Identification of acute kidney injury in African children with severe malaria: a multinational individual participant data meta-analysis

Abstract

Background: Historically, acute kidney injury (AKI) has been an underappreciated complication in children with severe malaria. We conducted an individual patient data meta-analysis to model the impact of AKI and its complications on inpatient mortality in African children hospitalized with malaria. Methods: Studies were identified using MEDLINE, EMBASE, Scopus, and PubMed with no language restrictions, as well as through outreach at scientific meetings. Investigators were contacted about participation in the study. Eligible studies included African children hospitalized with severe Plasmodium falciparum malaria, a serum creatinine measurement, and mortality assessed. The primary exposure was AKI, defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria based on serum creatinine. The primary outcome was all-cause in-hospital mortality, and dialysis requirement was a secondary outcome. Data were standardized and cleaned, and random-effects meta-analyses were conducted to generate pooled estimates. Results: We included 18 studies involving 8 countries and 13,528 children aged 3 months to 16 years over a 33-year period with 951 deaths (7%). The frequency of KDIGO-defined AKI was 47% (95% confidence interval: 46% to 48%), with 46% of children having KDIGO-defined Stage 1 AKI, 30% having Stage 2, and 23% having Stage 3 AKI. Overall, KDIGO-defined AKI was associated with a 2.87 increased odds of mortality (95% CI 2.28 to 3.61) with a monotonic increase in mortality across AKI stage. AKI was a robust risk factor for mortality across era, sex, region, and subgroups. The KDIGO AKI definition was operationalized using simplified age-based thresholds to support bedside recognition of AKI with comparable mortality performance. The WHO-defined AKI threshold (creatinine value > 3mg/dL) occurred in 3.4% (238) of children. All 238 cases identified by WHO criteria were classified as having AKI using KDIGO and age-based definitions, but WHO missed 93% (3059/3297) of additional AKI cases. Discussion: AKI was strongly associated with mortality in African children with severe malaria. Creatinine thresholds can be operationalized to facilitate early AKI recognition. These findings have clinical implications for the implementation of kidney-protective care and for enhanced monitoring of children with severe malaria.