ACKD

Acute Kidney Injury in Children

Scott M. Sutherland and David M. Kwiatkowski

Acute kidney injury (AKI) has become one of the more common complications seen among hospitalized children. The develop-
ment of a consensus definition has helped refine the epidemiology of pediatric AKI, and we now have a far better understanding
of its incidence, risk factors, and outcomes. Strategies for diagnosing AKI have extended beyond serum creatinine, and the most
current data underscore the diagnostic importance of oliguria as well as introduce the concept of urinary biomarkers of kidney
injury. As AKI has become more widespread, we have seen that it is associated with a number of adverse consequences
including longer lengths of stay and greater mortality. Though effective treatments do not currently exist for AKI once it
develops, we hope that the diagnostic and definitional strides seen recently translate to the testing and development of
more effective interventions.
Q 2017 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Acute kidney injury, Child, Pediatrics

INTRODUCTION fied AKI definition for children which they termed the
Historically, the term acute kidney failure was used to pediatric RIFLE (pRIFLE) criteria.2 The pRIFLE staging
describe an abrupt decline in kidney function hallmarked criteria are shown in Table 1. From this point forward,
by reduced excretion of waste products, disordered elec- the pediatric and adult communities worked together to-
trolytes, and disrupted fluid homeostasis. Regrettably, ward a harmonized definition. This process culminated
this term poorly described the phenomenon of kidney in the development of the Kidney Disease Improving
injury and disease, and furthermore, it proved too vague Global Outcomes (KDIGO) classification system.3 KDIGO
a definition. Clinically, there was a lack of consensus, unified the existing definitions, creating a single diagnostic
and academically, diagnostic criteria were inconsistently standard that was applicable to both adults and children
applied. In 2004, however, the Acute Dialysis Quality (Table 1). Great strides have been made to standardize
Initiative group replaced acute kidney failure with the the definition of AKI, and it is now imperative that all
term acute kidney injury (AKI).1 This more effectively studies utilize a consensus classification system.
described the disease state, and the Acute Dialysis Quality The importance of using a single definition is exemplified
Initiative used the opportunity to create the first consensus by a pediatric study that compared the incidence of AKI in
definition for AKI which they termed the Risk, Injury, Fail- hospitalized children using the pRIFLE, AKIN, and
ure, Loss, End Stage (RIFLE) criteria.1 Though RIFLE per- KDIGO definitions.4 The incidence of AKI ranged from
tained only to adults, pediatricians have since helped 37% to 51% depending on the definition employed, and
optimize the definition of AKI across the age spectrum. interdefinitional agreement was as low as 77%. Each defi-
The development of broadly relevant AKI diagnostic stra- nition has theoretical advantages and disadvantages; how-
tegies has proved to be a tremendous boon to the ever, the need to move toward the use of a single definition
nephrology and critical care communities. Nowhere has is unambiguous. It is our opinion that the best currently
this benefit been more pronounced than in the realm of available data support the use of the KDIGO criteria to
pediatric AKI. Once plagued by a lack of data and incon- diagnose AKI in children. This was the definition used
sistent methods, the last decade has seen tremendous by the Assessment of Worldwide AKI, Renal angina, and
growth in our knowledge regarding AKI in hospitalized Epidemiology (AWARE) study, the largest and most
children. The goal of this manuscript is to describe the comprehensive epidemiologic analysis of AKI in children
current state of pediatric AKI knowledge and to highlight performed to date.5 Use of KIDGO allows the entire AKI
differences between the disease in adults and children. community to apply the same definitional rigor to their
populations and will allow more effective comparative
DEFINING ACUTE KIDNEY INJURY IN CHILDREN studies.
Following the publication of the RIFLE criteria, a group of
pediatric nephrologists and intensivists developed a modi- DIAGNOSING ACUTE KIDNEY INJURY IN CHILDREN
Creatinine
From the Division of Nephrology, Department of Pediatrics, Stanford Univer- In practice, the diagnosis of AKI is typically made based
sity, Palo Alto, CA; and Division of Cardiology, Department of Pediatrics, Stan- upon an increase in serum creatinine levels. At this point,
ford University, Palo Alto, CA. a number of studies have demonstrated that creatinine is a
Financial Disclosure: The authors declare that they have no relevant finan- functional biomarker that is insensitive to kidney tubular
cial interests. injury. Commonly, significant elevations are not apparent
Address correspondence to Scott M. Sutherland, MD, Division of
Nephrology, Department of Pediatrics, Stanford University Medical Center,
until 24-48 hours after the inciting insult.6-8 In pediatrics,
300 Pasteur Drive, Room G-306, Palo Alto, CA 94304. E-mail: suthersm@ this is further complicated by the fact that children have
stanford.edu low serum creatinine values at baseline which can be
Ó 2017 by the National Kidney Foundation, Inc. All rights reserved. exaggerated by malnutrition and fluid overload.9-11 As a
1548-5595/$36.00 result, despite substantial relative increases, elevated
https://doi.org/10.1053/j.ackd.2017.09.007 values do not register as abnormally high; creatinine can

