Malaria associated pathogenesis of chronic kidney disease (MAP-CKD)

项目摘要/摘要 急性肾损伤(AKI)是一种突然的肾功能丧失，发生在25%-59%的住院儿童中 严重的疟疾。AKI是严重疟疾儿童死亡的最强危险因素之一，与 有长期的认知和肾脏问题。在受伤后，肾脏会经历修复过程以恢复 肾功能正常。如果修复过程出了问题，并且“不适应”，就会导致持续性的肾脏损伤 和慢性肾脏疾病(CKD)。我们先前的研究表明，严重疟疾患者患慢性肾脏病的风险增加。 幸存者。这些结果导致了我们的中心假设，即通路的持续激活与 严重疟疾相关-AKI有助于AKI后的适应不良修复，并增加CKD风险。朝向 在这一假设下，我们有初步数据表明，持续的免疫激活和血液变化的迹象 在一个月的随访中，血管功能与持续性肾脏疾病有关。估计15.6%的 乌干达儿童严重疟疾后持续肾脏损伤17.5%的儿童持续肾脏损伤 受伤患者在一年内死亡，而没有AKI患者的死亡率为3.7%。在强劲的初步数据指引下，我们 提出一项前瞻性多点观察队列研究，对750名乌干达儿童进行为期90天至15年的跟踪调查 因严重疟疾住院，以评估CKD的发病率。我们还将招收189个社区 以确定乌干达儿童中CKD的发病率。我们将追求两个具体目标 探讨重症急性和慢性肾脏疾病(MAP-CKD)的疟疾相关发病机制 疟疾。在目标1中，我们将确定与慢性肾脏病相关的临床风险因素，包括严重程度和病程。 AKI以及一种鲜为人知的疟疾并发症--黑水热。我们还将评估 儿童慢性肾脏病的遗传危险因素，重点关注与肾脏疾病相关的基因(例如，APOL1) 或预防严重疟疾(如镰状细胞性贫血)。在目标2中，我们将重点定义 通过测量儿童血液和尿液中的生物标记物进行AKI后的适应不良修复。这些 研究将有可能揭示AKI后适应不良修复的途径，从而导致 慢性肾功能不全的发展，并易于干预。我们的长期目标是防止儿童发育 CKD。这些研究将通过使我们能够识别CKD风险最高的儿童来实现这一目标，提供 慢性肾脏病的临床随访和早期治疗。其次，通过确定康复治疗的不适应性质 在这一过程中，我们将能够使用生物标记物来识别有CKD风险的儿童。第三，这些研究具有 有可能确定促进适应性肾脏修复和减少慢性肾脏病发展的治疗方法。总的来说，我们的 拟议的研究将为疟疾中的肾脏疾病提供新的见解，并可能为 以血管内溶血和AKI为特征的其他条件下的适应不良修复机制。这个 这项研究的结果将有助于确定低收入和中等收入国家AKI后慢性肾脏病的负担， 全球80%的AKI死亡发生在那里。

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is an abrupt loss of kidney function that occurs in 25-59% of children hospitalized with severe malaria. AKI is one of the strongest risk factors for death in children with severe malaria and is associated with long-term cognitive and kidney problems. Following injury, the kidney undergoes a repair process to restore normal kidney function. If the repair process goes awry and is ‘maladaptive’, it can lead to persistent kidney injury and chronic kidney disease (CKD). Our previous studies showed an increased risk of CKD in severe malaria survivors. These results led to our central hypothesis that persistent activation of pathways associated with severe malaria associated-AKI contributes to maladaptive repair following AKI and increases CKD risk. Towards this hypothesis, we have preliminary data showing that persistent immune activation and signs of altered blood vessel function are associated with persistent kidney disease at one-month follow-up. An estimated 15.6% of Ugandan children have persistent kidney injury after severe malaria with 17.5% of children with persistent kidney injury dying within one-year follow-up compared to 3.7% without AKI. Guided by strong preliminary data, we propose a prospective multi-site observational cohort study to follow 750 Ugandan children, 90 days to 15 years of age, hospitalized with severe malaria to assess the incidence of CKD. We will also enroll 189 community children of the same age to define the incidence of CKD in Ugandan children. We will pursue two Specific Aims to evaluate the malaria-associated pathogenesis of acute and chronic kidney disease (MAP-CKD) after severe malaria. In Aim 1, we will determine clinical risk factors associated with CKD, including the severity and duration of AKI as well as a poorly understood complication of malaria called blackwater fever. We will also evaluate the genetic risk factors for CKD in children over follow-up, focusing on genes linked to kidney disease (e.g., APOL1) or protection from severe malaria (e.g., sickle cell anemia). In Aim 2, we will focus on defining mechanisms of maladaptive repair following AKI by measuring biomarkers in children’s blood and urine over follow-up. These studies will have the potential to uncover pathways of maladaptive repair following AKI that lead to the development of CKD and are amenable to intervention. Our long-term goal is to prevent children from developing CKD. These studies will achieve this goal by allowing us to identify children at the highest risk of CKD, providing clinical follow-up and early treatment for CKD. Secondly, by determining the maladaptive nature of the healing process, we will be able to use biomarkers to identify children at risk of CKD. Third, these studies have the potential to identify treatments to promote adaptive renal repair and reduce CKD development. Collectively, our proposed research will provide new insights into kidney disease in malaria and may provide novel insights into mechanisms of maladaptive repair in other conditions characterized by intravascular hemolysis and AKI. The results from this study will help define the burden of CKD following AKI in low-and-middle-income countries, where 80% of global AKI deaths occur.