Mechanisms of acute kidney injury in malaria - Resubmission - 1

总结

Summary Acute kidney injury (AKI) is one of the least understood but most common complications of severe pediatric malaria and is strongly associated with increased mortality. Our previous results indicate that elevated levels of autoimmune antibodies circulating in children with severe falciparum malaria strongly correlate with parameters of kidney dysfunction. These results suggest that the pathogenesis of malaria-induced AKI could be similar to classical autoimmune diseases such as systemic lupus erythematosus, where autoimmune antibodies form immune complexes (IC) that induce kidney pathology. However, our previous work has also identified that markers of hemolysis (free-heme and hemoglobin), correlate with the development of AKI in African children. Hemolysis is a well-established cause of kidney injury, suggesting that lysis of erythrocytes induced by autoimmune antibodies may also contribute to AKI. Our overarching hypothesis is that autoimmune antibodies decisively contribute to kidney pathology in malaria. We intend to determine the relative contribution to malaria-induce kidney pathology of two possible autoantibody-induced mechanisms: (1) deposition of IC and (2) hemolysis-induced damage in the kidneys. Using mice models of malaria, we will test this hypothesis and determine the role of autoantibodies in kidney pathology. We will characterize whether IC deposition in the kidneys (aim 1.1) and/or hemolysis mediated by autoimmune antibodies (aim 1.2) are major causes of AKI during acute malaria. We will also test the role of neutrophil extracellular traps (NETs) in the formation of DNA-IC and in kidney dysfunction during malaria. In aim 2 we will characterize the relationship of autoantibodies and IC with hemolysis by analyzing the relation of the heme-axis (free-heme, hemopexin and cell-free hemoglobin, previously proposed to contribute to AKI in malaria), oxidative stress and nitric oxide bioavailability, with acute and persistent kidney dysfunction during malaria in a clinically well-characterized prospective cohort of 600 children with severe malaria followed for one year. This study will increase our understanding of kidney dysfunction in malaria both mechanistically and epidemiologically, paving the way for the finding of new biomarkers and the development of therapies.