Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis

INTRODUCTION — Acute kidney injury (AKI) is defined as the abrupt loss of kidney function that results in a decline in glomerular filtration rate (GFR), retention of urea and other nitrogenous waste products, and dysregulation of extracellular volume and electrolytes. The term AKI has largely replaced acute kidney failure as it more clearly defines kidney dysfunction as a continuum rather than a discrete finding of failed kidney function. Pediatric AKI presents with a wide range of clinical manifestations from a minimal elevation in serum creatinine to anuric kidney failure, arises from multiple causes, and occurs in a variety of clinical settings [1-7].

An overview of the causes, clinical presentation, and diagnosis of AKI in children will be presented here. The prevention, management, and outcomes of AKI in children and the approach to AKI in newborns are presented separately. (See "Prevention and management of acute kidney injury (acute renal failure) in children" and "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

DEFINITION — AKI is defined as a decrease in glomerular filtration rate (GFR), which traditionally is manifested by an elevated or a rise in serum creatinine from baseline, and/or a reduction in urine output. Clinically, as discussed below, the most widely used laboratory finding to make the diagnosis of AKI remains an elevated (or a rise in) serum creatinine. (See 'Diagnosis' below.)

However, serum creatinine is often a delayed and imprecise test as it reflects GFR in individuals at steady state with stable kidney function, and does not accurately reflect the GFR in a patient whose kidney function is changing [1-5]. For example, a child in the early stages of severe AKI with a markedly reduced GFR may have a relatively normal or slightly elevated creatinine, as there has not been sufficient time for creatinine accumulation [8]. In addition, creatinine is removed by dialysis, and it is not possible to assess kidney function using serum creatinine once dialysis is initiated. Furthermore, serum creatinine levels can vary with several nonrenal factors, including age, gender, muscle mass, presence of sepsis, and the nutritional and hydration status of the child. Despite these limitations, elevated or a rise in serum creatinine continues to be the most widely used laboratory finding to make the diagnosis of AKI in children. (See 'Diagnosis' below.)

While a decrease in urine output is an important criterion for the diagnosis of AKI, the majority of the published literature has utilized only serum creatinine changes, since the latter is more easily extracted from data in electronic health records. In addition, urine output changes in AKI are confounded by difficulties with measurement, hydration status, and the use of fluids and diuretics. Despite these limitations, available data have shown that the degree of oliguria is strongly associated with poor outcomes in children with AKI and that noninclusion of oliguria in the definition of AKI can lead to substantial underdiagnosis [9].

The inability of serum creatinine and urine output to accurately reflect kidney function has been especially problematic for clinical research in pediatric AKI. This has resulted in the use of more than 35 definitions of AKI in clinical studies, ranging from minimal changes in serum creatinine to dialysis requirement. Because of the lack of a consensus definition, comparisons among studies are difficult, resulting in a wide range of quoted epidemiology, morbidity, and mortality rates in the AKI pediatric literature [10]. Standardized and validated definitions for pediatric AKI include the KDIGO (Kidney Disease Improving Global Outcomes) and pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) classifications.

The KDIGO AKI definition and staging be used to guide clinical care based on consensus of pediatric nephrology experts following a systematic review of the literature. (See 'KDIGO definition' below.)

KDIGO definition — The KDIGO AKI definition and staging is recommended to guide clinical care, and as a standardized inclusion and outcome measure in AKI pediatric studies.

●Definition and staging – The KDIGO AKI Consensus Conference created a single definition of AKI that takes into account components of the RIFLE, pRIFLE, and AKIN criteria based on a systematic review of the literature (table 1) [11-13]:

•Increase in serum creatinine by ≥0.3 mg/dL from baseline (≥26.5 mcmol/L) within 48 hours, or

•Increase in serum creatinine to ≥1.5 times baseline within the prior seven days, or

•Urine volume ≤0.5 mL/kg/hour for six hours

Both the definition and staging include a 0.3 mg/dL serum creatinine increase from baseline criterion that is specifically applicable to pediatric AKI. In previously healthy children where the baseline serum creatinine is unknown, it is generally recommended to use a presumed baseline of 120 mL/min/1.73 m² [14]. An alternative approach is to use published minimum and maximum normative serum creatinine values for age and gender [15-18]. Imputed age- and gender-based serum creatinine norms have been successfully applied as a surrogate baseline to detect pediatric AKI in both the hospitalized [19] and the community [20] settings.

Modifications also allow for a child with estimated GFR (eGFR) <35 mL/min per 1.73 m² to be included in stage 3, in contrast with the adult criterion of ≥4 mg/dL serum creatinine, which would be unusual in infants and young children. Extension of the diagnostic timeframe for a serum creatinine rise to seven days allows for the inclusion of patients with late-onset AKI. The KDIGO AKI criteria have been validated in hospitalized children with both critical and noncritical illness [10,21].Clinically, as discussed below, the most widely used laboratory finding to make the diagnosis of AKI remains an elevated (or a rise in) serum creatinine. (See 'Diagnosis' below.)

●Risk stratification system to predict severe AKI – The renal angina index (RAI), determined by a composite of vasopressor use, invasive mechanical ventilation, percent fluid overload, and estimated creatinine clearance, has been shown in prospective studies to improve prediction of subsequent severe AKI (KDIGO Stage 2 to 3) in critically ill children when compared with an increase in serum creatinine alone [22,23]. So, one potential use of the RAI might be to identify those children who might benefit most from investigational biomarkers and potential early intervention [24,25]. In particular, integration of the RAI into electronic information systems for automated alerts is a promising approach that is actively being pursued. However, the routine clinical use of the RAI requires further validation.

Data demonstrating the ability of RAI for early prediction of AKI in children includes presentation in the emergency department [26] and in children with septic shock [27]. In addition, a meta-analysis of 11 studies involving 3701 children found the RAI predicted AKI in children with a high degree of sensitivity and specificity [28].

pRIFLE definition — pRIFLE (table 2) is a pediatric modification of the adult RIFLE classification and consists of three graded levels of injury (Risk, Injury, and Failure) based on change in creatinine clearance or urine output and two outcome measures (Loss of kidney function and End-stage kidney disease) [29]. Differences between the adult and pediatric classification include:

●In pRIFLE, estimated creatinine clearance is based on the original Schwartz formula (calculator 1) to quantitate the change in GFR rather than absolute changes in serum creatinine used in the adult version of RIFLE. This modification takes into account the expected normal changes in serum creatinine concentrations that accompany somatic growth. (See "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Serum creatinine and glomerular filtration rate'.)