380 Adv Chronic Kidney Dis. 2017;24(6):380-387

 Pediatric Acute Kidney Injury 381

double or triple and remain within the laboratory defined approved for use in adults, the few small pediatric studies
normal range. Despite these limitations in children, a available demonstrate that the risk score effectively pre-
relative change in serum creatinine remains the principal dicts AKI in children.19-21 Interestingly, several studies
method of diagnosing AKI. suggested that the threshold score in children is higher
(0.7-0.8 [ng/mL]2/1000) than it is in adults (0.3 [ng/mL]2/
Urine Output and Oliguria 1000).20,22 While few urinary biomarkers are
In addition to the creatinine-based AKI criteria, both pRI- commercially available and none are approved for use in
FLE and KDIGO include urine output (UOP) parameters. children, it is apparent that these assays will be a
Until recently, the vast majority of pediatric AKI studies significant part of AKI diagnostic strategies and risk
did not utilize these urinary criteria.4,12 This is likely profiling in the near future.
related to a number of pediatric-specific issues. The first
is that many pediatric intensive care unit (ICU) patients PATHOPHYSIOLOGY OF PEDIATRIC ACUTE KIDNEY
and nearly all acute care patients do not have Foley cathe- INJURY
ters in place. There has been a push to avoid bladder cath- The pathophysiology of AKI is multifactorial and incom-
eter use in hospitalized children in order to prevent pletely understood. The most frequent and best-studied
urinary tract infections; additionally, many practitioners insults, however, are hemodynamic perturbations that
are reluctant to place them in kids given the invasive na- result in kidney ischemia. The kidney modulates blood
ture of the procedure. Second, especially in small children flow via neurohormonal feedback pathways capable of
outside of the ICUs, UOP may be documented as a void regulating kidney arteriolar constriction and dilation,
count rather than volumetrically. However, the more thus maintaining relatively consistent perfusion pressure.
recently published AWARE This process, however, is
study clearly demonstrated CLINICAL SUMMARY
less effective at extremes of
that disregarding the UOP blood pressure and may be
criteria leads to an underdiag- hampered by medications

