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Pediatric Acute Kidney Injury: Focusing on Diagnosis and Management

Acute kidney injury (AKI) is common in critically ill children, and is associated with increased mortality and long-term renal sequelae. The definition of pediatric AKI was standardized based on elevation in serum creatinine levels or decrease in urine output; accordingly, epidemiological studies have ensued. Although new biomarkers appear to detect AKI earlier and predict prognosis more accurately than traditional markers, they are not frequently used in clinical setting. There is no validated pharmacological intervention for AKI, so prevention and early detection are the mainstays of treatment. For high risk or early stage AKI patients, optimization of volume status and blood pressure, avoidance of nephrotoxins, and sufficient nutritional support are necessary, and have been demonstrated to be effective in preventing the occurrence of AKI and improving prognosis. Nevertheless, renal replacement therapy is needed when conservative care fails.


Introduction
Acute kidney injury (AKI) is characterized by an abrupt deterioration of kidney function, and is common in critically ill children and adults. It occurs in approximately 30% of pediatric intensive care unit (PICU) 1) . Pediatric AKI has been associated with higher morbidity and mortality after adjustment for other risk factors 1) , and is a risk factor for hypertension and chronic kidney disease (CKD) in the long term 2,3) . Recently, many studies have been con ducted in the field of pediatric AKI following adult studies and have prompted new interest. This review summarizes pediatric AKI, with a focus on diag nosis and management.
to the amplitude of serum creatinine elevation form base line value or the duration of compromised urine output.
Physicians sometimes, however, experience difficulty in diagnosing and staging AKI using the KDIGO definition. Many patients exhibit elevated serum creatinine levels without previous measurement. It is not integrated to set baseline value without available measurement data within 48 h, as specified by the KDIGO criteria. Some have used the lowest serum creatinine level measured before or after AKI as a baseline value. Others propose that the baseline serum creatinine level can calculate backward using an esti mated glomerular filtration rate (eGFR) of 100-120 mL/ min/1.73 m 2 , assuming that previous kidney function was normal 5) .
For neonates, the neonatal modified KDIGO definition was used in a recent large cohort (Table 1) 6,7) . Although it is based on a modification of the KDIGO definition, it is dif ferent with urinary output checked in 24 h blocks. More over, the baseline value is the lowest previous serum creat inine level because serum creatinine, which reflects maternal creatinine in the first few days, declines physiologically within weeks of life at a rate that varies with gestational age 8,9) .

AKI biomarkers
Serum creatinine is currently widely used as a biomarker for AKI; however, it has some limitations. It is insensitive to small changes in GFR, and is not a realtime indicator. It may not change until up to 50% of kidney function is lost 10) , and rise up to 72 h after an insult. Furthermore, its concentration is affected by age, sex, muscle mass, and volume status 11) . For two decades, many researchers have been searching new biomarkers that are rapid, sensitive, specific, inexpensive, noninvasive, and unaffected by cli nical factors 12) . Cystatin C, neutrophil gelatinaseassociated lipocalin (NGAL), kidney injury molecule1, Nacetylβ Dglucosaminidase, interleukin18, livertype fatty acid binding protein, cycle arrest markers, and BPI containing family A member 2 have been evaluated. These appear to detect AKI earlier and predict prognosis more accurately than serum creatinine levels 12) .
Serum cystatin C is produced by all nucleated cells and, is therefore, unaffected by clinical factors 13) . Its level rises earlier (12-24 h after insult) than that of serum creatinine 14) . In studies involving specific pediatric populations (children who underwent cardiac surgery, treated with aminoglyco side or contrast agent, and preterm infants with respiratory distress syndrome), it predicted AKI earlier than serum creatinine level, predicted persistent AKI, and showed greater sensitivity and specificity 1417) . Its disadvantage is that it is affected by highdose corticosteroids, inflamma tion, and systemic diseases 18) . NGAL, a proximal tubular protein, is the most rapid predictive biomarker, and is ele vated <2 h after insult 19) . Studies investigated NGAL in pe diatrics have mainly involved patient undergoing cardiac surgery, and have reported that elevation of urinary NGAL was associ ated with poor prognosis 20,21) . Urinary NGAL increases during urinary tract infection, sepsis, and CKD regardless of AKI 22) . A combination of two cellcycle arrest markers urinary tissue inhibitor of metalloproteinase2 and insu linlike growth factorbinding protein 7 demonstrated high sensitivity (90%) and low specificity (49%) in critically ill adults 23) , and was approved by the United States Food and Drug Administration for use in adults. A few studies have shown that it has good diagnostic performance in pediatric, and neonatal AKI 24,25) .
Despite the excellent performance of new biomarkers, they are not frequently used in clinical setting due to se veral concerns. First, they were validated for specific etio logies of AKI, such as pediatric patients undergoing cardiac surgery, and their efficacy cannot be reproduced in AKIs of different etiologies 12) . Moreover, they are also elevated in other clinical conditions, such as inflammation 12) . Large prospective studies investigating and validating the clinical utility of these biomarkers, therefore, is warranted.

