Renin as a Biomarker of Acute Kidney Injury and Mortality in Children With Severe Malaria or Sickle Cell Disease

Abstract

Background: Globally, a very high percentage of acute kidney injury (AKI) occurs in low- and middle-income countries (LMICs) where late recognition contributes to increased mortality. There are challenges with using existing biomarkers of AKI in LMICs. Emerging evidence suggests renin may serve as a biomarker of kidney injury that can overcome limitations in creatinine-based diagnostics.

Methods: Two study populations in Uganda were assessed. Cohort #1 was a two-site, prospective cohort study enrolling 600 children with severe malaria (SM). Cohort #2 was a prospective cohort study enrolling 185 children with sickle cell disease (SCD) hospitalized with a vaso-occlusive crisis. Plasma or serum renin concentrations were measured in both cohorts of children at the time of hospital admission using Luminex® (Luminex Corporation, Austin, Texas, United States) or enzyme-linked immunosorbent assay (ELISA), respectively. We assessed the ability of renin to discriminate between children with or without AKI and between children who survived and children who died using receiver operating characteristic curves.

Results: In both cohorts, renin concentrations were strongly associated with AKI and mortality. Renin was able to discriminate between children with or without AKI with an area under the curve (AUC) of 0.70 (95%CI, 0.65-0.74) in children with SM and 0.72 (95%CI, 0.6co3-0.81) in children with SCD. Renin was able to discriminate between children who survived and children who died with an AUC of 0.73 (95%CI, 0.63-0.83) in children with SM and 0.94 (95%CI, 0.89-0.99) in children with SCD. In Cohort #2, we compared renin against urine neutrophil gelatinase-associated lipocalin (NGAL) as the leading biomarker of AKI, and it had comparable performance in discriminating AKI and predicting mortality.

Conclusions: In two independent populations of children at risk of AKI with key differences in the etiology of kidney injury, renin was strongly associated with AKI and mortality and had moderate to good diagnostic performance to predict mortality.

Keywords: acute kidney injury; mortality; renin; severe malaria; sickle cell disease.

Figure 1. Study flow diagram for children with severe malaria and children with sickle cell disease.

The frequency of AKI in both cohorts is depicted in the flow diagram. Cohort and demographic characteristics as well as testing procedures are illustrated in the chart. AKI: acute kidney injury; EDTA: ethylenediamine tetraacetic acid Manufacturer details: Luminex® MAGPIX®, R&D Systems, Inc., Minneapolis, Minnesota, United States; DuoSet® ELISA Development Systems, R&D Systems, Inc., Minneapolis, Minnesota, United States

Figure 2. Ability of renin to predict AKI or in-hospital mortality in the two cohorts.

(A) ROC curve showing the ability of increasing renin concentrations to predict AKI in children with SM (Cohort #1) or increasing renin and uNGAL concentrations to predict AKI in children with SCD (Cohort #2); (B) ROC curve showing the ability of increasing renin concentrations to predict mortality in children with SM (Cohort #1) or increasing renin and uNGAL concentrations to predict mortality in children with SCD (Cohort #2). Scatter plots depict renin concentrations with the median and IQR for children with SM or SCD. Gray shading on the plot represents the median (IQR) of renin levels measured in the community children from Cohort #1 as a population reference. Wilcoxon rank-sum test was used where ***p<0.001. The data are presented on log-transformed scale. ROC: receiver operating characteristic; AKI: acute kidney injury; SM: severe malaria; uNGAL: urine neutrophil gelatinase-associated lipocalin: SCD: sickle cell disease; IQR: interquartile range; AUC: area under the curve