Pathological increases in creatinine levels underlie a distinct inflammatory profile associated with Plasmodium vivax clinical severity

Background: Although Plasmodium vivax malaria is the most widespread form of the malaria, severe presentations are not commonly described and yet to be completely understood. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are scarce. Here, renal dysfunction is analyzed in a large cohort of vivax malaria patients with an attempt to dissect its association with disease severity and mortality, and to determine the role of inflammation in its progression. Materials and Methods: A retrospective analysis of 572 individuals from the Brazilian Amazon, including 179 patients with P. vivax monoinfection (161 symptomatic mild malaria, 12 severe non-lethal malaria, and 6 severe lethal malaria) and 165 healthy controls, was performed. Measurements of cytokines, chemokines, C-reactive protein (CRP), fibrinogen, creatinine, hepatic enzymes, bilirubin levels, free heme, and haptoglobin were performed to depict and compare profiles from patients according to creatinine levels. Results: Elevated creatinine levels were found predominantly in women. Malaria severity was highly associated with abnormal creatinine increases, and nonsurvivors presented the highest values of serum creatinine. Indication of kidney dysfunction was not associated with parasitemia levels. IFN-γ/IL-10 ratios and CRP values marked the immune biosignature of vivax malaria patients, and could distinct subjects with heightened creatinine levels who did not survive from those who did. Patients with elevated serum creatinine or severe vivax malaria displayed indication of cholestasis. Biomarkers of hemolysis did not follow increases in serum creatinine. Conclusions: These findings reinforce the hypothesis that renal dysfunction is a key component in P. vivax malaria associated with clinical severity and mortality, possibly through intense inflammation and immune imbalance. Our study argues for systematic evaluation of kidney function in vivax malaria as part of the initial clinical assessment.