Incidence
Two large, multinational epidemiological studies have been published in the pediatric and neonatal areas 1,7) . The Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology (AWARE) study described the epidemiology of AKI in 4,683 pediatric patients (age range 3 months to 25 years) who were admitted to the PICU 1) . It reported that AKI developed in 26.9% of patients and KDIGO stage 2 or 3 AKI in 11.6% within 7 days of PICU admission 1) . The Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN) study des cribed neonatal AKI in the neonatal ICU, and reported a prevalence similar to that of the AWARE study. The inci dence of AKI was 29.9%, with 13.9% reaching AKI stage 1, 7.1% reaching AKI stage 2, and 8.9% reaching AKI stage 3 7) . The incidence outside the ICU varies across medical centers. To our knowledge, there have been no largescale studies investigating AKI in noncritically ill children in Korea.

Outcomes
In the pediatric literature, AKI is consistently associated with poor outcomes, similar to adults. Many studies have demonstrated that AKI is an independent risk factor for prolonged stay in the PICU, longer duration of mechanical ventilation, and increased mortality among critically ill children 1,26,27) . In addition, several observational studies have reported a high prevalence of CKD, hypertension, and proteinuria among AKI survivors 2830) . Neonatal AKI is also a risk factor for mortality 7) . There have been no sufficiently large followup studies evaluating the relationship between neonatal AKI and longterm renal insufficiency. However, small observational studies have reported a high prevalence of CKD, and proteinuria in survivors of neonatal AKI 29,31) .

Risk factors and prevention
There are no effective medications for established AKI. Therefore, prevention and early detection are the mainstays of management. Monitoring highrisk patients and redu cing 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 nephro toxins, 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 over load) and patient risk factors (ICU admission, stem cell transplantation, ventilation and inotropy) 32) .
Despite its im portance, physicians often do not devote attention to the accumulation of risk factors and early dec line of kidney function as they perform or attend to other important aspects of care 33) . Recently, a system using elect ronic health records was implemented and helped physi cians detect AKI early and mitigate the influence of risk factors 34) . The system electronically flags highrisk patients to the medical team in near realtime. As such, the medical team does not miss highrisk 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 mo nitor more closely for the development of AKI. It demon strated a posi tive effect in decreasing exposure to multiple nephrotoxins and, finally, AKI events 36) .