Acute kidney injury (AKI) is increasingly common in
nosis of AKI. In this study, such as vasoactive agents,
hospitalized children, and recent standardization of the
isolated use of the creatinine definition has improved our epidemiologic understanding
steroids, nonsteroidal anti-
criteria would have missed of the disease. inflammatory drugs, and
over a third of AKI cases.5 renin-angiotensin-aldoste-
Thus, despite the challenges,
AKI has traditionally been diagnosed based upon an rone system inhibitors.
oliguria remains an integral increase in serum creatinine levels; however, recent data This reduced effectiveness
demonstrate the significance of oliguria in recognizing
part of AKI diagnosis in chil- is also seen in the setting
AKI and the potential benefit of using novel urinary
dren and decreases in UOP biomarkers of kidney injury.
of proinflammatory states
should prompt evaluation of such as following cardio-
kidney function and a search
In hospitalized children, AKI has been associated with pulmonary bypass or in
for injurious events. prolonged duration of mechanical ventilation, longer patients with sepsis.23 In
lengths of stay, and greater mortality; sequelae may hospitalized children, use
include CKD.
Biomarkers of the aforementioned
As previously stated, creati-
Children with AKI who require renal replacement therapy medications is ubiquitous
nine is a marker of kidney are a unique population that tends to have a poorer and inflammatory condi-
function, not injury, and there prognosis. tions are common. Thus,
has been a push to identify bio- in pediatric inpatients, the
markers of structural injury to homeostatic feedback
facilitate earlier identification of kidney tubular damage. mechanisms aimed to preserve adequate blood pres-
While the majority of data available are from adult popula- sure may operate under maladaptive conditions. While
tions, it is helpful to understand the pediatric-specific as- this mechanism is similar in both adults and children,
pects. Neutrophil gelatinase-associated lipocalin (NGAL) there are age-related physiologic differences that bear
is one of the most extensively studied biomarkers in chil- mention. The first is nephrogenesis, the process by
dren, especially in the cardiac surgery population. NGAL which nephrons are developed, which it is not complete
may be elevated as early as 2 hours after cardiopulmonary until the 34th-36th week of gestation. Children born
bypass and has been shown to be associated with AKI earlier than this have an incomplete nephron mass
severity, duration of mechanical ventilation, and length of and are particularly susceptible to hemodynamic
ICU stay.13,14 In children with septic shock and contrast- changes. This susceptibility is enduring since the extra-
induced nephropathy, as well as those undergoing solid or- uterine environment is less conducive to nephrogenesis,
gan transplantation, NGAL has been shown to be superior and these patients will never have a full complement of
to creatinine for early detection of AKI.15-18 NephroCheck nephrons.24 The second aspect that affects pediatric AKI
(Astute Medical, San Diego, California) is a urine assay risk is the fact that glomerular filtration rate (GFR) and
that assigns a risk score derived from the product of the tubular function change over time.24,25 GFR at birth is
concentration of insulin-like growth factor-binding pro- 10-20 mL/min/1.73m 2, and while it gradually
tein-7 and tissue inhibitor of metalloproteinases-2, two in- increases, it does not reach the full adult level of
ducers of cell cycle arrest. While the test is only FDA function (100-120 mL/min/1.73m2) until 2 years of age.

Adv Chronic Kidney Dis. 2017;24(6):380-387

382 Sutherland and Kwiatkowski

Table 1. Pediatric RIFLE and KDIGO AKI Diagnostic Classification Table 2. Neonatal Modifications (Suggested) to the KDIGO AKI
Systems2,3 Classification Systems25
AKI Stage KDIGO pRIFLE* Creatinine Change
Stage 1
Increase in
eGFR decrease by AKI Stage Criteria Urine Output Criteria
creatinine 1.5-1.9 25% Stage 1
No modification to
UOP # 1 mL/kg/h for
times baseline†
UOP , 0.5 mL/kg/h thresholds, however, 24 h

Absolute increase for 8 h baseline is defined as
$ 0.3 mg/dL lowest estimated

UOP , 0.5 mL/kg/h GFR in the previous
for 6-12 h 7 days
Stage 2
Increase in
eGFR decrease by Stage 2
Same as above
UOP # 0.5 mL/kg/h
creatinine 2.0-2.9 50% for 24 h
times baseline†
UOP , 0.5 mL/kg/h Stage 3
Absolute threshold
UOP # 0.3 mL/kg/h

UOP , 0.5 mL/kg/h for 16 h
for creatinine for 24 h
for 12-24 h
decreased from
Stage 3
Increase in
eGFR decrease by 4 mg/dL to 2.5 mg/dL
creatinine $ 3.0 75%
times baseline† eGFR , 35 mL/min/ Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease
or $ 4 mg/dL 1.73m2 Improving Global Outcome; UOP, urine output.

eGFR , 35 mL/min/
UOP , 0.5 mL/kg/h
1.73m2 for 24 h or anuria for epidemiology is the recently published AWARE study,

Receipt of kidney 12 h which examined 4683 children (ages 3 month to
replacement 25 years) admitted to 32 ICUs. The overall incidence of
therapy AKI during the first week of hospitalization was 27%

