Abstract
BACKGROUND: Severe malaria (SM) remains a leading cause of child mortality and an important global contributor to acute kidney injury (AKI), which can progress to chronic kidney disease (CKD) in some survivors. Notably, 80% of AKI deaths occur in low- and middle-income countries (LMIC). Despite this burden, the mechanisms and recovery trajectory of SM associated AKI remain poorly understood. There is a critical need to define the etiology and pathophysiology of SM-AKI, uncover pathways of maladaptive repair, identify risk factors for CKD, and evaluate long-term health and development. METHODS: This prospective multi-site cohort study will enroll children at three sites in Uganda: Mulago National Referral and Teaching Hospital, Jinja Regional Referral Hospital, and Lira Regional Referral Hospital. We aim to recruit 750 children with severe malaria and 375 community controls between 3 months of age and < 16 years. Participants will be followed for two years. Children with severe malaria will be assessed at 1-, 2-, and 4-months to evaluate short-term kidney recovery and 12- and 24-months to assess kidney function and health-related quality of life. The study will investigate short-term and long-term kidney disease risk factors following severe malaria. We will characterize host pathways involved in maladaptive kidney repair, focusing on mechanisms related to cell stress, angiogenesis, and tubulointerstitial injury. Additionally, we will assess the impact of AKI and persistent kidney disease on morbidity, mortality, and health-related quality of life. Cognitive and behavioral assessments, along with brain magnetic resonance imaging (MRI), will be used to evaluate the effects of AKI on brain injury and edema. DISCUSSION: This study will generate key insights into the prevalence of persistent kidney disease following SM-AKI and identify risk factors for CKD to inform clinical follow-up. Defining specific pathways involved with maladaptive repair in severe malaria will provide the foundation for targeted interventions to promote adaptive recovery. The research has the potential to transform long-term health outcomes following SM-AKI. TRIAL REGISTRATION: ISRCTN10885288.