Pediatr Nephrol (2009) 24:253–263 haplotype was present in 26% of newborns who developed AKI compared to 6% of newborns who did not develop AKI. The investigators suggested that the combination of these polymorphisms might lead to a greater inflammatory response and the development of AKI in neonates with infection [13]. As described below, future therapies for AKI might involve strategies to interrupt the inflammatory response. In other studies, the incidence of ACE I/D allele genotypes or the variants of the angiotensin I receptor gene did not differ in neonates with AKI compared to neonates without AKI, but they may be associated with patent ductus arteriosus and heart failure and indirectly contribute to CKD [14, 15]. AKI occurred more commonly in very low birth weight neonates carrying the heat shock protein 72 (1267) GG genetic variation, which is associated with low inducibility of heat shock protein 72 [16]. Given the important role of heat shock proteins in ischemic renal injury, these findings suggest that some neonates are more susceptible to ischemic injury [17]. Future studies of the genetic background of the child at risk for AKI due to medication exposure, toxin exposure, ischemic hypoxic insults or other insults will likely impact on the treatment of the child at risk for AKI and the management of AKI. Diagnosis and etiology of acute kidney injury Table 1 provides a partial listing of the many different and diverse causes of AKI in children. Currently, there is not a uniform definition of AKI in adult and pediatric patients, and AKI is defined in multiple ways, but the majority of definitions of AKI currently in use involve a change in the serum creatinine level. It is accepted that the concentration of serum creatinine is an insensitive and delayed measure of decreased kidney function following AKI. Other bio- markers under investigation include changes in plasma neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C levels and urinary changes in NGAL, interleukin- 18 (IL-18) and kidney injury molecule-1 (KIM-1) [18]. As described below, the development, testing and successful implementation of therapeutic strategies in AKI will require the development of sensitive biomarkers, so that therapy can be initiated in a timely manner. As described above, the definition of AKI in adults and pediatric patients has been quite variable. A new classification system entitled the RIFLE criteria (R risk for renal dysfunction, I injury to the kidney, F failure of kidney function, L loss of kidney function, and E end-stage renal disease) has been proposed as a standardized classification of acute kidney injury in adults [19] and has been adapted for pediatric patients [20]. The pediatric RIFLE (pRIFLE) was found to classify pediatric AKI better and to reflect the course of AKI in children admitted to the intensive care unit (ICU) [20]. The 255 pediatric RIFLE criteria appear to be quite promising for better characterization of AKI and has been validated in children; additional studies are needed to validate this classification further [20]. Further validation and utilization of pRIFLE criteria would allow inter-center comparisons to be made of AKI in children. The RIFLE criteria are utilized by the Acute Kidney Injury Network (AKIN), which is a group of adult nephrologists, pediatric nephrologists, critical care physicians and societal organizations interested in AKI research; the focus of AKIN is to facilitate international, interdisciplinary and intersociety collaborations to ensure progress in the field of AKI [21]. AKI can be divided into pre-renal injury, intrinsic renal disease, including vascular insults, and obstructive uropa- thies (see Table 1). Some causes of AKI, such as cortical necrosis and renal vein thrombosis, occur more commonly in neonates, whereas HUS is more common in young children, and RPGN generally occurs in older children and adoles- cents. An important cause of AKI in neonates is exposure to maternal drugs in utero that interfere with nephrogenesis such as angiotensin-converting enzyme inhibitors, angioten- sin receptor blockers and nonsteroidal anti-inflammatory drugs [22–25]. The history, physical examination, and laboratory tests such as urinalysis and radiographic studies can establish the likely cause(s) of AKI. In many instances, such as AKI occurring in hospitalized children, multiple factors are likely to be implicated in the etiology of AKI. Pre-renal injury Pre-renal injury occurs when blood flow to the kidney is reduced due to true intravascular volume contraction or to decreased effective blood volume. Since the kidneys are intrinsically normal, pre-renal injury is reversible once the blood volume and hemodynamic conditions have been restored to normal. Prolonged pre-renal injury can result in intrinsic AKI due to hypoxic/ischemic acute tubular necrosis (ATN). The evolution of pre-renal injury to intrinsic renal injury is not sudden, and several compensatory mechanisms maintain renal perfusion when renal hemodynamics are not optimal. When renal perfusion is compromised, the afferent arterioles relax their vascular tone to decrease renal vascular resistance and maintain renal blood flow. During renal hypoperfusion, the intrarenal generation of vasodilatory prostaglandins, including prostacyclin, mediates vasodilatation of the renal micro- vasculature to maintain renal perfusion. Administration of cyclo-oxygenase inhibitors such as aspirin or nonsteroidal anti- inflammatory drugs can inhibit this compensatory mechanism and precipitate acute renal insufficiency [26]. Similarly, when renal perfusion pressure is low, as in renal artery stenosis, the intraglomerular pressure necessary to drive filtration is, in part, mediated by increased intrarenal generation of angiotensin II