●Immediate placement of any child with an estimated creatinine clearance <35 mL/min per 1.73 m² into the "pRIFLE-F" category (ie, kidney failure class), instead of waiting for the serum creatinine concentration to reach 4 mg/dL as proposed by the original "RIFLE-F" staging. As an example, in infants and toddlers, a serum creatinine as low as 1 may reflect an estimated creatinine clearance <35 mL/min per 1.73 m², indicating kidney failure.

The use of pRIFLE has been advocated as a research and clinical tool as many experts in the field believe that it will improve the understanding of the epidemiology and outcomes of pediatric AKI. Support of pRIFLE is based on several reports that demonstrated AKI defined by the pRIFLE criteria was an independent risk factor for mortality and morbidity [15,30-33]. However, several limitations of the pRIFLE, which also apply to the adult RIFLE criteria, should be borne in mind:

●The "Risk," "Injury," and "Failure" criteria are defined by changes in either estimated creatinine clearance OR changes in urine output. There is no clear evidence to suggest that these two changes correspond to the same degree of AKI severity.

●The pRIFLE criteria still depend on changes in serum creatinine, which have major limitations in AKI due to the inability of serum creatinine to accurately reflect changing kidney function, as discussed above.

●Estimation of changes in creatinine clearance is challenging in children who do not have a pre-illness "baseline" serum creatinine and/or height measurements [13,15].

Other definitions — Other definitions that have not been adequately validated include:

●Acute Kidney Injury Network (AKIN) criteria – As a result of the limitations on the use of the RIFLE criteria, a new definition of AKI referred to as the AKIN criteria was developed. The AKIN criteria defined AKI as a ≥0.3 mg/dL increase in serum creatinine within a restrictive 48-hour period and eliminated the need to estimate creatinine clearance. However, the AKIN criteria have not been adequately validated for use in children and the restricted diagnostic timeframe of 48 hours for a rise in serum creatinine may limit their utility. (See "Definition and staging criteria of acute kidney injury in adults", section on 'Diagnostic criteria'.)

●pROCK criteria – Pediatric reference change value optimized for AKI in children (pROCK) was used to define AKI in a Chinese cohort of 156,075 hospitalized children with at least two serum creatinine tests within 30 days [34]. The incidence of AKI was lower using the pROCK criteria (defined AKI as creatinine level >20 micromol/L [0.23 mg/dL] of the reference change value based on age or 30 percent greater than an initial creatinine level) compared with the pRIFLE and KDIGO definitions (5.3 versus 15.2 and 10.2 percent, respectively). In this study, pROCK more accurately predicted mortality and adverse outcomes (eg, need for intensive care) than the other two definitions. In a subsequent study of 3338 children admitted to a Chinese pediatric intensive care unit, pROCK outperformed KDIGO in predicting mortality [35]. However, further validation of pROCK in other populations in its ability to predict clinical outcome is needed before this definition can be adopted.

●Duration criteria – The length of an AKI episode has been used to refine the diagnosis. Transient AKI (typically lasting less than 48 hours duration) portends a better prognosis than sustained AKI (of two to seven days duration). A new definition of acute kidney disease (AKD) has been proposed for AKI episodes that persist beyond seven days and up to 90 days (beyond which the condition is labeled as chronic kidney disease [CKD]). AKD represents a complex syndrome where recurrent bouts of injury, regeneration, and repair coexist within the context of preexisting kidney reserve, requiring recognition and tailored management [36].

EPIDEMIOLOGY

Hospitalized children

●Overall incidence – Rates of AKI in hospitalized children vary across studies due to the lack of a consensus AKI definition, different clinical settings, and various geographic locations [15]. Based on available data, the incidence of AKI varies from approximately 5 to 31 percent of noncritically ill hospitalized patients to approximately 55 percent in critically ill hospitalized patients [37-40]. Rates of moderate to severe AKI range from approximately 10 to 14 percent [41,42].

As an example, a meta-analysis comprising 94 studies (with 202,694 participants) from 26 countries reported the incidence of any AKI at 26 percent, with the incidence of moderate to severe AKI at 14 percent [42].

●Trends in incidence – Rates of AKI in children are increasing over time. In a study of 1.5 million children cared for in the Kaiser Permanente Northern California (KPNC) health system between 2008 and 2016, the incidence of AKI for hospitalized children rose from 6 percent in 2008 to 8.8 percent in 2016 [43].

A retrospective study from a tertiary care center in Thailand spanning 22 years reported a rise in the incidence of moderate to severe AKI (defined as a doubling of serum creatinine) with rates increasing from 4.6 to 9.9 cases per 1000 pediatric admissions from 1982 to 2004 [41]. However, the exclusion of children with mild AKI (stage 1 by KDIGO (table 1)) suggests that these data are an underestimation of the true incidence of AKI.

●Incidence across countries with varied resources – The meta-analysis described above comprising participants from 26 countries reported that the incidence of AKI was similar across high-, low-middle-, and low-income countries (27 percent, 25 percent, and 24 percent, respectively) [42].

However, the incidence of pediatric AKI in resource-limited areas is not well defined [44]. In less developed countries, acute tubular necrosis secondary to gastroenteritis with dehydration or sepsis and primary kidney diseases, such as hemolytic uremic syndrome and acute glomerulonephritis, are more likely to cause AKI [41,45-47].

●Critically ill versus noncritically ill children – In general, critically ill patients (cared for in the intensive care unit [ICU]) are more likely to develop AKI than noncritically ill patients. This is supported by a large retrospective study from a tertiary care center in the United States which analyzed two temporally defined cohorts of hospitalized children with known baseline serum creatinine values. Hospital-acquired AKI was defined using KDIGO definitions as a 1.5-fold or 0.3 mg/dL increase in serum creatinine from baseline. In critically ill ICU patients, AKI developed in 791/1332 (59 percent) of the first cohort and 470/866 (54 percent) of the second cohort. In non-ICU patients, 722/2337 (31 percent) in the first cohort and 469/1474 (32 percent) of the second cohort developed AKI [38].

In the KPNC study mentioned above, only one-third of the hospitalized children with AKI were cared for in the intensive care unit (ICU). Additionally, the majority of children with confirmed, unresolved severe AKI (KDIGO stage 2 or 3) did not receive early outpatient follow-up, indicating the unmet need for targeted post-discharge monitoring and management, even in developed countries [43].

