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

疟疾相关的慢性肾病发病机制（MAP-CKD）

• 批准号: 10522245
• 负责人: Andrea L. Conroy
• 金额: $ 64.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-24 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522245
• 关键词: 15 year old; APOL1 gene; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; African; Age; Autoantibodies; Biological Markers; Biometry; Blood; Blood Vessels; Cessation of life; Child; Childhood; Chronic Kidney Failure; Clinical; Cognitive; Cohort Studies; Communities; Complication; Consensus; Data; Development; Disease Progression; Early Intervention; Early treatment; Endothelium; Enrollment; Etiology; Fever; Functional disorder; Genes; Genetic; Glucosephosphate Dehydrogenase Deficiency; Goals; Health; Hemolysis; Hospitalization; Immune; Incidence; Inflammation; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Lead; Link; Malaria; Measures; Mediating; Medicine; Nature; Nephrology; Neurocognitive; Outcome; Oxidative Stress; Parasites; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Positioning Attribute; Predictive Factor; Predisposition; Prevalence; Problem behavior; Process; Prospective cohort study; Recovery; Renal function; Reporting; Research; Risk; Risk Factors; Role; Serum; Severities; Sickle Cell Anemia; Site; Specific qualifier value; Survivors; Testing; Time; TimeLine; Urine; Work; cell regeneration; clinical risk; design; disorder risk; experience; follow-up; genetic risk factor; healing; high risk; immune activation; improved; insight; low and middle-income countries; nephrotoxicity; novel; prevent; prospective; repaired; sex

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.

项目摘要/摘要 急性肾脏损伤（AKI）是肾功能突然丧失，在25-59％的住院儿童中发生 严重的疟疾。 AKI是严重疟疾儿童死亡的强大危险因素之一，与之相关 长期认知和肾脏问题。受伤后，肾脏进行了修复过程以恢复 正常的肾功能。如果维修过程出错并且“适应不良”，则可能导致持续的肾脏受伤 和慢性肾脏疾病（CKD）。我们以前的研究表明，严重疟疾中CKD的风险增加 幸存者。这些结果导致了我们的中心假设，即持续激活与 AKI后，严重的疟疾相关-Aki会导致适应不良的修复，并增加了CKD风险。向 这个假设，我们有初步数据，表明持续的免疫激活和血液改变的迹象 在一个月随访中，血管功能与持续的肾脏疾病有关。估计有15.6％ 乌干达儿童在严重的疟疾后持续肾脏受伤，有17.5％的儿童持续的肾脏 在一年内死亡的伤害死亡，而没有AKI的3.7％。在强大的初步数据的指导下，我们 提案一项前瞻性多站点观察队列研究，遵循750名乌干达儿童，90天至15年 年龄，患有严重疟疾的住院，以评估CKD的事件。我们还将注册189个社区 相同年龄定义乌干达儿童中CKD事件的孩子。我们将追求两个具体的目标 评估严重后，急性肾脏疾病（MAP-CKD）的疟疾相关发病机理 疟疾。在AIM 1中，我们将确定与CKD相关的临床风险因素，包括严重性和持续时间 AKI以及疟疾的并发症鲜为人知，称为黑水热。我们还将评估 在随访中，儿童CKD的通用危险因素，重点是与肾脏疾病有关的基因（例如，APOL1） 或防止严重疟疾（例如镰状细胞贫血）。在AIM 2中，我们将专注于定义机制 AKI后不良适应性修复，通过测量儿童血液和尿液中的生物标志物进行随访。这些 在AKI之后，研究将有可能发现适应不良的修复途径 CKD的开发，并且可以接受干预。我们的长期目标是防止儿童发展 CKD。这些研究将通过允许我们确定CKD风险最高的儿童来实现这一目标，提供 CKD的临床随访和早期治疗。其次，通过确定治愈的不良适应性质 过程，我们将能够使用生物标志物来识别有CKD风险的儿童。第三，这些研究具有 潜力识别治疗方法以促进自适应肾脏修复并减少CKD的发展。总体而言，我们的 拟议的研究将为疟疾中的肾脏疾病提供新的见解，并可能为您提供新的见解 在其他条件下以血管内溶血和AKI为特征的不良适应性修复机制。这 这项研究的结果将有助于确定在低和中等收入国家AKI之后CKD的燃烧， 80％的全球AKI死亡发生。