Review Article

An update and review of acute kidney injury in pediatrics

Rajit K. Basu, MD; Prasad Devarajan, MD; Hector Wong, MD; Derek S. Wheeler, MD

Objectives: To inform the pediatric intensivist of recent
advancements in acute kidney injury diagnosis and manage-
ment.
Data Sources: Studies were identified from MEDLINE (OVID),
PubMed, and the Cochrane Library for topics relevant to acute
kidney injury. We also reviewed bibliographies of relevant
studies.
Data Extraction, Synthesis, and Outline Review: Because of the
lack of prospective trials, a majority of information is extracted
from observational and retrospective data. The pathophysiology
section reviews acute kidney injury mechanisms and highlights
data regarding distal injury from experimental acute kidney in-
jury. The epidemiology section focuses on incidence and out-
comes of acute kidney injury, highlighting new strategies for
diagnosis. The management section cites studies investigating
hemodynamic optimization, nutrition, and fluid management, in-
cluding the indications and impact of continuous renal replace-
ment therapy in fluid overload.
Conclusions: There is limited data-driven evidence in pediat-
rics regarding effective therapy for acute kidney injury, a signif-
icant problem in the pediatric intensive care unit extending length
of stay, ventilator days, and overall mortality. Sublethal kidney
injury may be contributing to overall morbidity. We conclude that
prospective clinical trials are needed to evaluate specific diag-
nostic aids, such as biomarkers, and therapeutic strategies, such
as early initiation of continuous renal replacement therapy in
children with fluid overload. (Pediatr Crit Care Med 2011; 12:
339 –347)
KEY WORDS: acute kidney injury; children; intensive care; epi-
demiology; pathophysiology; management; renal replacement
therapy

A cute kidney injury (AKI) is in-
creasingly recognized as a
cause of increased morbidity in
critically ill children and
adults, and damage to the kidney, a cen-
tral mediator of homeostasis in the body,
affects patient survival (1– 4). AKI is now
known to be an independent risk factor
for mortality, and research pursues opti-
mization of diagnosis, management, and
outcome (5). The list of putative causes of
AKI in pediatrics is long (6) (Table 1);
however, the true etiology is likely mul-
tifactorial, related to a combination of
several factors, such as ischemia and rep-
erfusion injury, disruption of renal vaso-
motor homeostasis, hypoxic and oxida-
tive stress, and cytokine-driven effects.
The kidney is central to numerous real-
time homeostatic control mechanisms,
including water balance, electrolyte han-
From the Divisions of Critical Care (RKB, HW, DSW)
and Nephrology (PD), Department of Pediatrics, Cin-
cinnati Children’s Hospital and Medical Center, Univer-
sity of Cincinnati, Cincinnati, OH.
The authors have not disclosed any potential con-
flicts of interest.
For information regarding this article, E-mail:
rajit.basu@cchmc.org
Copyright © 2011 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/PCC.0b013e3181fe2e0b
dling, erythropoiesis, vascular tone, acid–
base status, and regulation of normal glu-
cose metabolism; however, AKI diagnosis
is based on downstream readouts. The
laboratory indicator, decreased glomeru-
lar filtration rate, factors in urine and
plasma solute concentration and is the
accepted reflection of nephron function.
Calculations of glomerular filtration rate
(Table 2) rely on serum creatinine and
are often unreliable because of variability
within age groups, gender, metabolic
state, body composition, and excretion by
the kidney itself (7–9). Definitions of ol-
iguria, the bedside indicator for AKI di-
agnosis, also are varied. Although clini-
cians have shown that sick kidneys affect
morbidity independently and synergisti-
cally with multi-organ disease, study of
the impact of kidney injury is limited by
having to use these markers of failure.
Also unfortunate is the mirrored variabil-
ity between diagnosis and treatment,
which is largely reactive and can differ
from patient to patient (10, 11).
AKI represents a serious burden to the
pediatric patient population (12). We fo-
cus this narrative review on evidence-
based AKI research, highlighting disturb-
ing epidemiologic trends for pediatric
AKI, novel detection strategies, the role
of AKI as an independent causative agent
of injury, and available evidence-based
data regarding management and out-
comes. Much further research in basic
science and in prospective trials is needed
to improve outcome for pediatric patients
with this significant affliction.
METHODS
An electronic search was performed in Jan-
uary 2010 using the PubMed, Ovid, MEDLINE,
and Cochrane databases for the following
search terms: acute kidney injury, renal isch-
emia, pediatrics, RIFLE (risk, injury, failure,
loss, end stage), Acute Kidney Injury Network,
epidemiology, renal replacement therapy, and
outcomes. Inclusion criteria were adult and
pediatric articles from 2000 to 2010 in the
English language. All retrospective pediatric
AKI studies performed from 2000 to 2010 were
included. Additionally, heavily cited articles
within our search results were considered for
inclusion.
Etiology of AKI
Traditional AKI causes are stratified into
location of injury relative to the kidney. The
diseases that fit into “pre-renal” and “intrinsic
renal” share the commonality that they alter
the regional perfusion of, and subsequent ox-
ygen delivery to, the kidney. “Post-renal” in-
jury refers to antegrade urine flow disruption
from the kidney. The pathophysiology of AKI
in the intensive care unit, however, is much
more complex and multifactorial.