Supportive care
Supportive care comprises optimization of volume status, blood pressure, avoidance of nephrotoxic agents, and nutri tional 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 im portant 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 Xray are also useful. Although volume depletion is a wellknown risk factor, volume overload is associated with poor prognosis 40) . Fluid accumulation in the acute phase, which is com mon in the PICU, is associated with high mortality in criti cally ill patients 40,41) . The pediatric literature suggests that 10-20% fluid overload is a critical threshold at which out comes are negatively impacted 41,42) . Administration of optimal fluid amount is crucial. Patients with a normal in travascular volume should initially be limited to insensible losses (400 mL/m 2 /d) plus an amount of fluid equal to the urine output and extrarenal loss 38) . Noticeable hypervole mic 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 pe diatric literature shows that clinicians should consider initi ating 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 pre vent volume depletion. Crystalloids are the preferred solu tions 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 intrave nous 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 hyper chloremic, can cause hyperchloremic metabolic acidosis, contributing to impaired recovery and poor clinical out comes 48) . Three recent large prospective studies have re ported conflicting results 4951) ; 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 hypo volemia is not suspected 52) . High blood pressure in patients with AKI is mostly due to volume overload or disturbed reninangiotensin 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 admini stered nephrotoxic mediations. Amphotericin, aminogly coside, vancomycin, nonsteroidal antiinflammatory drugs, angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, calcineurin inhibitors, cisplatin, and methotrexate are wellknown 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 adju sted 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 realtime renal function in AKI 22) . Contrast agent used for computed tomography and angiography are nephrotoxic. Contrast induced AKI is common in children 54) , and risk depends on the contrast agent dosage and type. Angiography re quires more attention because it requires more contrast agent than computed tomography. Highosmolality con trast agent carries a higher risk for AKI, but have been re placed by lowosmolality contrast agents, which have a lower risk 55) . Nevertheless, patients with a GFR <60 mL/ min/1.73m 2 or at high risk for AKI should be prepared be fore 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 NAcetylcysteine (NAC) will be discussed below.
Nutritional support is important for improving out comes 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 pro vided 56) , and hyperglycemia should be avoided 57) .

Pharmacological treatment
Many researchers have investigated candidate medica tions to prevent and treat AKI. Antiinflammatory, anti oxidative and antiapoptotic interventions are representa tive examples; however, their yield remains insignificant. Although a few medications have demonstrated effective ness in certain situations, most have yielded negative or conflicting results. Medications advocated in the past were not proven to be effective. The KDIGO guideline recom mend NAC to prevent contrastinduced AKI in highrisk patients 4) . However, two large, welldesigned studies re ported no benefit of NAC in reducing the incidence of con trastinduced 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. Lowdose 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 sur gery 63) . Even now, candidate medicines, such as recombi nant alkaline phosphate, costimulatory molecule CD28 receptor antagonist, p53 small interfering RNAs, and me senchymal stem cells, are under consideration 18) . To establish the basis for routine clinical use of new medications, addi tional multicenter, highquality trials are warranted.

RRT
RRT is required when conservative care fails. Indications for RRT include fluid overload (severe hypertension or pul monary edema), severe hyperkalemia, metabolic acidosis, and severe uremia 64) . The optimal timing of RRT initiation remains controversial. A recent metaanalysis of rando mized 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 initia tion 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 peri toneal dialysis and hemodialysis, and are now expanding to continuous renal replacement therapy (CRRT). We be lieve that all of these modalities represent viable manage ment options in pediatric AKI 67) . There is no definite evi dence that one dialysis modality is superior to another in terms of outcomes in AKI 68,69) . The modality should be de termined according to the patient characteristics, institu tional resources, and expertise 69) . Each modality has advan tages and disadvantages. Peritoneal dialysis can be used in small children such as preterm infants, but removes fluid and waste slowly and unpredictably 67) . Hemodialysis re moves 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 equip ment 69) . CRRT facilitates hemodynamic stability and make it possible to use them in small children, such as neonates. New devices, such as the CardioRenal 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.

Conclusion
AKI has attracted attention because of its high prevalence and association with poor outcomes. Many studies have been conducted to identify new biomarkers and effective pharmacological interventions, and significant improve ments have been achieved. Unfortunately, however, not many have been applied in actual clinical practice. Consi dering the gap between research achievements in adults and children, pediatric nephrologists have much to contri bute to developments in understanding and treating AKI.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or notfor profit sectors.

Conflicts of interest
No potential conflict of interest relevant to this article was reported.