UOP , 0.3 mL/kg/h and 12% of children developed severe AKI (KDIGO
for $ 24 h or anuria Stage 2/3).5 Outside of the ICU, AKI remains common; a
for 12 h retrospective single center study suggested that at least
Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease 5% of hospitalized children will experience AKI during
Improving Global Outcome; RIFLE, Risk, Injury, Failure, Loss, End their acute care stay.26 Perhaps the one area where pediat-
Stage. ric AKI has not yet been well characterized is in the ambu-
*pRIFLE stages R (risk), I (injury), and F (failure) correspond to latory setting. Several adult studies have examined
KDIGO Stages 1, 2, and 3, respectively. KDIGO eliminated pRIFLE
stages L (loss) and E (ESRD), recategorizing them as AKI outcomes. hospital and community-acquired AKI comparatively
†Baseline is most commonly described as the lowest creatinine in and while they suggest differences in incidence, risk
the prior 3 months. factors, and outcomes, several limitations limit our ability
to study this aspect of AKI in children.27,28 The largest
The reduced and dynamic nature of pediatric GFR issue is the lack of consistent baseline creatinine data.
makes assessment of kidney function challenging and Many children have never had chemistry panels
may result in inaccurate medication dosing and obtained prior to their admission; thus, their admission
consequent nephrotoxic AKI. The same is true of creatinine represents the only available value. Options
tubular function since it is not fully mature at birth. are to treat that admission creatinine as their baseline
Children are not able to reach adult levels of urinary (which may underdiagnose community-acquired AKI) or
concentration until 12 months of age.24,25 This can to extrapolate a baseline creatinine from an assumed base-
predispose to dehydration, intravascular volume line eGFR of 120 mL/min/1.73m2 (which may incorrectly
depletion, ischemia, and AKI. While these categorize patients with CKD as having AKI). Retrospec-
characteristics are unlikely to play a major role in tively, it is much easier to identify community-acquired
adolescents, they are clearly pathogenic in neonates AKI as should the creatinine trend down over the course
and infants where AKI is highly prevalent. In fact, of the admission, the lowest or discharge value can be
these differences have led neonatal focus groups to assumed to be the baseline. While all of these approaches
suggest neonatal modifications to the KDIGO are valid, it will be important for the pediatric community
definition (Table 2).25 to determine an optimal, consensus approach for much
headway to be made.
PEDIATRIC ACUTE KIDNEY INJURY INCIDENCE AND Among hospitalized children, AKI occurs at extremes of
EPIDEMIOLOGY age. One study found that the incidence of AKI increased
Before the publication of the RIFLE (2004) and pRIFLE in parallel with age, reaching its zenith in adolescents;
(2007) consensus criteria, studies utilized a variety of defi- however, approximately 20% of all AKI occurred in neo-
nitions which resulted in inconsistent descriptions of AKI nates and infants less than a month old.29 From a causative
epidemiology.1,2 Now that the majority of studies utilize standpoint, we have seen a dramatic shift. Though AKI
one of the standard definitions, the described incidence due to primary kidney disease was common historically,
is within a more confined range, although it has AKI is now due predominantly to systemic illnesses,
remained highly dependent on the population studied. multiorgan injury, and the treatments these conditions
Perhaps the most accurate assessment of pediatric AKI demand.29-31 In developed countries, the most common

Adv Chronic Kidney Dis. 2017;24(6):380-387

 Pediatric Acute Kidney Injury 383

causes of AKI are cardiopulmonary bypass, sepsis, heart port for longer than 2 days. These two studies highlight
failure, solid organ and stem cell transplantation, tumor several aspects relevant to AKI outcomes research. It is
lysis syndrome, and nephrotoxin exposure.5,30,32,33 On clear that larger studies are needed to see some effects of
the contrary, in developing countries, primary kidney AKI, and this is especially true when the AKI incidence
diseases are more prevalent with glomerulonephritis, is exceedingly high. The majority of large studies of hetero-
toxin exposure, hypovolemia, and sepsis being the most geneous populations (where AKI incidence is moderate)
common etiologies.34,35 Interestingly, there is striking have found that children who develop AKI tend to need
center variation as well. For instance, a study from a longer courses of mechanical ventilation, which is not
single US hospital found that oncologic disease was particularly surprising given the association between
responsible for 40% of AKI.36 Comparatively, a single cen- AKI and fluid overload.39
ter study from Spain found that the most common under-
lying disease was cardiac, while oncologic disease only Length of Stay
accounted for 3% of AKI.37 AKI has also been closely linked with longer ICU and hos-
pital lengths of stay (LOSs). A study by Selewski and col-
OUTCOMES IN CHILDREN WITH ACUTE KIDNEY leagues12 examined KDIGO defined AKI across 3000 ICU
INJURY hospitalizations. In this analysis, AKI was independently
associated with a 5-day longer ICU stay and a 12.5-day
Mechanical Ventilation longer hospital stay. Studies in noncritically ill children
Although the incidence of AKI varies across different pa- have demonstrated similar associations. Both children
tient populations, it remains consistently associated with with nephrotoxic AKI and those who developed AKI in
poorer outcomes in hospitalized children. A study by Mac- the setting of nephrotic syndrome experience longer LOS
Donald and colleagues found that among 66 children un- than their nonaffected counterparts.40,41 Though the data
dergoing cardiac transplantation, AKI occurred in 73% are unadjusted, a large study of ICU and non-ICU patients
and was associated with a mechanical ventilation course demonstrated that not only is AKI associated with pro-
that was 2 days longer.38 Of note, once they adjusted for co- longed LOS but that there was a stepwise association
variates, this association disappeared. A second study, such that as AKI severity increased, patients had signifi-
published in 2011, examined 311 critically ill children cantly longer LOS (Fig. 1).4
and found that AKI (incidence of 42%) was independently
associated with longer duration of mechanical ventila- Mortality
tion.6 Even after adjusting for confounders, patients with In adult patients, AKI has been independently associated
AKI were three times more likely to need mechanical sup- with higher mortality rates. This effect is distinct and

