Treatment of Malaria-Associated Acute Kidney Injury and Progression to Chronic Kidney Disease

PROJECT SUMMARY Malaria continues to be one of the top five leading causes of death in children under five, claiming the lives of roughly half a million children annually. In most cases, the infection manifests as the so-called uncomplicated or mild malaria, which resembles flu-like symptoms. However, if left untreated, malaria can rapidly progress to severe malaria, a potentially life-threatening complication with mortality rates up to 90% at home and 20% when patients are treated in hospital. Among the different manifestations of patients with severe malaria, ma- laria-associated acute kidney injury (MAKI) has emerged as one of the most common maladies; it is associated with poor prognosis and one of the strongest predictors of death. The impact of MAKI is beyond the associated mortality. After an episode of acute kidney injury, the risk of developing long-term neurological complications and chronic kidney disease (CKD) increases, even if the patient experiences a complete short-term recovery and has no pre-existing medical conditions. In addition, people growing up in hyperendemic areas of malaria are exposed to multiple episodes of malaria during their lifetime, with an estimated mean of 47.5 malaria infections since birth, thus multiplying the chances of developing both MAKI and CKD. The management recommendations of MAKI involve renal replacement therapy (RRT) in 25-75% of patients. The most commonly used interventions for RRT include hemodialysis, peritoneal dialysis, hemofiltration, and kidney transplantation. However, implementing these treatments in low-and middle-income countries, where malaria is endemic, poses multiple challenges, includ- ing financial constraints, limited infrastructure, and scarcity of trained personnel. Therefore, alternative therapies designed specifically for resource-limited regions are urgently needed to improve outcomes and reduce the burden of MAKI and the development of CKD. The central hypothesis is that ferroptosis and the FasL/Fas extrinsic apoptosis cell death pathways are pivotal in the pathogenesis of MAKI and that recurrent malaria in- fections elevate the risk of MAKI development and progression to CKD. This research proposal aims to extend our investigation into malaria-associated kidney disease, focusing on the therapeutic potential of targeting these two cell death pathways for treating MAKI. Additionally, utilizing our innovative mouse model of MAKI and in vitro systems, we will elucidate the mechanisms underlying the progression of MAKI to CKD and exam- ine the impact of multiple malaria infections on disease outcomes. The long-term goal of these studies is to develop alternatives to RRT to treat MAKI that can be implemented in low-and middle-income countries where this therapy is largely unavailable and to understand how multiple malar- ia infections contribute to the development of MAKI and the progression to CKD. To this end, we will (1) Targeting the ferroptosis cell death pathway as a potential therapeutical target in MAKI. (2) Determine the role of the extrinsic apoptosis pathway Fas/Caspase-8 in MAKI and its potential as a therapeutical target. (3) Investigating MAKI à CKD progression following multiple malaria infections in our mouse model.