Pediatr Crit Care Med 2011 Vol. 12, No. 3 339

Table 1. Common classifications and etiologies for pediatric acute kidney injury (6)
Classification Etiology
Prerenal Intravascular volume depletion
Intrinsic renal Acute tubular necrosis (vasomotor nephropathy)
Hypoxic-ischemic insults
Sepsis/toxin-mediated: endogenous and exogenous
Multiple organ dysfunction syndrome-driven
Interstitial nephritis: drug-induced and idiopathic
Tumor lysis syndrome (uric acid nephropathy)
Glomerulonephritis
Vascular thrombosis
Cortical necrosis
Hemolytic uremic syndrome
Cortical dysplasia or hypoplasia
Postrenal Obstructive uropathy: ureteral or urethral obstruction
Solitary kidney obstruction
Table 2. Formulas for calculation of glomerular filtration rate
Eq Formula Notes
Eq 1: Cockcroft-Gault (⬎7) GFR ⫽ [fr](140 ⫺ age) ⫻ Denominator: (0.85 ⫻ SCr in
weight(fd)0.8 ⫻ SCr females); weight in kilograms
Eq 2: Modified diet in renal GFR ⫽ 186.3 ⫻ SCr⫺1.154 ⫻
disease (9) age⫺0.203 ⫻ 1.212 (if African-
American) ⫻ 0.742 (if female)
Eq 3: Schwartz formula GFR ⫽ (k ⫻ height)/SCr k ⫽ 0.413
(for children) (8)
Eq, equation; GFR, glomerular filtration rate; SCr, serum creatinine.
Table 3. Extrinsic and intrinsic responses to clamp times during cardiopulmonary bypass
altered renal perfusion (13) (CPB) (15, 16). Direct effects on renal blood
flow in the microvasculature of the vasa recta
Response occur in sickle cell disease, rhabdomyolysis,
Extrinsic
hemolytic uremic syndrome, and tumor lysis
Juxtaglomerular apparatus stimulation
Arteriolar smooth muscle vasoconstriction syndrome.
Mesangial cell retraction Vasomotor Nephropathy. AKI occurs by
Sympathoadrenal activation stress-mediated glomerular endothelial re-
Efferent arteriolar vasoconstriction lease of vasoactive substances, proteases, reac-
Renin-angiotensin-aldosterone axis activation tive oxygen species, and nitric oxide. For ex-
Angiotensin II activation ample, the factor XII plasma contact system,
Arteriolar vasoconstriction
coagulation cascades, and complement path-
Aldosterone release
ways are activated in renal endothelium dur-
Prostaglandin formation
Phospholipase-A2 formation ing CPB (17, 18).
Renal venodilation Sepsis and AKI. Sepsis causes AKI in up to
Atrial natriuretic peptide stimulation 50% of cases (19, 20). Although the precise
Renal arterial vasodilation mechanism remains unclear, a gamut of cyto-
Intrinsic kines is implicated, as are circulating lympho-
Renal myocyte stimulation cytes, T cells, and native kidney tubular epi-
Arteriolar vasodilation thelial and endothelial cells. Interestingly,
Tubular epithelial cell stimulation
septic AKI does not appear to be ischemia-
Angiotensin inhibition
dependent, because it can occur in hyperdy-
namic renal blood flow (21).
Aberrant Oxygen Homeostasis. A natural
Altered Renal Perfusion. The kidneys re- degradation in oxygen tension exists from the
ceive a high percentage (20% to 25%) of the level of the renal artery to the counter-current
cardiac output at any moment. Aberrations in mechanism in the vasa recta (Fig.), making
the intricate regulatory mechanism in place to the kidney highly susceptible to both hy-
maintain renal perfusion pressure (Table 3) poxic and oxidative injury during ischemia-
lead to injury such as acute tubular necrosis reperfusion (22). Experimental ischemia
(13). Pediatric kidney transplant recipients of leads to renal dysoxia, a situation also seen
organs with increased ischemic times during in sepsis, in which renal cells are unable to
harvest have increased rates of acute tubular utilize oxygen for energy, regardless of oxy-
necrosis (14), as do patients with long cross- gen availability (23).
340
Nephrotoxins and AKI. Nephrotoxic medi-
cations in the intensive care unit contribute to
nearly 25% of AKI cases (3, 4). Common of-
fenders include aminoglycoside antibiotics,
nonsteroidal anti-inflammatory agents, radio-
opaque contrast, and immunosuppressives
such as calcineurin inhibitors (24, 25).
Associated Syndromes. AKI is seen in con-
junction with pulmonary, hepatic, and cardiac
failure (26, 27). The increased mortality re-
ported with these dual-axis syndromes under-
scores the kidney’s centrality to host survival.
Although exact mechanisms are unknown,
they all are almost certainly linked to aberra-
tions in blood flow distribution and to endo-
thelial activation (28 –30).
Isolated AKI. In complex cases, isolated
renal injury is difficult, if not impossible, to
identify and without concomitant fluid over-
load or electrolyte mishandling it is not felt
to be significant. However, laboratory evi-
dence shows that isolated AKI affects remote
organ homeostasis and host morbidity. A
wide set of regulatory genes and inflamma-
tory mediators are altered during isolated
renal ischemia and can lead to increased
pulmonary capillary permeability (31, 32),
decreased active fluid transport out of alve-
oli (33), and T-cell trafficking in rats (34).
Left ventricular systolic performance is re-
duced (35) and blood– brain barrier perme-
ability increases after renal ischemia (36). In
these experiments, distal changes were
found before any overt signs of renal injury,
highlighting a renal “distress” state during
which a host may be primed to further in-
jury. Further work aims to identify a phe-
notype to this distress state, its downstream