●Limitations of methods – Utilizing hospital claims data, diagnosis codes, electronic alert data to determine rates of AKI in children may limit the accuracy of results. As an example, a retrospective study from Taiwan that reviewed claims data from a national insurance database reported an average incidence of AKI of 1.4 percent from 2006 to 2010 in 60,338 children who were critically ill [48]. However, the reliance on ICD-9-CM codes to define AKI limits the accuracy of these data. This is in contrast to a study in Wales, which reported an incidence of 77.3 cases of AKI per 1000 person-years using data from a national electronic alert system [49]. Of the reported cases, 84 percent of patients had stage 1 AKI, and approximately half were the result of a triggered increase in creatinine from the baseline value for the patient.

Utilizing historic data also limits the accuracy of results, as illustrated by a secondary analysis of nearly 1.7 million patients using a historic analysis of the Kids' Inpatient Database, which reported that AKI occurred in 12.3/1000 hospitalizations [50].

Nonhospitalized children — Data are limited on the incidence of AKI among nonhospitalized children. The best estimated incidence of community-based AKI is approximately 0.7 cases per 1000 person-years based on a study of 1.5 million children cared for in the KPNC health system between 2008 and 2016 [43].

In addition, a multicenter study from China using electronic hospitalization information systems and laboratory databases found that seven percent of hospitalized children with AKI had community-acquired AKI (eg, hypovolemia from diarrhea or sepsis) [51].

RISK FACTORS — The risk of pediatric AKI increases for children and neonates who require intensive care, those who receive nephrotoxic drugs, and those who have underlying chronic diseases.

Critically ill patients — The risk of AKI is greatest in children cared for in intensive care units (ICUs) [10,21,29,31,38,52,53]. In addition, severe AKI in critically ill children is associated with increased mortality [54].

This was illustrated in a prospective multinational study that evaluated the risk and severity of AKI for 4683 patients (median age 66 months, range 3 months to 25 years) cared for in 32 pediatric ICUs across Asia, Australia, Europe, and North America during three consecutive months in 2014 [52]. In this cohort, 26.9 percent of patients developed AKI and 11.6 percent severe AKI (stage 2 or 3 AKI) based on the KDIGO criteria (table 1). Severe AKI was associated with an increased risk of death by day 28 after adjustment of confounding variables (eg, primary diagnosis, coexisting conditions at baseline, mechanical ventilation, and vasoactive therapy). In addition, stepwise increases in severity of AKI were associated with incremental increases in the risk of death. Severe AKI was associated with increased use of mechanical ventilation and kidney replacement therapy. This study also utilized both serum creatinine and urine output criteria to diagnose AKI in critically ill children (factors used in defining adult AKI). Over 67 percent of the children found to have AKI by oliguria would have been missed if using serum creatinine criteria alone. Furthermore, there was an increase in mortality when KDIGO stage 2 or 3 AKI was reached based on oliguria versus serum creatinine change (7.8 versus 2.9 percent). These data reinforce the need to identify patients at-risk for AKI or with mild AKI using both serum creatinine and urine output criteria similar to the adult criteria for AKI, so that early interventions can be given to prevent further injury. (See "Definition and staging criteria of acute kidney injury in adults" and "Prevention and management of acute kidney injury (acute renal failure) in children".)

The most prevalent risk factors for AKI in critically ill children include sepsis, multi-organ failure, nephrotoxins, congenital heart disease, malignancies, primary kidney disease, hypotension and shock, hypoxemia, and renal ischemia [48,55,56]. For patients requiring mechanical ventilation and/or vasopressor support, the reported risk of AKI jumps to over 80 percent [29]. During the coronavirus disease 2019 pandemic, a high incidence of AKI has been reported among critically ill adults and children [57].

Neonates — Infants cared for in the neonatal intensive care unit (NICU) are at risk for AKI, which increases mortality [58,59]. A multicenter retrospective cohort study of 2012 critically ill neonates cared for in NICUs in four countries (United States, Canada, Australia, and India) reported 21 percent of infants developed AKI (defined as a serum creatinine increase of ≥0.3 mL/dL, or a urine output of <1 mL/kg/hour on postnatal days 2 to 7) [58]. Infants with AKI compared with those without AKI had higher mortality and greater length of stay in the NICU.

Additional risk factors for neonatal AKI include congenital heart disease [60,61], very low birth weight (birth weight <1500 g) [62], sepsis [63], low gestational age [64], and perinatal asphyxia [65].

Nephrotoxins — The use of nephrotoxic medications is a common risk factor for AKI in children. However, the use of daily electronic health record screening of hospitalized children with high nephrotoxin exposure can identify an increase in serum creatinine and lead to clinical interventions that can reduce the rate of AKI [66].

●Drugs – In noncritically ill hospitalized children, the most commonly used nephrotoxic medications include nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycosides, vancomycin, piperacillin-tazobactam, antiviral agents, radiocontrast agents, angiotensin-converting enzyme inhibitors, and calcineurin inhibitors [32]. Combination of any of these different medications is associated with increased risk of AKI in hospitalized children as best illustrated for the combination of vancomycin and piperacillin-tazobactam [67-69].

NSAIDs is the most common potential nephrotoxin and accounts for 3 to 7 percent of AKI cases in hospitalized children [70,71]. The risk of NSAID-induced AKI is increased in children with renal hypoperfusion as observed in patients with hypovolemia due to acute gastroenteritis [71,72].

In a study of children admitted to the ICU, the most commonly administered nephrotoxic agents were furosemide, vancomycin and gentamicin [73]. Both furosemide and gentamicin conferred a two-fold greater risk of developing AKI after adjusting for other risk factors.

●Radiocontrast agents – The nephrotoxic potential of radiocontrast agents to cause AKI in children remains controversial, but the overall risk appears to be low in children with normal kidney function with the use of low osmolar radiocontrast agents.

•In a retrospective, single-center study of pediatric patients who underwent computed tomography (CT), the rates of AKI based on serum creatinine-defined KDIGO criteria were slightly higher for the 1773 children who received contrast compared with the 428 patients who received no contrast (3.3 versus 0.1 percent) [74]. However, following propensity score adjustment, there were no differences in risk for AKI between the contrast and noncontrast groups.

•Similar results were observed in another retrospective study that reported low hospitalized children with estimated GFR (eGFR) ≥60 mL/min/1.73 m² who underwent contrast-enhanced CT scanning with a propensity-matched control group of children who underwent abdominal ultrasounds without contrast [75]. The AKI rate was similarly low at 2.2 percent.

