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.

项目总结/摘要 急性肾损伤（阿基）是一种肾功能突然丧失，发生在25-59%的住院儿童中， 严重的疟疾阿基是严重疟疾儿童死亡的最强风险因素之一， 有长期的认知和肾脏问题受伤后，肾脏会经历一个修复过程， 肾功能正常如果修复过程出错并且“适应不良”，则可能导致持续性肾损伤 和慢性肾病（CKD）。我们以前的研究表明，在严重的疟疾患者中， 幸存者这些结果导致了我们的中心假设，即持续激活的途径与 严重疟疾相关的AKI导致阿基后的适应不良修复并增加CKD风险。朝向 我们有初步数据表明，持续的免疫激活和血液改变的迹象， 血管功能与一个月随访时的持续性肾脏疾病相关。据估计，15.6%的 乌干达儿童在严重疟疾后有持续性肾损伤，17.5%的儿童有持续性肾损伤 在一年的随访中，受伤死亡率为3.7%，而没有阿基。根据初步数据，我们 我建议进行一项前瞻性多中心观察性队列研究，对750名乌干达儿童进行为期90天至15年的随访 年龄，因严重疟疾住院，以评估CKD的发病率。我们还将招募189名社区成员 同龄儿童，以确定乌干达儿童CKD的发病率。我们将追求两个具体目标 评估严重急性和慢性肾脏病（MAP-CKD）后疟疾相关的发病机制， 疟疾在目标1中，我们将确定与CKD相关的临床风险因素，包括严重程度和持续时间 以及一种鲜为人知的疟疾并发症黑水热。我们还将评估 随访期间儿童CKD的遗传风险因素，重点关注与肾脏疾病相关的基因（例如，APOL 1） 或保护免受严重疟疾（例如，镰状细胞性贫血）。在目标2中，我们将专注于定义 通过在随访期间测量儿童血液和尿液中的生物标志物，研究阿基后的适应不良修复。这些 研究将有可能揭示阿基后适应不良修复的途径， CKD的发展，并进行干预。我们的长期目标是防止儿童发展 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， CKD的临床随访和早期治疗。其次，通过确定治疗的适应不良性质， 在这一过程中，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 确定治疗方法以促进适应性肾修复和减少CKD发展的潜力。总体而言，我们 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 在以血管内溶血和阿基为特征的其他病症中的适应不良修复机制。的 这项研究的结果将有助于确定中低收入国家阿基后CKD的负担， 全球80%的阿基死亡发生在那里。