Clinical Progress Note: Pediatric Acute Kidney Injury

Acute kidney injury (AKI) occurs in 5%-30% of noncritically ill hospitalized children.¹ Initially thought to be simply a symptom of more severe pathologies, it is now recognized that AKI independently increases mortality and is associated with the development of chronic kidney disease (CKD), even in children.² The wide acceptance of the Kidney Disease Improving Global Outcome (KDIGO) diagnostic criteria has enabled a more uniform definition of AKI from both clinical and research perspectives.² A better understanding of the pathophysiology and risk factors for AKI has led to new methods for early detection and prevention efforts. While serum creatinine (SCr) was historically one of the sole markers of AKI, novel biomarkers can facilitate earlier diagnosis of AKI, identify subclinical AKI, and guide clinical management. This clinical practice update addresses the latest clinical advances in risk assessment, diagnosis, and prevention of pediatric AKI, with a focus on AKI biomarkers.

Several sets of criteria have been used to diagnose AKI. The KDIGO classification, based on a systematic review of the literature and developed through expert consensus, is the current recommended definition.³ Increasing AKI stage, as defined by the KDIGO classification, is associated with increased mortality, the need for renal replacement therapy, length of stay, and CKD, thus underscoring the importance of accurate classification.³ Stage 1 AKI is defined by a rise in SCr of ≥0.3 mg/dL,1.5-1.9 times the baseline SCr, or urine output <0.5 ml/kg/h for six to 12 hours; stage 2 by a rise of ≥2.0-2.9 times the baseline SCr or urine output <0.5 ml/kg/h for >12 hours; and stage 3 by a rise of ≥4.0 mg/dL, ≥three times the baseline SCr, initiation of renal replacement therapy, urine output <0.3 ml/kg/h for ≥24 hours, or anuria ≥12 hours. However, these criteria rely on SCr, which is a suboptimal marker of renal dysfunction, as it rises only once the glomerular filtration rate (GFR) has already decreased, in some cases by as much as 50%. Additionally, interpretation of SCr in the diagnosis of AKI requires a prior Scr measurement to determine the magnitude of change from the baseline value, which is often lacking in children. To mitigate this limitation, different formulas exist to estimate a baseline SCr value based on height or age, an approach that assumes patients have preexisting normal renal function.

The limitations of SCr have led to interest in identifying more accurate biomarkers of AKI. Although many candidates have been identified, we will limit our discussion to those currently available for clinical use: serum cystatin C, urine neutrophil gelatinase-associated lipocalin (NGAL), urine TIMP-2, and urine IGFBP7 (Table).^4-8 While urine NGAL and cystatin C are measured individually, TIMP-2 and IGFBP7 are measured on the same panel and the product of their multiplied values is used for clinical guidance. While each of these biomarkers have good predictive accuracy for AKI when used independently, their combined use increases the accuracy of AKI diagnosis. These biomarkers can be divided into broad categories based on their utility as either functional markers or markers of injury.⁶ Serum cystatin C is a functional marker and as such can be used to estimate GFR more accurately than SCr.⁹ Comparatively, urine NGAL is a marker of renal injury, while TIMP2 and IGFBP7 are markers of renal stress. These markers are not useful in estimating GFR, but rather aid in the prediction and diagnosis of AKI (Figure). Despite the limitations of SCr, these biomarkers have yet to be incorporated into the diagnostic criteria. They have, however, helped to refine our understanding of the pathophysiology of AKI.

AKI has classically been divided into three categories based on the etiology of injury, namely prerenal azotemia, intrinsic renal disease, and postrenal causes. The discovery of new biomarkers adds nuance to the classification of AKI. Two groups of biomarkers are particularly helpful in this regard: markers of structural injury (eg, NGAL) and functional markers (eg, cystatin C). The combination of these biomarkers with SCr has refined the categories of AKI (Figure). For example, NGAL can accurately distinguish between a rise in SCr due to functional AKI, previously referred to as prerenal azotemia, and a rise in SCr due to intrinsic kidney injury. An elevation of structural injury biomarkers in the absence of a significant rise in SCr is referred to as subclinical AKI. Patients with subclinical AKI have worse outcomes than those without AKI but better outcomes than patients with AKI with elevation of both SCr and NGAL (Figure).^2,6 Time to resolution of AKI further refines our ability to predict prognosis and outcomes. Transient AKI, defined as resolution within 48 hours, is associated with a better prognosis than persistent AKI. Renal dysfunction lasting more than seven days but less than 90 days is referred to as acute kidney disease (AKD). While both transient AKI and AKD represent different entities on the continuum between AKI and CKD, further research is needed to better elucidate these classifications.²