Comorbid conditions — The overall incidence of AKI is rising with the increasing use of intensive and advanced technology for children with chronic conditions or those who are critically ill [48,76]. As a result, the incidence of AKI is substantially higher in specialized populations with severe illnesses and including children with congenital heart disease that requires surgical intervention [77-84], cancer [85,86], hematopoietic stem cell transplantation [87,88], liver transplantation [89], nephrotic syndrome [90], or sickle cell vaso-occlusive pain crisis [91].

CLASSIFICATIONS — Several AKI classification schemas have been developed.

The most widely used classification and the one used in this review separates the causes of AKI into the following three categories based on the anatomic location of the initial injury. This schema is helpful for understanding the underlying pathophysiology and outlining a management approach. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Major causes and pathogenesis of kidney disease'.)

●Prerenal disease – Prerenal disease, also referred to as volume-responsive or functional AKI, is caused by reduced renal perfusion. It is the most common form of pediatric AKI and is due to hypovolemia (bleeding or gastrointestinal, urinary or cutaneous losses), or reduction of effective circulation (eg, heart failure, septic shock, and cirrhosis). In this form of AKI, although glomerular filtration rate (GFR) is reduced, renal tubular function remains intact with avid reabsorption of sodium and water in response to renal hypoperfusion, leading to oliguria. When normal renal perfusion is restored, urine flow and GFR usually return to normal.

●Intrinsic kidney disease – Intrinsic or intrarenal AKI is characterized by structural damage to the renal parenchyma. The most common causes of intrinsic disease are prolonged hypoperfusion, sepsis, nephrotoxins, or severe glomerular diseases.

●Postrenal disease – Postrenal or obstructive AKI is typically the result of congenital or acquired anatomic obstructions to the lower urinary tract.

Although less frequently used, AKI may also be classified by:

●Clinical setting or circumstance

•Community-acquired AKI is more likely to be associated with a single predominant insult, most commonly volume depletion, and is frequently reversible.

•Hospital-acquired AKI, especially in the critical care setting, is frequently multifactorial and often part of a more extensive multiorgan failure. This form of AKI often accompanies other organ disease processes and markedly complicates patient management and outcome.

●Urine output – Measurement of urine output is especially useful in the critical care setting, since the degree of oliguria affects fluid and electrolyte management and is strongly associated with poor outcomes [9]. However, the presence of a normal volume of urine does not preclude AKI.

•Anuria – No urine output.

•Oliguria – Urine output <1 mL/kg per hour in infants, and in children and adults, urine output <0.5 mL/kg per hour for greater than six hours.

•Nonoliguria – Urine output for greater than six hours of >1 mL/kg per hour for infants and >0.5 mL/kg per hour for children and adults.

•Polyuria – Urine output of greater than 3 mL/kg per hour. Some patients with a urinary concentrating defect will present with polyuric AKI, particularly those with acute tubular necrosis and those with nephrotoxic AKI.

ETIOLOGY AND PATHOGENESIS — As discussed above, the causes and mechanisms of pediatric AKI can be classified based on the anatomic location of the initial injury.

●Vascular – Blood from the renal arteries is delivered to the glomeruli. Interruption of perfusion to the kidneys results in prerenal AKI.

●Glomeruli – Ultrafiltration occurs at the glomeruli forming an ultrafiltrate, which subsequently flows into the renal tubules. Glomerular injury resulting in disruption of glomerular filtration rate (GFR) is one of the major causes of intrinsic AKI.

●Renal tubule – Reabsorption and secretion of solute and/or water from the ultrafiltrate occurs within the tubules. Acute tubular necrosis due to nephrotoxins or hypoperfusion is one of the major causes of intrinsic AKI.

●Urinary tract – The final tubular fluid, the urine, leaves the kidney, draining sequentially into the renal pelvis, ureter, and bladder, from which it is excreted through the urethra. Postrenal AKI is due to obstruction of urine anywhere along the urinary tract in a single kidney and, in patients with two kidneys, bilateral obstruction usually at the bladder or urethral level.

Prerenal acute kidney injury — Causes of prerenal AKI (table 3) result in decreased perfusion to the kidneys and, as a consequence, a reduction in GFR due to the following two pathogenetic mechanisms:

●True volume depletion due to bleeding (eg, surgery or trauma), intestinal loss (eg, gastroenteritis), excessive cutaneous loss (eg, burns) or excessive urine loss (eg, diabetic ketoacidosis) [92,93].

●Effective renal hypoperfusion as a result of decreased arterial pressure (due to decreased cardiac output [heart failure]) or effective arterial blood volume (due to decreased intravascular volume despite normal or increased total body water [eg, septic shock or cirrhosis]). (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of effective arterial blood volume'.)

In patients with decreased arterial blood volume, the release of vasoactive agents (norepinephrine and angiotensin II) is one of the main systemic compensatory mechanisms that maintains perfusion to the brain and heart by normalizing intravascular volume and blood pressure, but diminishes renal perfusion and as a consequence reduces GFR.

There are several renal compensatory mechanisms that attempt to maintain GFR in patients with decreased renal perfusion.

●The most effective of these renal compensatory systems involves the increased intrarenal generation of vasodilatory prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs), however, inhibit this response and can therefore precipitate AKI even when following appropriate dosing [70,94]. The risk of AKI is higher when these agents are used in the setting of renal hypoperfusion. Two common pediatric scenarios in which this occurs are the use of indomethacin for closure of a patent ductus arteriosus in neonates, and the use of ibuprofen in febrile children with hypovolemia due to gastroenteritis [72].

●A second mechanism involves intrarenal angiotensin II, which constricts both the afferent and efferent arteriole. The effect is greater in the efferent arteriole leading to increased hydrostatic pressure across the glomerulus and maintenance of GFR. The administration of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker therapy blocks this compensatory mechanism.

●Myogenic autoregulation refers to the unique ability of the afferent arterioles to vasodilate in response to a decrease in lateral stretch caused by hypoperfusion. Calcineurin inhibitors such as cyclosporine and tacrolimus that are commonly used for immunosuppression following kidney transplants can interfere with this myogenic response.

Intrinsic acute kidney injury — The most common underlying etiology for intrinsic AKI is prolonged renal hypoperfusion. However, in critical care settings, intrinsic AKI is frequently multifactorial in etiology with concurrent ischemic, nephrotoxic, and septic insults that can exacerbate the severity of kidney injury (table 3).

