Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria

Abstract

Background Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. Methods Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. Results The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI ( p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI ( p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI ( p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA ( p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy ( p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. Conclusions AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria. Electronic supplementary material The online version of this article (10.1186/s12916-019-1332-7) contains supplementary material, which is available to authorized users.

Methods to estimate baseline creatinine and define acute kidney injury in lean Ugandan children with severe malaria: a prospective cohort study

“…Our results are consistent with a high prevalence of AKI in children with severe malaria irrespective of age [25], and challenge the paradigm that AKI in severe malaria is more frequent in older children and adults [18]. The children in this study were 12 and under.…”

“…Heights were also measured on unscheduled sick visits over follow-up. To identify within-subject height outliers, linear mixed effects models were used and standardized residuals were used to flag heights for further review [24,25]. Models included height as the dependent variable and age and sex as fixed effects with a subject specific random intercept and slope.…”

“…Accurate assessment of height in critically ill populations can be challenging, and appropriate measurement tools are not always available in resource-constrained settings. This study was able to assess the reliability of height measures over time using mixed effects models adjusting for child age and sex to correct individual-level outliers as described [24,25]. We identified several heights that required adjustment based on the child's individual growth trajectory or the mean height-for-age score for the population.…”

“…Further, AKI is a risk factor for the long-term development of chronic kidney disease (CKD) in both adult and pediatric populations [25,[36][37][38][39][40][41]. In Ugandan severe malaria survivors AKI is a risk factor for long-term neurocognitive impairment and behavioral problems [25,42]. The use of sensitive AKI definitions is important to identify children at risk of inhospital mortality, but also to identify children at risk for post-discharge morbidity (e.g.…”

Renal detection of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in malaria associated acute kidney injury: a retrospective case–control study

“…Acute kidney injury (AKI), is a frequent presentation in severe malaria which is associated with mortality [1][2][3][4][5]. Overall, AKI has been shown to have a global prevalence in about 20-50% hospitalized malaria cases [6,7]. While P. falciparum is found all over the tropical world, P. vivax is highly prevalent in South America, India and South East (S. E.) Asia, and P. knowlesi has been shown to cause malaria predominantly in S.E.…”