ramifications, and whether it is reversible.
Epidemiology of AKI in the
Intensive Care Unit
Diagnosis. A review of nearly 30 studies
conducted over 25 yrs showed that no two
studies used the same criteria to define AKI
(37). To amend this variability, the Acute Di-
alysis Quality Initiative group standardized the
definition of AKI in 2002 using the RIFLE
criteria, a mnemonic for three levels of sever-
ity, risk, injury, and failure, and two out-
comes, loss and end-stage kidney disease (38).
Based on glomerular filtration rate, serum
creatinine values, and urine output plotted
against time of admission, RIFLE marks pro-
gressive degrees of injury in both intensive
care unit and non-intensive care unit adult
patients. In 2004, the Acute Kidney Injury
Network devised strata that defined AKI based
on time in relation to absolute creatinine in-
crease, percentage increase, or documented
oliguria, broadening the window for time of
AKI diagnosis and creating an automatic “fail-
ure” designation for any patient administered
renal replacement therapy (39). Although
Acute Kidney Injury Network criteria have
shown close approximations to RIFLE strati-
fications of patients (40, 41), both schemes
Pediatr Crit Care Med 2011 Vol. 12, No. 3
equate specific changes in serum creatinine to of AKI, up to 67% for intensive care patients, 82% (Table 5), with a recent study finding an
specific worsening of oliguria, an assumption which increases mortality in sepsis, trauma, incidence of 339 of 3,396 (⬇10%) patients
yet to be prospectively proven. burn, transplantation, and acute respiratory admitted to the pediatric intensive care unit
Incidence and Outcome. Within the new distress syndrome, is an independent risk fac- (48). Using a modification of the RIFLE crite-
strata (Table 4), it is clear that the incidence of tor for mortality (with odds ratios as high as ria (pediatric RIFLE), approximately 50% of
AKI is considerable in adults and children and 4.8), and independently increases hospital pediatric patients studied had some degree of
outcomes can be severe. Increases in RIFLE costs, length of stay, and ventilator days. The kidney injury early in their hospital stay
and Acute Kidney Injury Network criteria cor- incidence of AKI after CPB in adults ranges (mean time to pediatric RIFLE stratum, 3.3 ⫾
relate with increased morbidity. from 30% to 50% and increases mortality to 3.1 days; 82% diagnosed within 7 days) (49). In
Adults. Before the validation of the new nearly 80% in some reports (45, 46). AKI also a study of nearly 4,000 critically ill children,
classification schemes, reported incidence in leads to end-stage renal disease in a significant AKI increased mortality and lengthened inten-
adults varied from 7% to 25% (42, 43). Hoste portion of adults (47). sive care stay four-fold (48). AKI increases
et al (44) now report that 18% to 63% of all Pediatrics. The reported incidence of AKI mortality with multi-organ failure, marrow or
adult hospitalized patients have some degree in pediatric populations varies from 1% to solid organ transplantation, extracorporeal
membrane oxygenation, or acute respiratory
distress syndrome from 10% to 57.1% (12,
50 –51). AKI has a high risk of death indepen-
dent of Pediatric Risk of Mortality II scores in
these patients (49). AKI affects between 2.7%
and 28% of children after CPB and has a
notable increased morbidity risk, including
longer duration of ventilation and overall
length of stay (52, 53). For these children,
even a small creatinine increase of ⱖ25% is a
high risk factor for AKI (54). Finally, at 3- to
5-yr follow-up, 40% to 50% of pediatric pa-
tients who had AKI show signs of chronic
renal insufficiency, indicating that sublethal
injury permanently alters the renal bed (55).
Biomarkers. RIFLE, pediatric RIFLE, and
Acute Kidney Injury Network criteria have lim-
ited real-time/pre-injury utility because they rely
on creatinine and urine output. Accordingly, the
search is on for a real-time markers of AKI that
would allow for rapid and reliable diagnosis, the-
oretically providing a therapeutic advantage to
intensivists akin to troponins in myocardial in-
farction (56). Many candidate biomarkers of AKI
have been identified (Table 6) (57, 58). Serum
cystatin C levels show high correlation to estab-
Figure 1. Degradation in oxygen tension through renal cortex and medulla (22). The cortex has an lished AKI and are used by some urologists as a
ample blood supply and is generally well-oxygenated. The medullary ray areas are devoid of glomeruli marker of disease progression after kidney trans-
and are supplied by venous blood ascending from the medulla. The medulla has a low blood supply and plantation (59). Kidney injury molecule-1, inter-
is poorly oxygenated but is responsible for concentration of the urine. Medullary hypoxia results from leukin-18, and liver fatty acid-binding protein
the countercurrent exchange of oxygen within the vasa recta and from the consumption of oxygen by have been shown to be associated with kidney
the medullary thick ascending limbs. Renal medullary hypoxia is an obligatory part of the process of ischemia (60, 61). Clinical studies indicate urine
urinary concentration. Reproduced with permission from Brezis and Rosen (22). and serum neutrophil gelatinase-associated li-

