Pediatr Nephrol (2009) 24:253–263 neonates also demonstrated improved renal function and decreased excretion of beta-2 microglobulin in neonates given theophylline within one hour of birth [61–63]. However, the clinical significance of the improved renal function was not clear, and the incidence of persistent pulmonary hypertension was higher in the neonates who had received theophylline group. Additional studies are needed to determine the significance of these findings and the potential side effects of theophylline. Diuretics and dopamine receptor agonist Diuretics and ‘renal-dose’ dopamine are commonly used to prevent or limit AKI. There have been several clinical studies using mannitol, diuretics, and ‘renal-dose’ dopamine for AKI [64–71]. The stimulation of urine output eases management of AKI, but conversion of oliguric to non- oliguric AKI has not been shown to alter the course of renal failure [64]. Furosemide may increase the urine flow rate to decrease intratubular obstruction and will inhibit Na-K- ATPase, which will limit oxygen consumption in already damaged tubules with a low oxygen supply. In a randomized controlled trial, two groups of adult patients with AKI requiring dialysis were given furosemide therapy or placebo; diuresis was achieved in a significantly shorter time in the group that received furosemide than in the group that had received placebo [64]. However, there was not a difference in the number of dialysis sessions, time on dialysis, or patients’ survival [64]. In patients who do respond to diuretic therapy with an increase in urine output, continuous infusions may be associated with less toxicity than bolus administration [65]. A retrospective study actually demon- strated that the use of diuretics in AKI was associated with adverse outcomes [66]. Since high doses of furosemide can cause ototoxicity, continued use in individual patients with AKI needs to take into consideration the risks and potential benefits or lack of benefits. The use of ‘renal-dose’ dopamine (0.5 μg/kg per minute to 3-5 μg/kg per minute) to improve renal perfusion following an ischemic insult has become very common in intensive care units. While dopamine increases renal blood flow by promoting vasodilatation and may improve urine output by promoting natriuresis, there have been no definitive studies to demonstrate that low doses of dopamine are effective in decreasing the need for dialysis or improve survival times in patients with AKI [67–71]. In fact, a placebo controlled randomized study of low doses of dopamine in adult patients demonstrated that low doses were not beneficial and did not confer clinically significant protection from renal dysfunction [67]. Other studies have demonstrated that ‘renal-dose’ dopamine is not effective in the therapy of AKI, and one study demonstrated that low doses worsened renal perfusion and renal function [69]. 259 Three separate meta-analyses have shown no benefit of dopamine in AKI [68, 70, 71]. Fenoldopam is a potent, short-acting, selective, dopamine-1 receptor agonist that decreases vascular resistance while increasing renal blood flow [72]. A recent meta-analysis of 16 trials of fenoldopam concluded that therapy with fenoldopam decreased the incidence of acute kidney injury, decreased the need for renal replacement therapy, decreased ICU stay and de- creased the number of deaths from any cause [73]. Fenoldopam has been used in a few children with acute kidney injury, including two children receiving therapy with a ventricular-assist device as a bridge to cardiac transplantation; therapy with fenoldopam was thought to avoid the need for renal replacement therapy in one child [74]. Additional studies utilizing fenoldopam need to be performed on children with acute kidney injury. Therapies to decrease injury and promote recovery While there is no current specific therapy to prevent renal injury or promote recovery in human ATN, several potential therapies are being studied, and future manage- ment of AKI may also include antioxidant, anti-adhesion molecule therapy and the administration of vascular mediators or mesenchymal stem cells to prevent injury and/or promote recovery [35, 36, 75–77]. Several different therapies have been shown to prevent, decrease or promote recovery in animal models of AKI. Melanocyte-stimulating hormone (MSH) has anti-inflammatory activity and has been shown to protect renal tubules from injury [75]. In other animal models of AKI, post-ischemic infusion of growth factors, including insulin-like growth factor-1 (IGF- 1), epidermal growth factor, and hepatocyte growth factor, resulted in accelerated recovery of renal function, less severe histological alterations and decreased mortality rates [75–77]. Scavengers of free radicals and reactive oxygen and nitrogen molecules, as well as anti-adhesion molecules, have been shown to decrease the degree of injury in animal models of AKI [77]. Recently, very interesting studies have also demonstrated that multipotent mesenchymal stem cells (MSCs) may have a role in promoting recovery from AKI in animal models [78]. Despite the promise of animal models of intervention in AKI, clinical studies in humans have been largely dis- appointing, including studies that utilized anaritide (atrial natriuretic peptide) and IGF-1 [79, 80]. Since therapy in these studies was initiated when renal failure was well established, it is likely that the opportunity to intervene and have an impact on the recovery from AKI had been missed [81, 82]. As mentioned previously, the development and testing of interventions for AKI will require the develop- ment of early biomarkers of injury that are much more sensitive than serum concentrations of creatinine.