30

25
Median Length of Stay (Days)

20

15

10

0
non-ICU ICU
No AKI 4 3
Stage 1 8 6
Stage 2 12 11
Stage 3 13 28
No AKI Stage 1 Stage 2 Stage 3

Figure 1. Median length of stay in hospitalized children according to AKI severity stage. In non-ICU admissions, hospital
length of stay (LOS) increases in conjunction with AKI severity; the shortest LOS was in children without AKI (4 days), and
the longest was in children with stage 3 AKI (13 days). A similar trend is seen in ICU admissions. LOS is 3 days in children
without AKI and 28 days in children with stage 3 AKI. LOS increases significantly from stage to stage in both non-ICU and
ICU admissions (P , 0.05 when each stage is compared to the one prior across all analyses). Abbreviations: AKI, acute kidney
injury; ICU, intensive care unit.

Adv Chronic Kidney Dis. 2017;24(6):380-387

384 Sutherland and Kwiatkowski

35.0%

30.0%

Mortality (%) 25.0%

20.0%

15.0%

10.0%

5.0%

0.0%
non-ICU ICU
No AKI 0.8% 2.30%
Stage 1 0.6% 6.40%
Stage 2 0.7% 10%
Stage 3 1.0% 32.30%
No AKI Stage 1 Stage 2 Stage 3

Figure 2. Mortality rate in hospitalized children according to AKI severity stage. In non-ICU admissions, there was no differ-
ence in mortality among children with and without AKI; this was true regardless of AKI severity (P . 0.05 for all analyses). In
ICU admissions, mortality was higher in children with AKI. Mortality increased in a stepwise fashion and was higher at each
successive severity stage. The increases at Stages 3 and 1 were statistically significant when compared with the prior stage
(P , 0.05). All stages had significantly higher mortality than patients without AKI (P , 0.05). Abbreviations: AKI, acute kidney
injury; ICU, intensive care unit.

