Biomarkers for Diagnosis and Prognosis of AKI in Children: One Size Does Not Fit All

Abstract

Pediatric AKI has become a significant health concern due to its rising incidence and association with adverse outcomes. Because of the limitations of serum creatinine, ongoing research has evaluated multiple novel biomarkers for the early detection of AKI. Identifying biomarkers that precede changes in serum creatinine is vital, because these biomarkers provide opportunities to improve outcomes through early diagnosis and timely disease management. In this review, we discuss salient findings on 16 candidate biomarkers and their association with AKI. We explore the differences in biomarker distribution by age and discuss why adult biomarker research findings cannot be directly extrapolated to children. With future research, more consideration needs to be given to how the maturing kidney affects biomarker levels and how we interpret biomarker performance in children. A comprehensive approach using age-specific biomarker reference ranges is required to develop pediatric biomarkers and improve outcomes for children with kidney disease.

Keywords: Epidemiology and outcomes; acute renal failure; albuminuria; kidney development; pediatric intensive care medicine; pediatric nephrology.

Figure 1.

Original research manuscripts studying biomarkers of AKI are increasing over time but primarily focused on adult cohorts. The original manuscripts were identified using a PubMed search with the terms “biomarker” and “AKI.” The following filters were applied: humans, observational studies, clinical trials. To identify the pediatric studies, the filter “Child: birth-18 years” was applied. Publication dates January 1, 2005 through December 6, 2016 were included. Studies were included if they examined the association between a biomarker and AKI. Studies were excluded if they focused on one specific type of primary kidney disease (e.g., hemolytic uremic syndrome). yo, years old.

Figure 2.

First postoperative albuminuria measurements and association with stage I AKI or higher differ by age. Urine albumin-to-creatinine ratio is displayed as milligrams of albumin per gram of creatinine. Optimal threshold value is the biomarker value to obtain maximal sensitivity and specificity. To convert to SI units (milligrams albumin per millimole creatinine), divide albumin-to-creatinine ratio by 8.84.

Figure 3.

Urine neutrophil gelatinase associated lipocalin (NGAL) changes with age in patients without kidney disease. Age-associated urine NGAL levels in premature neonates, full-term neonates, children, adolescents, and adults without kidney disease. NGAL levels were obtained from (5,9,23,46). GA, gestational age; IQR, interquartile range; yo, years old.

Figure 4.

First postoperative urine IL-18 and KIM-1 collected 0–6 hours after cardiac surgery differs between children and adults. (A) Comparing children to adults, IL-18 shows a similar association with AKI but different distribution and biomarker cutoffs. (B) KIM-1 shows a similar control distribution but a different association with AKI. AKI was defined by receipt of acute dialysis or a doubling in serum creatinine from the preoperative serum creatinine value (stage II AKI). Sample collection protocols and biomarker assays were similar in adults and children. KIM-1, kidney injury molecule 1; 95% CI, 95% confidence interval.