Acute Kidney Injury Interacts With Coma, Acidosis, and Impaired Perfusion to Significantly Increase Risk of Death in Children With Severe Malaria

Abstract

Background: Mortality in severe malaria remains high in children treated with intravenous artesunate. Acute kidney injury (AKI) is a common complication of severe malaria, but the interactions between AKI and other complications on the risk of mortality in severe malaria are not well characterized.

Methods: Between 2014 and 2017, 600 children aged 6-48 months to 4 years hospitalized with severe malaria were enrolled in a prospective clinical cohort study evaluating clinical predictors of mortality in children with severe malaria.

Results: The mean age of children in this cohort was 2.1 years (standard deviation, 0.9 years) and 338 children (56.3%) were male. Mortality was 7.3%, and 52.3% of deaths occurred within 12 hours of admission. Coma, acidosis, impaired perfusion, AKI, elevated blood urea nitrogen (BUN), and hyperkalemia were associated with increased mortality (all P < .001). AKI interacted with each risk factor to increase mortality (P < .001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared with those with no indications for dialysis (odds ratio, 6.56; 95% confidence interval, 3.41-12.59).

Conclusions: AKI interacts with coma, acidosis, or impaired perfusion to significantly increase the risk of death in severe malaria. Among children with AKI, those who have hyperkalemia or elevated BUN have a higher risk of death. A better understanding of the causes of these complications of severe malaria, and development and implementation of measures to prevent and treat them, such as dialysis, are needed to reduce mortality in severe malaria.

Keywords: Severe malaria; acidosis; acute kidney injury; coma; mortality; predictors.

Figure 1.

Pie charts of mortality by clinical complication. Pie charts showing the frequency of children death in children with severe malaria (gray) for the entire cohort (left) and specific clinical complications organized from the most common complications to the least frequent. Complications associated with increased mortality are shaded in gray while complications not associated with mortality (severe anemia, repeated convulsions, hyperparasitemia) are shaded in white. Abbreviation: AKI, acute kidney injury.

Figure 2.

Clinical features in severe malaria associated with increased mortality. Forest plot depicting the adjusted odds ratio from a logistic regression adjusting for child age, sex, and site. Results significant following adjustment for multiple comparisons (n = 24) are shaded in black. Composite variables of organ dysfunction are presented as a diamond based on the following definitions: cerebral complications, the presence of coma or multiple seizures on admission; cardiovascular complications, cold peripheries, delayed capillary refill, shock; respiratory complications, deep breathing, respiratory distress, hypoxemia; hematological complications, leukocytosis, severe anemia, thrombocytopenia, abnormal bleeding, blackwater fever; liver complications, jaundice, hypoalbuminemia; kidney complications, AKI, elevated blood urea nitrogen. Abbreviations: AKI, acute kidney injury; OR, odds ratio.

Figure 3.

Interrelationship between AKI and clinical complications associated with severe malaria mortality. A, top row, Bar graphs showing that mortality in children with or without AKI and the presence of coma, impaired or poor perfusion (cold peripheries), acidosis, elevated BUN, or hyperkalemia. For each complication there is evidence of interaction between the clinical complication and AKI with mortality substantially higher in children with both complications (P < .0001 in clinical model based on the interaction term). B, Venn diagram showing the intersection of clinical complications with mortality with the number of complications in each area indicated and the frequency of mortality in the specified groups presented in the brackets as a percentage. Abbreviations: AKI, acute kidney injury; BUN, blood urea nitrogen; CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio; WHO, World Health Organization.

Figure 4.

Mortality increases substantially in children with severe malaria according to the number of indications for dialysis present on admission. A, Kaplan-Meier survival graph showing percent survival during hospitalization based on admission kidney function. Children with no AKI are in green, children with AKI but no clinical indications for dialysis in yellow, children with 1 indication for dialysis (blood urea nitrogen > 100 mg/dL, bicarbonate < 8 mmol/L, potassium > 7.1 mmol/L) in orange, children with 2 indications in red, and 3 indications for dialysis in dark red. B, Bar graph showing the frequency of death based on the number of clinical indications for dialysis. Abbreviation: AKI, acute kidney injury.