There are no effective medications for established AKI. Therefore, prevention and early detection are the mainstays of management. Monitoring high-risk patients and reducing additional risk factors can prevent the occurrence of AKI and improve outcomes. Prematurity, and chronic diseases such as CKD render the host susceptible to AKI, and events such as volume depletion, exposure to nephrotoxins, sepsis, major surgery, and critical illness lead to AKI [4]. The renal angina index was proposed to predict AKI in critically ill children on the basis of subtle kidney injury (changes in estimated creatinine clearance or fluid overload) and patient risk factors (ICU admission, stem cell transplantation, ventilation and inotropy) [32].

Despite its importance, physicians often do not devote attention to the accumulation of risk factors and early decline of kidney function as they perform or attend to other important aspects of care [33]. Recently, a system using electronic health records was implemented and helped physicians detect AKI early and mitigate the influence of risk factors [34]. The system electronically flags high-risk patients to the medical team in near real-time. As such, the medical team does not miss high-risk patients and monitors them carefully. It has been shown to improve the rate of recovery from AKI [35]. In the pediatric literature, this system was developed to screen children who experienced multiple nephrotoxin exposures, which prompted clinicians to monitor more closely for the development of AKI. It demonstrated a positive effect in decreasing exposure to multiple nephrotoxins and, finally, AKI events [36].

Supportive care comprises optimization of volume status, blood pressure, avoidance of nephrotoxic agents, and nutritional support. It is important to maintain adequate renal perfusion through fluid and hemodynamic management [37]. Volume status should be optimal (i.e., not excessive, not insufficient). The medical history and symptoms are important to evaluate volume status. Body weight, fluid intake, urine and stool output, and vital signs should be monitored daily, and lung sound and lower extremity edema should be checked [38,39]. Serum chemistries and chest X-ray are also useful. Although volume depletion is a well-known risk factor, volume overload is associated with poor prognosis [40]. Fluid accumulation in the acute phase, which is common in the PICU, is associated with high mortality in critically ill patients [40,41]. The pediatric literature suggests that 10–20% fluid overload is a critical threshold at which outcomes are negatively impacted [41,42]. Administration of optimal fluid amount is crucial. Patients with a normal intravascular volume should initially be limited to insensible losses (400 mL/m²/d) plus an amount of fluid equal to the urine output and extrarenal loss [38]. Noticeable hypervolemic patients require further fluid restriction, omitting the replacement of insensible fluid losses, urine output, and extrarenal losses while considering adequate nutritional support [38]. Diuretics therapy, especially loop diuretics, should be considered for hypervolemic patients. The pediatric literature shows that clinicians should consider initiating renal replacement therapy (RRT) at a fluid overload of >20%, while a fluid overload 10–20 % requires further evaluation [42].

The proper type of fluid should be administered to prevent volume depletion. Crystalloids are the preferred solutions because data supporting the routine use of colloids for volume resuscitation are lacking [43]. Colloid solution was not superior to crystalloid in terms of the prevention of AKI in children who underwent cardiac surgery [44]. Among crystalloids, some studies have reported that a balanced solution, such as Ringer’s lactate solution, is superior to normal saline [45]. Balanced solutions are defined as intravenous fluids having an electrolyte composition close to that of plasma. They have low chloride content of about 100–110 mmol/L, which is the most altered in normal saline as compared to plasma [46,47]. Normal saline, which is hyperchloremic, can cause hyperchloremic metabolic acidosis, contributing to impaired recovery and poor clinical outcomes [48]. Three recent large prospective studies have reported conflicting results [49-51]; as such, debate regarding which solution is best among crystalloids continues.

Maintaining optimal blood pressure is crucial, although there is no currently definitive target value for pediatric AKI. For patients with hypotension, fluid resuscitation is initially considered if hypotension is due even partially to hypovolemia [18]. Norepinephrine is recommended if hypovolemia is not suspected [52]. High blood pressure in patients with AKI is mostly due to volume overload or disturbed renin-angiotensin axis [22]. Diuretics are attempted first unless patients exhibit signs of intravascular depletion [22].