Intrinsic AKI can be classified further into disorders that affect the kidney vasculature, glomeruli, tubule, and interstitium.

Vascular disease — Pediatric kidney vascular causes of intrinsic AKI include thrombosis (arterial and venous), typical and atypical hemolytic uremic syndrome, thrombotic microangiopathies, and vasculitides. (See "Overview of hemolytic uremic syndrome in children" and "Vasculitis in children: Incidence and classification" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Glomerular disease — The principal pediatric glomerular cause of AKI is acute glomerulonephritis, which is most commonly poststreptococcal and an important etiology in developing countries. (See "Poststreptococcal glomerulonephritis" and "Overview of the pathogenesis and causes of glomerulonephritis in children".)

Tubular and interstitial disease — Prolonged prerenal AKI with reduction in renal perfusion and tubular nephrotoxins are important causes of intrinsic AKI. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

Causes of tubular and interstitial disease in children include infections and adverse reaction to drugs [95]. Common drugs associated with tubulointerstitial disease include nonsteroidal antiinflammatory agents, aminoglycosides, amphotericin B, calcineurin inhibitors, and cisplatin [32,96,97]. However, iodinated contrast does not appear to be associated with AKI in hospitalized children with estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m² [75]. (See 'Nephrotoxins' above and "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)

Intrinsic AKI can also be induced by the release of endogenous nephrotoxins such as myoglobinuria due to rhabdomyolysis [98-100] and hemoglobinuria due to intravascular hemolysis. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

Postrenal acute kidney injury — Postrenal AKI is due to bilateral urinary tract obstruction or obstruction of the urinary tract of a solitary kidney. Causes of postrenal AKI include renal calculi, clots, neurogenic bladder, and medications that cause urinary retention. Children with chronic kidney disease from uncorrected congenital obstructive uropathies remain at significant risk of AKI from ischemic, septic, and nephrotoxic insults. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Anomalies of the collecting system' and "Clinical presentation and diagnosis of posterior urethral valves".)

CLINICAL FINDINGS

Clinical presentation — AKI in children can present in several different ways.

●In most children, AKI presents with signs and symptoms that result directly from alterations of kidney function. These include edema (due to progressive fluid accumulation), decreased or no urine output, gross and microscopic hematuria, and/or hypertension. In these patients, there is often a known etiologic factor that predisposes the child to AKI, such as shock or heart failure, or a preceding streptococcal infection seen in patients with poststreptococcal glomerulonephritis. (See 'History' below.)

●Laboratory monitoring of at-risk patients identifies alterations of kidney function, such as elevations of serum creatinine and/or blood urea nitrogen (BUN), or abnormal urinalysis. For example, ongoing monitoring frequently will identify a rise in serum creatinine in children postcardiac surgery, those undergoing treatment for malignancy, or those receiving potentially nephrotoxic agents. (See 'Nephrotoxins' above.)

AKI, identified by laboratory testing, is common in critically ill patients with multiorgan failure or dysfunction [29,31,96]. In these patients cared for in the intensive care setting, prognosis is guarded as AKI is associated with mortality and significant morbidity [31,52]. (See 'Critically ill patients' above.)

●Less frequently, patients without signs or symptoms of kidney injury will present as a result of unexpected laboratory findings of an elevated serum creatinine or BUN, or abnormal urinalysis. This may occur in a patient presenting with vasculitis (eg, immunoglobulin A vasculitis [Henoch-Schönlein purpura]) who initially presents with a rash, arthritis, and abdominal pain, in whom the initial evaluation demonstrates an elevated serum creatinine and/or abnormal urinalysis. In addition, patients with acute interstitial nephritis may also present with an acute rise in serum creatinine and an abnormal urinalysis with no or nonspecific symptoms (eg, malaise and vomiting). (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Clinical manifestations in children' and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Clinical features'.)

Other laboratory findings — In addition to an elevated serum creatinine or BUN, disruption of kidney function may result in the following abnormal laboratory findings:

●Hyperkalemia – Several factors may contribute to hyperkalemia in patients with AKI. These include a reduced glomerular filtration rate (GFR), decreased tubular secretion of potassium, tissue breakdown with release of intracellular potassium, and metabolic acidosis resulting in transcellular movement of potassium (each 0.1 unit reduction in arterial pH raises serum potassium by 0.3 mEq/L). Hyperkalemia is most pronounced in patients with significant tissue breakdown (rhabdomyolysis, hemolysis, and tumor lysis syndrome). Symptoms are nonspecific and may include malaise, nausea, and muscle weakness. Electrocardiogram changes occur in patients with hyperkalemia. These include (in sequence according to the severity of hyperkalemia) tall peaked T waves, prolonged PR interval, flattened P waves, widened QRS complex, ventricular tachycardia, and fibrillation. (See "Causes and evaluation of hyperkalemia in adults" and "Clinical manifestations of hyperkalemia in adults".)

●Abnormal serum sodium

•Hyponatremia is a common laboratory finding and generally due to dilution from fluid retention and/or administration of hypotonic fluids. Less common causes of hyponatremia include sodium depletion (hyponatremic dehydration), hyperglycemia (serum sodium concentration decreases by 1.6 mEq/L for every 100 mg/dL increase in serum glucose above 100 mg/dL), and pseudohyponatremia. (See "Hyponatremia in children: Etiology and clinical manifestations".)

•Hypernatremia is less common in children with AKI. It is usually due to hypernatremic dehydration causing prerenal failure, excessive sodium administration (eg, excessive sodium bicarbonate administration), and/or the inability to excrete a sodium load. (See "Hypernatremia in children".)

●A high anion gap metabolic acidosis is common and is secondary to the impaired kidney excretion of acid, and reabsorption and regeneration of bicarbonate. Acidosis is most severe in critically ill children with shock, sepsis, or impaired respiratory compensation. (See "Approach to the child with metabolic acidosis", section on 'Increased acid concentration: High anion gap metabolic acidosis'.)

●Hypocalcemia is commonly encountered in AKI, and is due to increased serum phosphate and impaired kidney conversion of vitamin D to the active form. Hypocalcemia is most pronounced in patients with rhabdomyolysis. Metabolic acidosis increases the fraction of ionized calcium (the active form). Therefore, it is important that the clinician is aware that rapid correction of metabolic acidosis with bicarbonate therapy can decrease the concentration of ionized calcium and precipitate symptoms of hypocalcemia (eg, tetany, seizures, and cardiac arrhythmias).

