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Mechanisms of acute kidney injury in malaria - Resubmission - 1

疟疾急性肾损伤的机制 - 重新提交 - 1

基本信息

批准号：
10318648
负责人：
ANA RODRIGUEZ
金额：
$ 21.04万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318648
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Admission activity Affect Affinity African Anemia Antibodies Antibody Response Antigen-Antibody Complex Arginine Autoantibodies Autoimmune Diseases Bacteria Binding Biological Assay Biological Availability Blood Circulation Cell Death Cells Cessation of life Child Childhood Chronic Kidney Failure Clinical Complement Complication Cytolysis DNA Deposition Development Disease Disease Progression Drug Metabolic Detoxication Epidemiology Erythrocytes Falciparum Malaria Haptoglobins Heme Hemin Hemoglobin Hemolysis Hemopexin Hospitalization Human Infection Inflammatory Response Injury to Kidney Kidney Kidney Diseases Malaria Mediating Mus Nitric Oxide Oxidative Stress Parasites Pathogenesis Pathology Pathway interactions Patients Phagocytosis Phosphatidylserines Plasma Plasmodium yoelii Play Prospective cohort Renal function Risk Role Sampling Severities Systemic Lupus Erythematosus Testing Tissues Uganda Virus Work acute infection biomarker development epidemiology study experimental study extracellular follow-up hospital readmission in vivo Model kidney dysfunction mortality mouse model neutrophil novel therapeutics oxidation pathogen response targeted treatment therapy development

项目摘要

Summary Acute kidney injury (AKI) is one of the least understood but most common complications of severe pediatric malaria and is strongly associated with increased mortality. Our previous results indicate that elevated levels of autoimmune antibodies circulating in children with severe falciparum malaria strongly correlate with parameters of kidney dysfunction. These results suggest that the pathogenesis of malaria-induced AKI could be similar to classical autoimmune diseases such as systemic lupus erythematosus, where autoimmune antibodies form immune complexes (IC) that induce kidney pathology. However, our previous work has also identified that markers of hemolysis (free-heme and hemoglobin), correlate with the development of AKI in African children. Hemolysis is a well-established cause of kidney injury, suggesting that lysis of erythrocytes induced by autoimmune antibodies may also contribute to AKI. Our overarching hypothesis is that autoimmune antibodies decisively contribute to kidney pathology in malaria. We intend to determine the relative contribution to malaria-induce kidney pathology of two possible autoantibody-induced mechanisms: (1) deposition of IC and (2) hemolysis-induced damage in the kidneys. Using mice models of malaria, we will test this hypothesis and determine the role of autoantibodies in kidney pathology. We will characterize whether IC deposition in the kidneys (aim 1.1) and/or hemolysis mediated by autoimmune antibodies (aim 1.2) are major causes of AKI during acute malaria. We will also test the role of neutrophil extracellular traps (NETs) in the formation of DNA-IC and in kidney dysfunction during malaria. In aim 2 we will characterize the relationship of autoantibodies and IC with hemolysis by analyzing the relation of the heme-axis (free-heme, hemopexin and cell-free hemoglobin, previously proposed to contribute to AKI in malaria), oxidative stress and nitric oxide bioavailability, with acute and persistent kidney dysfunction during malaria in a clinically well-characterized prospective cohort of 600 children with severe malaria followed for one year. This study will increase our understanding of kidney dysfunction in malaria both mechanistically and epidemiologically, paving the way for the finding of new biomarkers and the development of therapies.

摘要急性肾损伤(AKI)是儿科重症患者最不了解但最常见的并发症之一。疟疾与死亡率上升密切相关。我们之前的研究结果表明，高水平的严重恶性疟疾儿童循环中的自身免疫抗体与肾功能不全的参数。这些结果表明，疟疾诱导的AKI的发病机制可能类似于经典的自身免疫性疾病，如系统性红斑狼疮，抗体形成免疫复合体(IC)，导致肾脏病理。不过，我们之前的工作也是发现溶血标志物(游离血红素和血红蛋白)与急性肾功能衰竭的发生有关。非洲儿童。溶血是肾脏损伤的一个公认的原因，这表明红细胞的溶解自身免疫抗体诱导的AKI也可能参与AKI的发生。我们的主要假设是，自身免疫抗体在肾脏病理中起决定性作用。疟疾。我们打算确定两种可能的对疟疾引起的肾脏病理的相对贡献自身抗体诱导的机制：(1)IC沉积；(2)溶血所致肾脏损害。利用疟疾的小鼠模型，我们将检验这一假说，并确定肾脏中自身抗体的作用病理学。我们将表征IC在肾脏中的沉积(目标1.1)和/或溶血是否由自身免疫抗体(AIM 1.2)是急性疟疾期间AKI的主要原因。我们还将测试中性粒细胞胞外陷阱(Net)在DNA-IC形成和疟疾期间肾功能障碍中的作用。在目标2中，我们将通过分析自身抗体和IC与溶血的关系来表征其与溶血的关系的血红素轴(游离态的血红素、血红蛋白和游离的血红蛋白)，以前被认为对AKI有贡献。 (疟疾)、氧化应激和一氧化氮生物利用度，并伴有急性和持续性肾功能障碍在一项临床特征良好的600名患有严重疟疾的儿童的前瞻性队列中，对一名儿童进行了随访年。这项研究将增加我们对疟疾肾功能障碍的了解，无论是从机制上还是从在流行病学方面，为发现新的生物标记物和开发治疗方法铺平了道路。