Table 4. Current criteria used for diagnosis of acute kidney injury

Scheme Stage Creatinine Criteria Urine Output Criteria

RIFLE (38) R 1 ⱖ1.5⫻ or 2 glomerular filtration rate ⱖ25% ⬍0.5 mL/kg/hr for 6 hrs
I 1 ⱖ2⫻ or 2 glomerular filtration rate ⱖ50% ⬍0.5 mL/kg/hr for 12 hrs
F 1 ⱖ3⫻ or serum creatinine ⬎350 ␮mol/L ⬍0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs
L Persistent failure ⬎4 wks
E Persistent failure ⬎3 mos
Pediatric RIFLE (49) R eCCl 2 ⱖ25% ⬍0.5 mL/kg/hr for 8 hrs
I eCCl 2 ⱖ50% ⬍0.5 mL/kg/hr for 16 hrs
F eCCl 2 ⱖ75% or eCCl ⬍35 mL/min/1.73m2 ⬍0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs
L Persistent failure ⬎4 wks
E Persistent failure ⬎3 mos
AKIN (39) 1 1 ⱖ0.3 mg/dL or 1 to 150%–200% baseline ⬍0.5 mL/kg/hr for 6 hrs
2 1 to 200%–300% baseline ⬍0.5 mL/kg/hr for 12 hrs
3 1 to ⱖ300% baseline or ⱖ4.0 mg/dL ⬍0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs
with an acute 1 of 0.5 mg/dL

RIFLE, risk, injury, failure, loss, end stage; AKIN, Acute Kidney Injury Network; eCCl, estimated creatinine clearance.