●Hyperphosphatemia in AKI is primarily due to impaired kidney excretion and can contribute to hypocalcemia. Hyperphosphatemia is most pronounced in patients with significant tissue breakdown (eg, tumor lysis syndrome or rhabdomyolysis).

DIAGNOSIS — The current diagnosis of AKI is made clinically based on the presence of characteristic signs and symptoms, and laboratory findings indicative of an acute change in kidney function.

●Signs and symptoms include edema, fluid overload, decreased or no urine output, gross hematuria and/or hypertension. (See 'Clinical findings' above.)

●Laboratory findings include elevated or rising serum creatinine. An abnormal urinalysis may also provide support for acute injury to the kidney.

The above findings typically occur in a clinical setting, in which AKI is an expected or reasonable consequence (eg, critically ill patient or a condition in which kidney disease is often encountered). Further evaluation is generally focused on identifying the underlying cause and/or contributing factors of AKI. (See 'Identifying the underlying cause' below.)

Laboratory tests

Serum creatinine — The most common laboratory test used to identify reduced glomerular filtration rate (GFR) as an indication of AKI is serum creatinine. As noted above, serum creatinine only accurately reflects GFR in patients with stable kidney function; however, in most clinical settings of AKI, the exact knowledge of GFR is not required. What is clinically important is whether there is a reduction of GFR due to kidney injury, which is reflected by an increase in serum creatinine.

As a result, in most settings, an elevated creatinine is used to make the diagnosis of AKI. However, an initial creatinine level may not be helpful, as baseline creatinine levels are unknown in the majority of children and normal serum creatinine levels vary depending on the age, sex, muscle mass, and nutritional and hydration status of the child. When a baseline serum creatinine level is not available, age- and sex-based serum creatinine norms can be used to detect pediatric AKI in both the hospitalized [19] and the community [20] settings.

The following are the ranges of normal serum creatinine values by age [16]:

●Newborn – 0.3 to 1 mg/dL (27 to 88 micromol/L)

●Infant – 0.2 to 0.4 mg/dL (18 to 35 micromol/L)

●Child – 0.3 to 0.7 mg/dL (27 to 62 micromol/L)

●Adolescent – 0.5 to 1 mg/dL (44 to 88 micromol/L)

Because of the wide range of normal serum creatinine, an initial value of 0.4 mg/dL (35 micromol/L) may be normal or elevated in an infant or young child. In a child whose normal creatinine is 0.2 mg/dL (18 micromol), a serum creatinine of 0.4 mg/dL (35 micromol/L) may reflect a 50 percent or greater decrease in GFR.

When it is uncertain whether the GFR is reduced based on an initial creatinine, subsequent measurements showing a daily rise in serum creatinine or at 12-hour intervals confirms the diagnosis of AKI. The change in creatinine is dependent on the amount of residual kidney function, the endogenous production of creatinine based on muscle mass, and the volume of distribution. In some settings, the serum creatinine may not rise until there is a 50 percent or more reduction in GFR.

Despite these limitations, there is currently no better laboratory test to make the diagnosis of AKI in children. However, it appears that serum cystatin C may in the future be a laboratory measurement that more accurately predicts pediatric AKI.

Cystatin C is a ubiquitous protein produced by all nucleated cells at a steady rate. It is freely filtered by the kidney with complete reabsorption and catabolism in the proximal tubule and no significant urinary excretion [101]. Thus, serum cystatin C levels are much less affected by nonrenal factors that complicate creatinine measurements, such as gender, age, body size and composition, muscle mass, and nutritional status. Several studies and a systematic review have documented the utility of cystatin C measurements for the early diagnosis as well as prognosis of AKI in adults and children [102-104]. However, serum cystatin C measurements are not uniformly available, and the test is more expensive than serum creatinine. Despite international efforts at assay standardization, there is still variability in results reported across laboratories. In addition, serum cystatin C levels can be altered by thyroid dysfunction, administration of corticosteroids, inflammatory diseases, and high cell turnover states [101].

Urinalysis — An abnormal urinalysis provides supportive diagnostic evidence for AKI. However, in patients with prerenal AKI, the urinalysis may be normal. In contrast, patients with intrinsic AKI, particularly those with glomerular disease or acute tubular necrosis, commonly will have hematuria and/or proteinuria. Thus, a normal urinalysis does not preclude the diagnosis of AKI.

Urinalysis is often helpful in identifying the underlying cause of AKI as discussed below. (See 'Urinalysis' below.)

Biomarkers of acute kidney injury — Because serum creatinine is often a delayed and imprecise test for AKI, research has focused on identifying biomarkers that accurately predict AKI in the early stages of injury. Novel biomarkers, such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin 18, fibroblast growth factor 23, insulin growth factor-binding protein 7, and tissue inhibitor of metalloproteinases 2 show promise in both their diagnostic and prognostic utility in the setting of AKI and may allow for early intervention prior to the onset of serum creatinine rise, severe metabolic derangements, and fluid overload [105-112]. However, future studies are needed to establish whether any of these markers will provide beneficial clinical guidance in the diagnosis and management of AKI in children. (See "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Overview'.)

DIFFERENTIAL DIAGNOSIS — A common differential diagnosis for AKI is the initial presentation of chronic kidney disease (CKD). The distinction between these two forms of kidney disease is based on disease duration. The disease process in patients with AKI generally resolves over days and weeks, whereas those with CKD will have persistent kidney dysfunction for months to years. As an example, children with AKI due to acute poststreptococcal glomerulonephritis (PSGN) and those with CKD due to membranoproliferative glomerulonephritis (MPGN) may both present acutely with edema, hematuria, hypertension, and hypocomplementemia. In patients with PSGN, symptoms generally resolve and the C3 level returns to normal by six to eight weeks. In contrast, those with MPGN continue to have persistent signs of nephritis and hypocomplementemia beyond two months. (See "Poststreptococcal glomerulonephritis", section on 'Differential diagnosis' and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Although the initial presentation may be similar with signs and symptoms of impaired kidney function, a number of findings may differentiate the two different types of kidney disease (table 4). For example, children with CKD may have impaired growth or a history of chronic hypertension. In addition, kidney ultrasound may be helpful as kidneys in patients with CKD are frequently small due to nephron loss or congenital hypoplasia, whereas the kidneys in patients with AKI are normal in size or enlarged (due to inflammation or edema). (See "Chronic kidney disease in children: Clinical manifestations and evaluation".)

