256 to increase efferent arteriolar resistance. Administration of angiotensin-converting enzyme inhibitors in these conditions can eliminate the pressure gradient needed to drive filtration and precipitate AKI [27, 28]. Thus, administration of medications that can interfere with compensatory mechanisms to maintain renal perfusion can precipitate AKI in certain clinical circumstances. Pre-renal injury results from renal hypoperfusion due to true volume contraction from hemorrhage, dehydration due to gastrointestinal losses, salt-wasting renal or adrenal diseases, central or nephrogenic diabetes insipidus, in- creased insensible losses, as occurs in burns, and in disease states associated with third space losses, such as sepsis, nephrotic syndrome, traumatized tissue, and capillary leak syndrome. Decreased effective blood volume occurs when the true blood volume is normal or increased but renal perfusion is decreased due to diseases such as congestive heart failure, cardiac tamponade, and hepatorenal syndrome. Whether pre-renal injury is caused by true volume depletion or decreased effective blood volume, correction of the underlying disturbance will return renal function to normal. Several measures of urinary parameters, including urine osmolality, urine sodium concentration, the fractional excretion of sodium, and the renal failure index, have all been proposed to be used to help differentiate pre-renal injury from hypoxic/ischemic AKI. Hypoxic/ischemic AKI is also called vasomotor nephropathy and/or acute tubular necrosis, since there are early intense vascular constrictions followed by later tubular injury. Renal tubules are working appropriately in pre-renal injury and are able to conserve salt and water appropriately, whereas, in vasomotor nephropathy, the tubules have progressed to irreversible injury and are unable to conserve salt appropriately [1–5, 29, 30]. During pre-renal injury the tubules respond to decreased renal perfusion by appropriately conserving sodium and water such that the urine osmolality is greater than 400– 500 mosmol/l, urine sodium is less than 10–20 mEq/l, and the fractional excretion of sodium is less than 1%. Because the renal tubules in newborns and premature infants are relatively immature compared with those in older infants and children, the corresponding values suggestive of renal hypoperfusion are urine osmolality greater than 350 mosmol/l, urine sodium less than 20– 30 mEq/l, and fractional excretion of sodium of less than 2.5% [29, 30]. When the renal tubules have sustained injury, they cannot conserve sodium and water appropri- ately, so that the urine osmolality is less than 350 mosmol/l, the urine sodium is greater than 30–40 mEq/l, and the fractional excretion of sodium is greater than 2.0%. The use of these values to differentiate pre-renal injury from ATN requires that the patient have normal tubular function initially. However, newborns with immature tubules and children with pre-existing renal disease or salt-wasting renal Pediatr Nephrol (2009) 24:253–263 adrenal disease, as well as other diseases, might have pre- renal injury with urinary indices suggestive of ATN but might, in reality, have pre-renal injury. Thus, it is essential that we consider the state of the function of the tubules before the potential onset that might precipitate vasomotor nephropathy/ATN, so that ascribing pre-renal injury to vasomotor nephropathy/ATN does not occur. In addition, the fractional excretion of sodium is often difficult to interpret in patients who have received diuretic therapy. Intrinsic renal disease Hypoxic/ischemic acute kidney injury Hypoxic/ischemic AKI is characterized by early vasocon- striction followed by patchy tubular necrosis. Recent studies suggest that the vasculature of the kidney may play a role in acute injury and chronic injury as well, and the endothelial cell has been identified as a target of injury. Peritubular capillary blood flow has been shown to be abnormal during reperfusion, and there is also loss of normal endothelial cell function in association with dis- torted peritubular pericapillary morphology and function [31, 32]. The mechanism of cellular injury in hypoxic/ ischemic AKI is not known, but alterations in endothelin or nitric oxide regulation of vascular tone, ATP depletion and alterations in the cytoskeleton, changes in heat shock proteins, initiation of the inflammatory response and the generation of reactive oxygen and nitrogen molecules may each play a role in cell injury [31–48]. Nitric oxide is a vasodilator produced from endothelial nitric oxide synthase (eNOS), and nitric oxide helps regulate vascular tone and blood flow in the kidney [37, 38]. Recent studies suggest that loss of normal eNOS function occurs following ischemic/hypoxic injury which could precipitate vasoconstric- tion [37]. In contrast, inducible nitric oxide synthase (iNOS) activity increases following hypoxic/ischemic injury, and iNOS can participate in the generation of reactive oxygen and nitrogen molecules. Inducible nitric oxide synthase, with the generation of toxic nitric oxide metabolites including peroxynitrate, has been shown to mediate tubular injury in animal models of acute kidney injury [38, 39]. Endothelin (ET) peptides are potent vasoconstrictors that have also been shown to play a role in the pathogenesis of AKI in animal models [40–42]. In rat models of AKI, circulating levels of endothelin-1 and tissue expression of endothelin-1 protein levels was substantially increased, while ET(A) and ET(B) receptor gene expression was also increased after ischemic injury [41]. Endothelin receptor agonist for the A receptor have been shown to be shown to decrease AKI in animal models [42]. Thus, alterations in the balance of vasoconstric- tive and vasostimulatory stimuli are likely to be involved in the pathogenesis of hypoxic/ischemic AKI.