Acute Kidney Injury Is Common in Pediatric Severe Malaria and Is Associated With Increased Mortality

Abstract

Background. Acute kidney injury (AKI) is a well recognized complication of severe malaria in adults, but the incidence and clinical importance of AKI in pediatric severe malaria (SM) is not well documented. Methods. One hundred eighty children aged 1 to 10 years with SM were enrolled between 2011 and 2013 in Uganda. Kidney function was monitored daily for 4 days using serum creatinine (Cr). Acute kidney injury was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Blood urea nitrogen (BUN) and Cr were assessed using i-STAT, and cystatin C (CysC) was measured by enzyme-linked immunosorbent assay. Results. Eighty-one (45.5%) children had KDIGO-defined AKI in the study: 42 (51.9%) stage 1, 18 (22.2%) stage 2, and 21 (25.9%) stage 3. Acute kidney injury evolved or developed in 50% of children after admission of hospital. There was an increased risk of AKI in children randomized to inhaled nitric oxide (iNO), with 47 (54.0%) of children in the iNO arm developing AKI compared with 34 (37.4%) in the placebo arm (relative risk, 1.36; 95% confidence interval [CI], 1.03-1.80). Duration of hospitalization increased across stages of AKI (P = .002). Acute kidney injury was associated with neurodisability at discharge in the children receiving placebo (25% in children with AKI vs 1.9% in children with no AKI, P = .002). Mortality increased across stages of AKI (P = .006) in the placebo arm, reaching 37.5% in stage 3 AKI. Acute kidney injury was not associated with neurodisability or mortality at discharge in children receiving iNO (P > .05 for both). Levels of kidney biomarkers were predictive of mortality with areas under the curves (AUCs) of 0.80 (95% CI, .65-.95; P = .006) and 0.72 (95% CI, .57-.87; P < .001), respectively. Admission levels of CysC and BUN were elevated in children who died by 6 months (P < .0001 and P = .009, respectively). Conclusions. Acute kidney injury is an underrecognized complication in young children with SM and is associated with increased mortality.

Keywords: acute kidney injury; children; creatinine; inhaled nitric oxide; severe malaria.

Figure 1.

Flow chart of study population. A flow chart showing the children enrolled in the study, the incidence of Kidney Disease: Improving Global Outcomes-defined acute kidney injury (AKI) by stage, and mortality across stages of AKI at day 14 and 6-month follow up.

Figure 2.

Changes in creatinine over hospitalization according to outcome and stage of acute kidney injury (AKI). (A) Line graphs showing individual creatinine plots for each child according to trial arm with children randomized to placebo in black and children randomized to inhaled nitric oxide (iNO) in blue. Line graphs showing individual creatinine plots for children with AKI according to stage [(B) stage 1 AKI; (C) stage 2 AKI; (D) stage 3 AKI] and trial arm. (E) Line graphs showing individual creatinine plots for each child according to outcome with survivors shown in black and in-hospital deaths shown in red. (B–D) Line graphs showing individual creatinine plots for children with AKI according to stage [(F) stage 1 AKI; (G) stage 2 AKI; (H) stage 3 AKI] and the timing of creatinine peak, with early indicating the peak creatinine recorded on day 1 or 2 of hospitalization, and late indicating the peak creatinine recorded on day 3 or 4 of hospitalization.

Figure 3.

Biomarkers of renal function measured at admission across stages of acute kidney injury (AKI) and their association with acute mortality. (A–D) Scatter plots showing the median and distribution of renal biomarkers at admission in children with no AKI (normal), and AKI stratified by stage. The relationship between biomarkers and AKI was evaluated using a test for trend (Jonckheere-Terpstra Test for Ordered Alternatives). (E–H) Scatter plots showing the median, interquartile range, and distribution of renal biomarkers in survivors (n = 162) vs nonsurvivors (n = 16). Analysis was performed by Mann–Whitney U test. Abbreviations: BUN, blood urea nitrogen; eGFR, estimated GFR.

Figure 4.

Relationship between serum creatinine (Cr) and cystatin C (CysC) in children over hospitalization according to renal function. (A–D) Plots showing the relationship between Cr and CysC over hospitalization using linear regression stratified by acute kidney injury (AKI) stage.