substantial. As an example, Chawla and colleagues found found that 39% of AKI survivors had a reduced GFR
that adults with AKI were two times more likely to die (,90 mL/min/1.73m2) 1-3 years after experiencing AKI.
than those who experienced myocardial infarction.42 In Menon and colleagues46 found that children who develop
children, AKI has also been independently associated nephrotoxic AKI later experience a reduced GFR 23.4% of
with death. Alkandari and colleagues43 examined over the time; 68.5% and 37.6% of children had proteinuria and
2000 PICU admissions and found that children with AKI hypertension, respectively. Hollander and colleagues47
were 4-8 times more likely to die than those without. A examined 88 children undergoing cardiac transplantation
study of children undergoing corrective cardiac surgery and found that while AKI was associated with CKD, this
also found an independent effect on survival; children was only observed in patients who did not fully recover
who developed Stage 3 AKI had an adjusted odds ratio from their initial AKI event. Interestingly, two longitudinal
for death of nearly 10.7 These findings have been corrobo- studies examining AKI following cardiopulmonary
rated by the aforementioned AWARE study in which bypass did not find an association between AKI and
KDIGO Stage 2/3 AKI was associated with higher mortal- CKD although they did find evidence of persistently
ity even after adjusting for 16 covariates.5 Although few elevated urinary biomarkers.8,48 While a signal certainly
studies have been performed, this morality effect seems
to be confined to critically ill patients, at least in children.
In one representative study, although AKI was associated Table 3. CRRT Survival Rates According to Underlying Disease51
with higher mortality in the pediatric ICU, this was not the Primary Diagnosis/Disease Survival (%)
case in patients receiving acute care (Fig. 2).4 While none of
these studies are able to prove true causation, it is clear that Liver disease/transplant 31
the accumulated data available demonstrate that critically Pulmonary disease/transplant 45
Stem cell transplant 45
ill children who develop AKI experience higher mortality.
Malignancy (not including tumor lysis) 48
Cardiac disease/transplant 51
Chronic Kidney Disease Sepsis 59
In addition to adverse short-term outcomes, a number of Ischemia/shock 68
observational studies have demonstrated that CKD is Other 71
highly prevalent in AKI survivors. Askenazi and col- Inborn error of metabolism 73
leagues44 examined 29 children 3-5 years after an AKI Kidney disease 84
event and found that 14% had developed a GFR , Tumor lysis syndrome 83
Drug intoxication 100
90 mL/min/1.73m2. Similarly, Mammen and colleagues45

Adv Chronic Kidney Dis. 2017;24(6):380-387

 Pediatric Acute Kidney Injury 385

100%

90%

80%

70%
65%

60%
55%
Survival (%)

53%
50%
43%
40%
35%

30%

20%

10%

0%
1 week 2 weeks 3 weeks 4 weeks > 4 weeks

Figure 3. Survival rates for children receiving continuous kidney replacement therapy. Among children with AKI who need
continuous renal replacement therapy (CRRT), the duration of therapy correlated inversely with survival (P , 0.05). Chil-
dren who receive CRRT for a week or less experience survival rates of 65%. Conversely, children who require CRRT for
more than 4-week experience survival rates of 35%. This likely reflects the underlying severity of illness and kidney injury.
Abbreviation: AKI, acute kidney injury.

seems present, it is possible that the relationship between transplantation (Table 3). One area where survival has
AKI and CKD is not as strong as that seen in adults due improved is among the smallest patients. While children
to the fact that children have relatively fewer weighing less than 10 kg have poorer survival than those
comorbidities that affect kidney function. weighing more than 10 kg (43% vs 64%, P ¼ 0.001), pa-
tients weighing less than 5 kg have similar survival rates
Renal Replacement Therapy to those weighing 5-10 kg (44% vs 42%, P ¼ 1.0).53
Children with AKI who require renal replacement ther- Finally, duration of CRRT correlates with survival
apy (RRT) are a subgroup that is at risk for inferior out- (Fig. 3).51 Children who only undergo therapy for a
comes. This is not surprising as RRT is an indicator of week or less have higher survival than those who
significant AKI progression, and these children are require CRRT for longer periods of time. Of note, both
likely to have the most severe kidney injuries. The hemodialysis and peritoneal dialysis (PD) can be used
need for RRT is not uncommon in children, especially in lieu of CRRT to manage severe AKI. Though many he-
among those requiring critical care. The AWARE study modynamically unstable children do not tolerate hemo-
reported that 1.5% of ICU admissions receive RRT; this dialysis, PD has become the modality of choice in many
equates to nearly 6% of children with AKI.5 In devel- developing countries due to scarcity of resources. A
oped countries, continuous renal replacement therapy number of studies have demonstrated similar survival
(CRRT) has become the mainstay for treating progres- rates with PD, and it should be considered a viable
sive AKI and its sequelae.49,50 This is due to the fact RRT modality in critically ill children with AKI.54,55
that CRRT removes fluid and solutes gradually,
allowing for more stable hemodynamics and slower TREATMENT OF ACUTE KIDNEY INJURY
fluid shifts. This is especially advantageous in A comprehensive description of treatment strategies for AKI
neonates and smaller children as well as critically ill and its sequelae is beyond the scope of this manuscript; how-
children with cardiovascular instability. In general, ever, it is important to understand the basic concepts and
pediatric CRRT outcomes have improved over the past how they pertain to children. Fundamentally, despite
20 years; general survival rates have improved from numerous studies, there are no validated medications or
40-45% to 55-60%.36,39,51,52 That said, survival is highly therapies which can reverse or mitigate AKI once it develops.
dependent on underlying disease severity and type. In children, a handful of medications (ie, aminophylline, ste-
CRRT survival is highest in children with primary roids, dexmedetomidine, fenoldopam, n-acetylcyseinine, ne-
kidney disease, metabolic disturbances, and drug siritide, etc.) have shown promise; however, controlled trials
intoxication. Survival is lowest in children with liver of these treatments have not shown consistent benefit.56-63
disease and those who have undergone stem cell Thus, nearly all available therapies are directed at

