Mechanisms of acute kidney injury in malaria - Resubmission - 1

总结 急性肾损伤（阿基）是小儿重症急性肾损伤最常见的并发症之一， 疟疾，并与死亡率上升密切相关。我们之前的研究结果表明， 严重恶性疟患儿体内循环的自身免疫抗体与 肾功能不全的参数。这些结果表明，疟疾诱导的阿基的发病机制可能与疟疾的发病机制有关。 类似于经典的自身免疫性疾病，如系统性红斑狼疮，其中自身免疫性 抗体形成诱导肾脏病理的免疫复合物（IC）。然而，我们以前的工作也 确定了溶血标志物（游离血红素和血红蛋白）与阿基的发生相关， 非洲儿童。溶血是肾损伤的公认原因，表明红细胞溶解 自身免疫抗体诱导的AKI也可能导致阿基。 我们的总体假设是，自身免疫抗体决定性地促进肾脏病理， 疟疾我们打算确定两种可能的对疟疾诱导的肾脏病理的相对贡献， 自身抗体诱导的机制：（1）IC沉积和（2）溶血诱导的肾脏损伤。 我们将使用疟疾小鼠模型来检验这一假设，并确定自身抗体在肾脏中的作用。 病理我们将描述肾脏中的IC沉积（目的1.1）和/或溶血是否由 自身免疫抗体（目的1.2）是急性疟疾期间阿基的主要原因。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。 目的2通过分析自身抗体和IC与溶血的关系， 血红素轴（游离血红素、血红素结合蛋白和无细胞血红蛋白，先前提出在阿基中起作用， 疟疾），氧化应激和一氧化氮生物利用度，急性和持续性肾功能不全， 在一个临床特征良好的前瞻性队列中，600名患有严重疟疾的儿童随访了一个 年 这项研究将增加我们对疟疾肾功能不全的理解， 流行病学上，为发现新的生物标志物和开发治疗方法铺平了道路。

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.