Pediatr Nephrol (2009) 24:253–263 An initial response to hypoxic/ischemic AKI is ATP depletion, which leads to a number of detrimental biochemical and physiologic responses, including disruption of the normal cytoskeletal organization with loss of the apical brush border and loss of polarity with Na+K+ATPase localized to the apical as well as the basolateral membrane [43]. This has been shown in several animal models of AKI, and it has also been shown in human renal allografts that loss of polarity with mislocation of Na+K+ATPase to apical membrane contrib- utes to kidney dysfunction in transplanted kidneys [44]. Reactive oxygen molecules are also generated during reperfusion and can contribute to tissue injury [34]. While tubular cells and endothelial cells are susceptible to injury by reactive oxygen molecules, studies have shown that endo- thelial cells are more sensitive to oxidant injury than tubular epithelial cells are [35]. Other studies have shown an important role for heat shock protein in modifying the renal response to ischemic injury as well as playing a role in promoting recovery of the cytoskeleton following AKI [45]. In children with multiorgan failure, the systemic inflam- matory response is thought to contribute to AKI as well as other organ dysfunction by the activation of the inflamma- tory response, including increased production of cytokines and reactive oxygen molecules, activation of polymorpho- nuclear leukocytes (PMNs), and increased expression of leukocyte adhesion molecules [46]. Reactive oxygen molecules can be generated by several mechanisms includ- ing activated PMNs, which may cause injury by the generation of reactive oxygen molecules including super- oxide anion, hydrogen peroxide, hydroxyl radical, hypo- chlorous acid, and peroxynitrite, or by the release of proteolytic enzymes. Myeloperoxidase from activated PMNs converts hydrogen peroxide to hypochlorous acid, which may react with amine groups to form chloramines; each of these can oxidize proteins, DNA, and lipids, resulting in substantial tissue injury [34, 47]. Leukocyte endothelial cell adhesion molecules have been shown to be unregulated in ATN, and administration of anti-adhesion molecules can substantially decrease renal injury in animal models of ATN [36]. As described below, several animal models have shown that interference with the inflammatory response may be the future therapy for hypoxic/ischemic AKI. Studies of humans with AKI have demonstrated an increased evidence of oxidation of proteins reflecting oxidant stress [48]. In the past it was thought that recovery from hypoxic/ ischemic and nephrotoxic AKI was complete with return of renal function to normal, but recent studies have shown that recovery may be partial and that the patient is at higher risk for later chronic kidney disease [31]. In addition, hypoxic/ ischemic insults can result in physiologic and morphological alterations in the kidney that can lead to kidney disease at a later time [49]. 257 Nephrotoxic acute kidney injury Medications associated with AKI, at least in part due to toxic tubular injury, include aminoglycoside antibiotics, intravascular contrast media, amphotericin B, chemothera- peutic agents such as ifosfamide and cisplatin, acyclovir, and acetaminophen, while other medications have been implicated less commonly. Aminoglycoside nephrotoxicity typically presents with nonoliguric AKI, with urinalysis showing minimal urinary abnormalities. The incidence of aminoglycoside antibiotic nephrotoxicity is related to the dose and duration of the antibiotic therapy as well as the level of renal function prior to the initiation of aminoglyco- side therapy. The etiology is thought to be related to the lysosomal dysfunction of proximal tubules and is reversible once the aminoglycoside antibiotics have been discontin- ued. However, after the aminoglycoside has been discon- tinued, the serum creatinine may continue to increase for several days due to ongoing tubular injury from continued high parenchymal levels of the aminoglycoside. Cisplatin, ifosfamide, acyclovir, amphotericin B, and acetaminophen are also nephrotoxic and may precipitate AKI. Several other drugs have also been associated with AKI, but the incidence of AKI with other drugs is less common. Hemolysis and rhabdomyolysis from any cause can result in sufficient hemoglobinuria or myoglobinuria to induce tubular injury and precipitate AKI. The mechanisms of injury are complex but may be related to vasoconstriction, precipitation of the pigments in the tubular lumen, and/or heme-protein–induced oxidant stress [50]. Uric acid nephropathy and tumor lysis syndrome Children with acute lymphocytic leukemia and B-cell lymphoma are at the highest risk of AKI due to uric acid nephropathy and/or the tumor lysis syndrome [51, 52]. Although the pathogenesis of uric acid nephropathy is complex, a potentially important mechanism of injury is related to the precipitation of crystals in the tubules, which obstruct urine flow, or in the renal microvasculature, which obstruct renal blood flow [51, 52]. A common cause of AKI in leukemia is the development of the tumor lysis syndrome during chemotherapy [51–53]. Therapy with allopurinol will limit the increased excretion of uric acid with chemotherapy, but allopurinol therapy will result in markedly increased excretion of uric acid precursors, including hypoxanthine and xanthine, and precipitate xanthine nephropathy [51, 54]. Xanthine is less soluble than uric acid, and precipitation of hypoxanthine and xanthine may play a role in the development of AKI during the tumor lysis syndrome [54]. Rasburicase is a recombi- nant form of urate oxidase that catalyzes uric acid to allantoin, which is five times more soluble than uric acid