Distinct inflammatory profile underlies pathological increases in creatinine levels associated with Plasmodium vivax malaria clinical severity

Abstract

Although Plasmodium vivax infection is a frequent cause of malaria worldwide, severe presentations have been more regularly described only in recent years. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are relatively scarce. Here, renal dysfunction is retrospectively 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. A retrospective analysis of a databank containing 572 individuals from the Brazilian Amazon, including 179 patients with P. vivax monoinfection (161 symptomatic malaria, 12 severe non-lethal malaria, and 6 severe lethal disease) and 165 healthy controls, was performed. Data on levels of cytokines, chemokines, C-reactive protein (CRP), fibrinogen, creatinine, hepatic enzymes, bilirubin levels, free heme, and haptoglobin were analyzed to depict and compare profiles from patients per creatinine levels. Elevated creatinine levels were found predominantly in women. Vivax 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 ratio and CRP values marked the immune biosignature of vivax malaria patients, and could distinguish subjects with elevated 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. 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 as part of the clinical assessment in vivax malaria patients, and warrants additional studies in experimental models for further mechanism investigations. Severe clinical presentations of Plasmodium vivax malaria are not completely understood. Multi-organ involvement is described in severe vivax cases, however data associating it with kidney dysfunction are relatively scarce, in part because the clinical signs only appear late during kidney injury. We analyzed biomarkers of renal function in groups of patients from the Brazilian Amazon with different presentations of vivax malaria to determine its associations with disease progression. Inflammatory biomarkers were also analyzed to assess inflammation related to kidney dysfunction. The results indicate that severe disease presentation in these patients was associated with abnormal serum creatinine elevations and exacerbated systemic inflammatory response. The highest levels of creatinine were observed in nonsurvivors. Biomarkers of hemolysis did not directly follow increases in serum creatinine. These readouts suggest that kidney dysfunction probably influences vivax malaria severity and mortality. As P. vivax is a widely distributed species of Plasmodium in the world, and severe cases are increasingly being reported, it is important to better understand the role of kidney injury in these presentations, especially considering that it may affect clinical outcomes.