IDENTIFYING THE UNDERLYING CAUSE — Once the diagnosis of known or suspected AKI is made, further evaluation is focused towards identifying the underlying cause.

The evaluation consists of a complete history, physical examination, and laboratory evaluation. Kidney imaging is often performed, and, rarely, a kidney biopsy is required.

History — The initial history is directed towards uncovering an obvious risk factor or cause for AKI (table 3).

The following historical findings are often indicative of an underlying etiology (table 5):

●A short duration of vomiting, diarrhea, or decreased oral intake associated with decreased urine output suggests prerenal AKI.

●A history of bloody diarrhea three to seven days prior to the onset of oliguria suggests hemolytic uremic syndrome. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

●A history of pharyngitis or impetigo a few weeks prior to the onset of gross hematuria or edema suggests poststreptococcal glomerulonephritis. (See "Poststreptococcal glomerulonephritis".)

●In hospitalized patients, nephrotoxic medications or periods of hypotension are associated with intrinsic AKI.

●Other systemic complaints (eg, fever, joint complaints, and rash) may be seen in patients with autoimmune diseases or vasculitides, such as immunoglobulin A vasculitis (Henoch-Schönlein purpura) or systemic lupus erythematous (SLE) (picture 1 and picture 2 and picture 3 and picture 4). (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

●A diligent search for all drugs and medications ingested is especially important, even when another obvious cause for AKI is evident.

Physical examination — The physical examination should include measurement of blood pressure and assessment for edema, recent weight gain, and signs of systemic disease such as rash or joint disease.

The presence of the following physical findings often points to a specific underlying etiology (table 6):

●Signs of volume depletion (eg, dry mucous membranes, tachycardia, decreased skin turgor, orthostatic falls in blood pressure, and decreased peripheral perfusion) are indicative of prerenal AKI.

●Edema may be present in children with nephrotic syndrome or glomerulonephritis. (See "Pathophysiology and etiology of edema in children", section on 'Etiology'.)

●Hypertension is a common finding in children with glomerulonephritis. (See "Glomerular disease: Evaluation in children", section on 'Clinical features' and "Epidemiology, risk factors, and etiology of hypertension in children and adolescents", section on 'Kidney disease'.)

●Rash is commonly seen in children with AKI due to IgAV (HSP), interstitial nephritis, and the acute onset of SLE. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Diagnosis' and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Clinical manifestations in children' and "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

●Enlarged palpable kidneys may be an indication of renal vein thrombosis. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Other venous thrombosis'.)

●An enlarged bladder may suggest urethral obstruction.

Assessment of fluid overload — Serial assessment of daily weights is essential, especially for critically ill children, in whom a fluid overload >10 percent above their admission weight is independently associated with increased morbidity and mortality [113]. This is especially true in children with AKI requiring kidney replacement therapy, in whom mortality increases by more than eight times with a fluid overload >20 percent [114]. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Fluid overload'.)

Laboratory and imaging evaluation — Laboratory tests and kidney imaging that may be useful in determining the underlying etiology of AKI include:

●Urinalysis

●Fractional sodium excretion to differentiate between pre- and intrinsic AKI

●Kidney ultrasound

Urinalysis — The urinalysis is often helpful in determining the underlying cause of AKI, as characteristic findings are suggestive of certain disease processes. (See "Urinalysis in the diagnosis of kidney disease".)

●Muddy brown granular casts and epithelial cell casts are highly suggestive of intrinsic AKI or acute tubular necrosis (ATN) (picture 5 and picture 6). (See "Urinalysis in the diagnosis of kidney disease" and "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

●The finding of red cell casts is diagnostic of glomerulonephritis. The concurrent finding of dysmorphic red cells and heavy proteinuria indicates an active "nephritic" urinary sediment, which is also commonly associated with glomerulonephritis (picture 7 and picture 8 and picture 9). (See "Glomerular disease: Evaluation in children", section on 'Urinalysis and urinary protein'.)

●Pyuria with white cell, granular, or waxy casts are suggestive of tubular or interstitial disease, or urinary tract infection (picture 10A-E). White cells and white cell casts may also be seen in acute glomerulonephritis.

●A positive response for heme on a urine dipstick in the absence of red blood cells in the sediment is seen in patients with hemolysis or rhabdomyolysis.

●The urinalysis in children with prerenal AKI is typically normal.

●Urine specific gravity – Loss of concentrating ability is an early and almost universal finding in ATN with a urine specific gravity below 1.010. In contrast, urine specific gravity greater than 1.020 is suggestive of prerenal disease.

Urine osmolality is a more accurate measure of concentrating ability. Patients with ATN generally have urine osmolality below 350 mosmol/kg, whereas patients with prerenal disease usually have values above 500 mosmol/kg.

Tests to distinguish between prerenal and intrinsic ATN —  (table 7)

Fractional excretion of sodium — The fractional excretion of sodium (FENa) is a commonly used laboratory test to differentiate between prerenal AKI and intrinsic disease due to ATN. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

FENa is calculated from measured concentrations of urinary sodium (UNa) and creatinine (UCr), and plasma sodium (PNa) and creatinine (PCr):

Calculators are available for FENa expressed using either standard units (calculator 2) or SI (international units) (calculator 3).

FENa is a direct measurement of the kidney handling of sodium, which is similar in children and adults. As a result, the FENa values in children that differentiate prerenal AKI from ATN are the same as those used in adults.

●A FENa below 1 percent suggests prerenal AKI, in which the reabsorption of almost all the filtered sodium represents an appropriate response to decreased perfusion

●A FENa above 2 percent suggests ATN

●A FENa between 1 and 2 percent is nondiagnostic

However, in neonates, especially preterm infants, sodium reabsorption is decreased. As a result, the FENa cutoff values differentiating prerenal AKI and ATN in neonates are higher. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Fractional excretion of sodium'.)

●In term infants, the FENa is usually below 2 percent in prerenal AKI and usually greater than 2.5 percent in ATN.

●In preterm infants, FENa cutoff values increase with decreasing gestational age, although it is unclear how helpful FENa is in differentiating between prerenal disease and ATN.

