Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance

Abstract

Background: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood.

Methods: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression.

Results: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity.

Conclusions: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.

Keywords: Acute kidney injury; Blackwater fever; Children; Malaria; Mortality.

Fig. 1

Flow chart of study population. A Flow chart of study population. B Overview of study activities

Fig. 2

Relationship between host markers of inflammation and endothelial injury, blackwater fever, and severe AKI. Forest plot depicting the median (interquartile range) of biomarkers of immune and endothelial activation by blackwater fever (BWF) and severe AKI status with the corresponding adjusted risk ratio (aRR) and 95% confidence interval (95% CI) generated from a Poisson model with robust variance adjusting for participant age and sex. Biomarkers significant following adjustment for multiple comparisons (n = 24) using the Bonferroni method are shaded in black with an adjusted p < 0.002

Fig. 3

Blackwater fever and severe AKI in children with an acute febrile illness. Heat map of standardized biomarker levels with the mean in each group plotted and differences between groups analyzed using linear regression models. Biomarkers are the dependent variable and severe AKI (sAKI) and blackwater fever (BWF) are predictor variables, with an interaction term, where *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 4

Mortality in hospitalized children across different clinical complications based on the presence of severe AKI or blackwater fever (BWF). Bar graphs depicting the mortality rate in children with severe AKI (stage 2 or 3 AKI, sAKI) or a history of blackwater fever (BWF) based on clinical complications present on admission. Mortality was assessed based on sAKI or BWF using Pearson’s Chi-square or Fisher’s exact test and relationships significant (p < 0.05) are depicted with an *