Adv Chronic Kidney Dis. 2017;24(6):380-387

386 Sutherland and Kwiatkowski

managing AKI sequelae. Examples include the use of 11. Viollet L, Gailey S, Thornton DJ, et al. Utility of cystatin C to monitor
intravenous fluids to manage intravascular volume renal function in Duchenne muscular dystrophy. Muscle Nerve.
depletion, diuretics to manage fluid overload, 2009;40:438-442.
12. Selewski DT, Cornell TT, Heung M, et al. Validation of the KDIGO
antihypertensives to manage hypertension, and alkali
acute kidney injury criteria in a pediatric critical care population.
therapy to manage acidosis. While these therapies have Intensive Care Med. 2014;40:1481-1488.
proven effective at treating their respective AKI sequelae, 13. Krawczeski CD, Goldstein SL, Woo JG, et al. Temporal relationship
none of them have demonstrated a beneficial impact on and predictive value of urinary acute kidney injury biomarkers after
patient outcomes. Given the paucity of therapeutic options, pediatric cardiopulmonary bypass. J Am Coll Cardiol. 2011;58:2301-
there has been an attempt to identify patients at risk for 2309.
AKI earlier with the goal of preventing the disease before it 14. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of
occurs. Strategies have included AKI alerts, AKI predictive acute kidney injury after cardiac surgery: a prospective study. Clin
tools (“AKI sniffers”), and identification of patients exposed J Am Soc Nephrol. 2008;3:665-673.
15. Wheeler DS, Devarajan P, Ma Q, et al. Serum neutrophil gelatinase-
to significant kidney injuries (ie, large nephrotoxin
associated lipocalin (NGAL) as a marker of acute kidney injury in
exposure).33,64-66 critically ill children with septic shock. Crit Care Med. 2008;36:1297.
16. Hirsch R, Dent C, Pfriem H, et al. NGAL is an early predictive
SUMMARY biomarker of contrast-induced nephropathy in children. Pediatr
AKI is a common complication in hospitalized children and Nephrol. 2007;22:2089.
is associated with poorer short- and long-term outcomes. 17. Mishra J, Ma Q, Kelly C, et al. Kidney NGAL is a novel early marker
Despite extensive research, there are no specific therapies of acute injury following transplantation. Pediatr Nephrol.
available to treat AKI. Thus, effective interventions are aimed 2006;21:856-863.
at early identification and prevention, and all management 18. Sirota JC, Walcher A, Faubel S, et al. Urine IL-18, NGAL, IL-8 and
strategies are largely supportive.65 However, tremendous serum IL-8 are biomarkers of acute kidney injury following liver
strides have been made over the past decade to improve transplantation. BMC Nephrol. 2013;14:17.
our ability to identify and diagnose AKI more reliably and 19. Meersch M, Schmidt C, Van Aken H, et al. Validation of cell-cycle
arrest biomarkers for acute kidney injury after pediatric cardiac sur-
consistently. It is our hope that a consensus definition and
gery. PLoS One. 2014;9:e110865.
encouraging biomarker data will promote goal-directed ther- 20. Gist KM, Goldstein SL, Wrona J, et al. Kinetics of the cell cycle arrest
apy for those at highest risk as well as facilitate studies de- biomarkers (TIMP-2*IGFBP-7) for prediction of acute kidney injury
signed to develop and validate novel therapies. in infants after cardiac surgery. Pediatr Nephrol. 2017.
21. Westhoff JH, T€ onshoff B, Waldherr S, et al. Urinary tissue inhibitor
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