Limitations in use of FENa include:

●Previous fluid administration

●Diuretic therapy

●AKI due to contrast nephropathy or pigment nephropathy

Other tests — Other tests that have been used to distinguish between prerenal disease and ATN include:

●Serum blood urea nitrogen (BUN)/creatinine ratio is markedly elevated (>20) in patients with prerenal AKI, whereas in patients with ATN, it remains in the normal range of 10 to 15. The difference is due to the avid urea reabsorption by the proximal tubule, which is impermeable to creatinine. However, the utility of this test is limited because elevated BUN is seen in patients with increased urea production due to administration of steroids or total parenteral nutrition, tissue breakdown (catabolism), or gastrointestinal bleeding.

●The fractional excretion of urea (FEUrea) has been proposed as a more accurate determinant of prerenal AKI, especially in patients receiving diuretics [115]. Patients with prerenal AKI generally have FEUrea below 35 percent, while patients with ATN will have FEUrea >50 percent. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury", section on 'Fractional excretion of other molecules'.)

Diagnostic fluid challenge — In some cases, a fluid challenge of 10 to 20 mL/kg of normal saline may be diagnostic as well as therapeutic. This intervention may be useful in the following two clinical scenarios:

●Patients present with an increase in serum creatinine and a history and physical findings consistent with a prerenal etiology, but the duration of the prerenal insult is unknown.

●Patients present with an increase in serum creatinine, but the cause is unclear.

After administration of a fluid bolus, a reduction in BUN and serum creatinine would indicate a prerenal etiology, whereas an absence of improvement in these parameters (and/or the development of fluid overload) would suggest a diagnosis of intrinsic AKI.

Fluid challenge is contraindicated in patients with obvious volume overload or heart failure.

Additional laboratory measurements — Other laboratory studies that may be useful in determining the underlying etiology of AKI include:

●Complete blood count – Microangiopathic hemolytic anemia associated with thrombocytopenia in the setting of AKI is diagnostic for hemolytic uremic syndrome. Severe hemolysis, whether drug-induced or secondary to hemoglobinopathies, may also result in ATN due to massive hemoglobinuria. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

Eosinophilia and/or urine eosinophiluria may be present in some cases of interstitial nephritis. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

●Complement studies including C3, C4, CH50, and AH50 – Hypocomplementemia is seen in patients with poststreptococcal glomerulonephritis (PSGN), shunt nephritis, and nephritis associated with subacute bacterial endocarditis. (See "Glomerular disease: Evaluation in children", section on 'Blood tests' and "Overview and clinical assessment of the complement system".)

●Serologic testing for streptococcal infection – The presence of antistreptococcal antibodies is a diagnostic criterion for PSGN. (See "Poststreptococcal glomerulonephritis", section on 'Serology'.)

●Elevated serum levels of aminoglycosides are associated with ATN. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

●Uric acid – AKI may result from markedly elevated uric acid levels, which may occur in children with tumor lysis syndrome secondary to chemotherapy treatment of childhood leukemia or lymphoma. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Uric acid kidney diseases".)

Kidney imaging — A kidney ultrasound should be considered in all children with AKI of unclear etiology. It can document the presence of one or two kidneys, delineate kidney size, and survey the renal parenchyma. It is also particularly helpful in diagnosing urinary tract obstruction or occlusion of the major renal vessels. (See "Radiologic assessment of kidney disease".)

In addition, kidney ultrasound may be useful in differentiating AKI from chronic kidney disease (CKD). Typically, the kidneys in AKI are normal in size or enlarged (due to inflammation or edema), with increased echogenicity, whereas those in CKD are frequently small and shrunken. (See 'Differential diagnosis' above.)

Kidney biopsy — A kidney biopsy is rarely indicated in AKI, but should be considered when noninvasive evaluation fails to establish a diagnosis. In pediatric AKI, it is most commonly indicated to help guide treatment in patients with suspected acute glomerulonephritis (to identify crescentic forms or specific vasculitides), suspected interstitial nephritis, or suspected lupus nephritis (to classify the disease and establish the activity and chronicity). (See "The kidney biopsy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Acute kidney injury (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Acute kidney injury (AKI) is defined as the abrupt loss of kidney function that results in a decline in glomerular filtration rate (GFR), retention of urea and other nitrogenous waste products, and dysregulation of extracellular volume and electrolytes. (See 'Definition' above.)

●Incidence – The precise incidence and prevalence of pediatric AKI are not known, largely due to the lack of a consensus definition in published studies. However, in developed countries, the incidence of pediatric AKI is rising, primarily due to the increased use of intensive and advanced technology for children with chronic conditions or those who are critically ill. (See 'Epidemiology' above.)

●Classification and causes – The causes of pediatric AKI are most commonly classified by their anatomic location, as follows (see 'Classifications' above and 'Etiology and pathogenesis' above):

•Prerenal AKI – This is due to decreased renal perfusion and is most commonly caused by hypovolemia, or decreased effective arterial perfusion due to heart failure, sepsis, or cirrhosis (table 3). (See 'Prerenal acute kidney injury' above.)

•Intrinsic AKI – This is due to injury to the renal parenchyma and is most commonly caused by prolonged hypoperfusion, sepsis, nephrotoxins, or severe glomerular diseases (table 3). (See 'Intrinsic acute kidney injury' above.)

•Postrenal AKI – This results from anatomic obstructions to the lower urinary tract. (See 'Postrenal acute kidney injury' above.)

●Clinical presentation – Most children with AKI present with signs and symptoms due to impaired kidney function that include edema, reduce urine output, gross hematuria, and/or hypertension. Other children are identified by elevated serum creatinine as a result of ongoing monitoring in at-risk patients or as an unanticipated laboratory finding. Other laboratory findings at presentation include hyperkalemia, serum sodium abnormalities, metabolic acidosis, hypocalcemia, and hyperphosphatemia. (See 'Clinical findings' above.)

●Diagnosis – The diagnosis of pediatric AKI is made clinically based on the above signs and symptoms of kidney impairment as well as laboratory findings of kidney injury including an elevated or rising serum creatinine and/or abnormal urinalysis. (See 'Diagnosis' above.)

●Differential diagnosis – The main differential diagnosis of AKI is an acute presentation of chronic kidney disease (CKD). The two forms of kidney disease are differentiated by the duration of the disease process as well as a number of clinical findings that distinguish between the two entities (table 4). (See 'Differential diagnosis' above.)

●Identifying the cause – Further evaluation focused on identifying the underlying cause of AKI includes a complete history (table 5), physical examination (table 6), and laboratory evaluation. Kidney imaging is often performed, and, rarely, a kidney biopsy is required. (See 'Identifying the underlying cause' above.)