Nephrotoxin exposure is one of the most common causes of AKI in hospitalized children [53]. Critically ill patients who are at high risk for AKI have the opportunity to be administered nephrotoxic mediations. Amphotericin, aminoglycoside, vancomycin, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcineurin inhibitors, cisplatin, and methotrexate are well-known nephrotoxins [18]. Clinicians must balance the therapeutic benefits versus the risk for nephrotoxicity. If the use of nephrotoxic medications is inevitable, their dosage or dosing interval should be adjusted and monitored to reduce renal toxicity. Drug levels should be measured, if possible, and adjusted accordingly. If not possible, medications should be adjusted based on eGFR. Be aware that eGFR does not account for real-time renal function in AKI [22]. Contrast agent used for computed tomography and angiography are nephrotoxic. Contrastinduced AKI is common in children [54], and risk depends on the contrast agent dosage and type. Angiography requires more attention because it requires more contrast agent than computed tomography. High-osmolality contrast agent carries a higher risk for AKI, but have been replaced by low-osmolality contrast agents, which have a lower risk [55]. Nevertheless, patients with a GFR <60 mL/min/1.73m² or at high risk for AKI should be prepared before exposure [22]. The key preventive measure is hydration. An isotonic crystalloid solution at 1 mL/kg/h should be administered intravenously for 12 hours before and after the procedure [18]. If contrast agent should be administered urgently, 3 mL/kg/h 1 h before and 6–9 mL/kg over 4–6 h after the procedure should be administered [18]. In addition, nephrotoxins should be discontinued for >24 h before the procedure [18]. The use of N-Acetylcysteine (NAC) will be discussed below.

Nutritional support is important for improving outcomes in children with AKI. For critically ill children with AKI, nutritional requirements should be individualized and assessed frequently [56]. In general, 120–130% of basal calories needs, and 2–3 g/kg/day of protein should be provided [56], and hyperglycemia should be avoided [57].

Many researchers have investigated candidate medications to prevent and treat AKI. Anti-inflammatory, antioxidative and antiapoptotic interventions are representative examples; however, their yield remains insignificant. Although a few medications have demonstrated effectiveness in certain situations, most have yielded negative or conflicting results. Medications advocated in the past were not proven to be effective. The KDIGO guideline recommend NAC to prevent contrast-induced AKI in high-risk patients [4]. However, two large, well-designed studies reported no benefit of NAC in reducing the incidence of contrast-induced AKI [58,59]. Diuretics are not recommended for the prevention of AKI because their use does not alter outcomes in those with established AKI [60]. Diuretics should be used only to control fluid overload. Low-dose dopamine and fenoldopam did not have a positive effect on protection against AKI [61,62]. Perioperative statins did not reduce the incidence of AKI among patients undergoing cardiac surgery [63]. Even now, candidate medicines, such as recombinant alkaline phosphate, costimulatory molecule CD28 receptor antagonist, p53 small interfering RNAs, and mesenchymal stem cells, are under consideration [18]. To establish the basis for routine clinical use of new medications, additional multicenter, high-quality trials are warranted.

RRT is required when conservative care fails. Indications for RRT include fluid overload (severe hypertension or pulmonary edema), severe hyperkalemia, metabolic acidosis, and severe uremia [64]. The optimal timing of RRT initiation remains controversial. A recent meta-analysis of randomized controlled trials revealed that early initiation of RRT does not reduce mortality when compared with standard or late initiation in adults [65]. Although one investigation involving pediatric patients demonstrated that early initiation improved mortality in cardiac surgery patients [66], it was small and retrospective in design; thus, more studies are needed. RRT modalities for AKI have begun with peritoneal dialysis and hemodialysis, and are now expanding to continuous renal replacement therapy (CRRT). We believe that all of these modalities represent viable management options in pediatric AKI [67]. There is no definite evidence that one dialysis modality is superior to another in terms of outcomes in AKI [68,69]. The modality should be determined according to the patient characteristics, institutional resources, and expertise [69]. Each modality has advantages and disadvantages. Peritoneal dialysis can be used in small children such as preterm infants, but removes fluid and waste slowly and unpredictably [67]. Hemodialysis removes toxins rapidly, but is dangerous for small children and hemodynamically unstable patients [67]; additionally, it requires expertise. Currently, CRRT becomes the preferred modality in developed countries as improvement of equipment [69]. CRRT facilitates hemodynamic stability and make it possible to use them in small children, such as neonates. New devices, such as the Cardio-Renal Pediatric Dialysis Emergency Machine, and Newcastle Infant Dialysis and Ultrafiltration System, have provided promising results for the treatment of neonates requiring RRT [70,71]. However, the device should be operated in the PICU, so that children must endure anxiety about being separated from their parents during treatment.