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.

项目概要/摘要 急性肾损伤 (AKI) 是一种肾功能突然丧失的情况，25-59% 的住院儿童会发生这种情况 严重疟疾是严重疟疾儿童死亡的最强危险因素之一，并且与严重疟疾相关。 患有长期认知和肾脏问题的人在受伤后，肾脏会经历修复过程以恢复。 正常的肾功能如果修复过程出现问题并且“适应不良”，可能会导致持续性肾损伤。 我们之前的研究表明，严重疟疾导致 CKD 的风险增加。 这些结果得出了我们的中心假设，即与幸存者相关的通路的持续激活。 严重疟疾相关 AKI 会导致 AKI 后的适应不良修复，并增加 CKD 风险。 根据这个假设，我们有初步数据表明，持续的免疫激活和血液迹象 在 1 个月的随访中，估计有 15.6% 的血管功能与持续性肾脏疾病相关。 乌干达儿童患严重疟疾后出现持续性肾损伤，17.5%的儿童患有持续性肾损伤 与没有 AKI 的情况相比，一年内受伤死亡的人数为 3.7%。 提出一项前瞻性多中心观察队列研究，对 750 名乌干达儿童进行为期 90 天至 15 岁的跟踪研究 我们还将招募 189 名因严重疟疾住院的社区来评估 CKD 的发病率。 确定乌干达儿童 CKD 发病率 我们将追求两个具体目标。 评估重症后与疟疾相关的急性和慢性肾脏病 (MAP-CKD) 的发病机制 在目标 1 中，我们将确定与 CKD 相关的临床危险因素，包括严重程度和持续时间。 我们还将评估 AKI 以及一种人们知之甚少的疟疾并发症——黑水热。 随访中儿童 CKD 的遗传风险因素，重点关注与肾脏疾病相关的基因（例如 APOL1） 或预防严重疟疾（例如镰状细胞性贫血）。在目标 2 中，我们将重点关注定义机制。 通过在随访中测量儿童血液和尿液中的生物标志物来修复 AKI 后的适应不良。 研究将有可能揭示 AKI 后适应不良修复的途径，从而导致 我们的长期目标是预防儿童发展为 CKD。 这些研究将通过让我们识别 CKD 风险最高的儿童来实现这一目标，并提供 其次，通过确定愈合的适应不良性质来进行 CKD 的临床随访和早期治疗。 在此过程中，我们将能够使用生物标志物来识别有 CKD 风险的儿童。 第三，这些研究具有以下特点。 确定促进适应性肾脏修复和减少 CKD 发展的治疗方法的潜力。 拟议的研究将为疟疾中的肾脏疾病提供新的见解，并可能为以下方面提供新的见解： 其他以血管内溶血和 AKI 为特征的疾病中适应不良修复的机制。 这项研究的结果将有助于确定中低收入国家 AKI 后 CKD 的负担， 全球 80% 的 AKI 死亡发生在此处。