Mechanisms of acute kidney injury in malaria - Resubmission - 1

疟疾急性肾损伤的机制 - 重新提交 - 1

• 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
• 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; 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

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.

概括 急性肾脏损伤（AKI）是严重儿科最不知情但最常见的并发症之一 疟疾，与死亡率增加密切相关。我们先前的结果表明 严重恶性疟疾儿童循环的自身免疫性抗体与 肾功能障碍的参数。这些结果表明，疟疾引起的AKI的发病机理可以 类似于经典的自身免疫性疾病，例如全身性红斑狼疮，自身免疫性 抗体形成诱导肾脏病理学的免疫复合物（IC）。但是，我们以前的工作也 鉴定出溶血的标记（自由状 - 血红蛋白和血红蛋白）与AKI的发展相关 非洲儿童。溶血是肾脏损伤的一个公认的原因，表明红细胞裂解 自身免疫性抗体诱导的也可能导致AKI。 我们的总体假设是自身免疫性抗体果断地有助于肾脏病理学 疟疾。我们打算确定两种可能的疟疾诱导肾脏病理学的相对贡献 自身抗体诱导的机制：（1）IC和（2）溶血引起的肾脏损伤的沉积。 使用疟疾的小鼠模型，我们将检验该假设并确定自身抗体在肾脏中的作用 病理。我们将表征肾脏中的IC沉积（AIM 1.1）和/或由 自身免疫性抗体（AIM 1.2）是急性疟疾期间AKI的主要原因。我们还将测试 疟疾期间DNA-IC和肾功能障碍的中性粒细胞外陷阱（网）。 在AIM 2中，我们将通过分析关系来表征自身抗体和IC与溶血的关系 血红素轴（自由血红素，血红素和无细胞血红蛋白，先前提出的 疟疾），氧化应激和一氧化氮生物利用度，急性和持续的肾功能障碍 疟疾在临床表征良好的前瞻性队列中，有600名严重疟疾的儿童接下来 年。 这项研究将通过机械和 从流行学上讲，为寻找新的生物标志物和疗法的发展铺平了道路。