were increased in systolic HF patients with renal dysfunction versus those with preserved renal function. Others have reported that urine AnxA1 is a biomarker of glomerular injury. Our objective is to extend our previous findings and determine the prognostic value of AnxA1 as a biomarker of renal injury in acute HF with renal dysfunction. Using the urine specimens from the ROSE-AHF study, we will measure urine AnxA1 to determine whether it predicts the development of worsening renal function or type 1 acute CRS and if it correlates with GFR. Specific Aim 3 will determine the renal actions of LCZ 696, a combined angiotensin receptor/ neprilysin inhibitor, and the renal interaction between LCZ 696 and ANX-042 in human CRS. In the PARADIGM study, LCZ 696 reduced death and heart failure hospitalization in patients with heart failure with reduced ejection when compared to Enalapril. Neprilysin degrades the natriuretic peptides, including ANX-042 and is most abundant in the renal proximal tubules. In experimental heart failure, we have previously demonstrated a synergistic renal enhancing action between Neprilysin inhibitor and natriuretic peptides. Our objective is to determine the renal actions of LCZ 696 and if LCZ 696 will enhance the renal action of ANX-042 in patients with systolic HF and renal dysfunction. Our Specific Aims are as follows: Specific Aim 1 Determine the efficacy of a novel renal specific peptide, ANX-042, in enhancing GFR without significant hypotension in human CRS. Specific Aim 2 Define the prognostic value of urine Annexin A1 as a biomarker of renal Injury in acute CRS. Specific Aim 3 Determine the renal actions of LCZ 696, a combined angiotensin receptor/ neprilysin inhibitor, and the renal interaction between LCZ 696 and ANX-042 in human CRS. To address these objectives related to human CRS, we will pursue translational high definition physiological human studies taking advantage of the extensive clinical facilities, patient populations, the NIH funded Center for Clinical and Translational Science (CCaTS) at the Mayo Clinic and also the biomarker specimen bank of the NHLBI HF Clinical Research Network, which makes our proposed research highly feasible, innovative and of significant clinical importance.

 描述(由申请人提供)：本次更新的广泛目标是促进我们对人类心脏肾综合征(CRS)的病理生理机制的理解，该机制的定义是收缩性心力衰竭和肾功能不全，目的是为患者开发新的治疗和诊断方法。在第一个资助周期中，我们研究了利尿剂治疗、肾素-血管紧张素-醛固酮系统(RAAS)和环3‘-5’-鸟苷单磷酸(CGMP)途径之间的生物相互作用。具体地说，我们完成了以下工作：1)证明短期(3周)减少速尿剂量对慢性收缩性心力衰竭(HF)患者和改善肾功能的患者具有良好的耐受性；2)利用尿蛋白组学方法，我们发现Annexin A1是CRS潜在的尿液生物标记物；3)我们拨款的初步数据表明，小剂量奈西立肽可导致潜在的肾脏特异性作用。 ROSE-AHF研究的设计和完成是在NHLBI心力衰竭临床研究网络内进行的。ROSE-AHF研究表明，小剂量奈西立肽不是肾脏特异性的，会增加低血压的发生率，也不会增强急性心力衰竭和肾功能障碍患者的肾功能。因此，强调了对人类CRS进行肾脏特异性治疗的必要性。具体目标1将确定一种新的肾脏特异性多肽ANX-042的有效性，该多肽是根据申请人和同事发现的选择性剪接的B型利钠肽(BNP)设计的，可以在不显著降低人体CRS血压的情况下增强GFR。我们已经确定了B型利钠肽(ASBNP)的选择性剪接的mRNA，它包括一个独特的、独特的较长的羧基末端。在此基础上，我们设计了一个截短的多肽形式(ANX-042)，该形式含有其C-末端的前13个氨基酸。在实验性心力衰竭中，ANX-042具有有效的利尿和利钠作用，而不具有血管扩张性降压特性。在最近完成的一项人类首例研究中，我们证明了ANX-042是安全的，它激活第二信使cGMP的剂量没有导致健康人类出现症状性降压。我们的目标是首次确定ANX-042是否能在不降低血压的情况下增强收缩性心衰和肾功能不全患者的肾功能。特异性目标2将验证尿Annexin A1(AnxA1)是急性心力衰竭合并肾功能不全患者肾损伤的生物标志物的假设，具有预后价值。AnxA1是一种重要的内源性抗炎分子，也参与调节细胞增殖和细胞死亡信号，促进细胞对凋亡细胞的有效吞噬。我们发现肾功能不全的收缩期心力衰竭患者尿液AnxA1蛋白水平高于肾功能正常的患者。其他人报告说，尿液AnxA1是肾小球损伤的生物标志物。我们的目标是扩展我们先前的发现，并确定AnxA1作为急性心衰肾功能不全患者肾损伤的生物标志物的预后价值。使用ROSE-AHF研究的尿样，我们将测量尿液AnxA1，以确定它是否可以预测肾功能恶化或1型急性CRS的发展，以及它是否与GFR相关。具体目标3将确定血管紧张素受体/奈普赖素联合抑制剂LCZ 696的肾脏作用，以及LCZ 696和ANX-042在人CRS中的肾脏相互作用。在范例研究中，与依那普利相比，与依那普利相比，LCZ 696减少了射血减少的心力衰竭患者的死亡和心力衰竭住院时间。Neprilysin可降解包括ANX-042在内的利钠肽，并在肾近端小管中含量最高。在实验性心力衰竭中，我们先前已经证明了Neprilysin抑制剂和利钠肽之间的协同肾脏增强作用。我们的目标是确定LCZ 696的肾脏作用，以及LCZ 696是否会增强ANX-042在收缩性心衰和肾功能不全患者中的肾脏作用。我们的具体目标如下：具体目标1确定一种新的肾脏特异性多肽ANX-042在不显著降压的情况下增强人CRS的GFR的有效性。特定目的2明确尿Annexin A1作为急性CRS肾损伤生物标志物的预后价值。具体目的3确定血管紧张素受体/奈普赖素联合抑制剂LCZ 696对人CRS的肾脏作用，以及其与ANX-042的相互作用。为了解决这些与人类CRS相关的目标，我们将利用广泛的临床设施、患者群体、位于梅奥诊所的NIH资助的临床和翻译科学中心(CCATS)以及NHLBI HF临床研究网络的生物标记物标本库，进行翻译高清晰度生理学人体研究，这使得我们提议的研究具有高度的可行性、创新性和重要的临床重要性。