Pediatr Crit Care Med 2011 Vol. 12, No. 3 341

Table 5. Incidence of pediatric acute kidney injury in the past 20 yrs

Renal
Mean Replacement
Authors Year Population n Age (yrs) AKI Criteria Incidence (%) Therapy (%) Mortality (%)

Giuffre et al (105) 1992 After CPB 2782 44 (1.6%) 40 (1.4%) 27 (61.4%)

Kist-van Holthe tot 2001 After CPB 1075 关Cr兴 doubling 180 (17%) 25 (2.3%)
Echten et al (106)
Michael et al (83) 2004 Stem cell 272 13 ⫾ 5 Diagnosis made by 26 (9.6%) 14 (5.1%) 10 (38.5%)
attending
nephrologist
(glomerular
filtration rate)
Agras et al (107) 2004 Neonatal intensive 45 关Cr兴 ⬎1.5 mg/dL 31% in preterm 24.4%
care unit
Plötz et al (108) 2005 Septic shock 22 4.0 Continuous renal 7 (31.8%) 4 (57.1%)
replacement
therapy
requirement
Skippen and 2005 After CPB 101 关Cr兴 doubling 11 (11%)
Krahn (52)
Mishra et al (109) 2005 After CPB 71 2.1 关Cr兴 doubling 20 (28%)
Mathur et al (110) 2006 Neonatal intensive 200 Serum blood urea 52 (26%) 70.2%
care unit nitrogen ⬎20
mg/dL
Akcan-Arikan 2007 Intubated PICU 150 6.4 ⫾ 6.4 pRIFLE 123 (82%) 11 (8.9%) 18 (14.6%)
et al (49)
Bailey et al (111) 2007 PICU 985 6.0 ⫾ 5.7 关Cr兴 doubling 44 (4.5%) 7 (0.7%) 12 (27.3%)
Dent et al (112) 2007 After CPB 120 4.9 ⫾ 0.7 关Cr兴 doubling 45 (37%)
Kendirli et al (113) 2007 PICU 332 9.6 ⫾ 7.4 Continuous renal 21 (6.3%) 14 (66.7%)
replacement
therapy
requirement
Bennett et al (62) 2008 After CPB 198 4.8 ⫾ 0.5 关Cr兴 doubling 99 (51%)
Plötz et al (114) 2008 Intubated PICU 103 6.1 ⫾ 5.5 pRIFLE 60 (58%) 6 (6%) 17 (17%)
Nguyen et al (115) 2008 After CPB 106 4.3 ⫾ 5.5 关Cr兴 doubling 32 (30.2%)
Palmieri et al (116) 2009 Burn 123 pRIFLE 56 (45.5%) 5 (8.9%)
Zappitelli et al (54) 2009 After CPB 390 2.8 ⫾ 4.7 pRIFLE 140 (35.9%)
Schneider et al (48) 2010 PICU 3396 4.3–7.5 RIFLE 339 (10%) 30%–32%
mos
Askenazi et al (51) 2010 Nonsurvivor neonates 2175 0–30 关Cr兴 ⬎1.5 mg/dL 19% vs 3.9% without
administered days acute kidney injury
extracorporeal
membrane
oxygenation
Askenazi et al (51) 2010 Nonsurvivor children 1962 关Cr兴 ⬎1.5 mg/dL 32.3% vs. 12% without
administered acute kidney injury
extracorporeal
membrane
oxygenation

AKI, acute kidney injury; CPB, cardiopulmonary bypass; PICU, pediatric intensive care unit; 关Cr兴, serum creatinine; RIFLE, risk, injury, failure, loss,
end stage; pRIFLE, pediatric RIFLE staging criteria.
Reported incidence of acute kidney injury in select pediatric studies.

pocalin as highly sensitive, specific, and predic-
tive of AKI in many different disease processes
(62, 63). A recent meta-analysis demonstrated
high neutrophil gelatinase-associated li-
pocalin sensitivity in AKI for a value of se-
rum neutrophil gelatinase-associated lipoca-
lin ⬎150 ng/mL (64). In pediatrics,
neutrophil gelatinase-associated lipocalin
has been studied after CPB, after nephro-
toxin administration and contrast nephrop-
athy, in sepsis, and in cardiorenal syndrome.
Urine neutrophil gelatinase-associated li-
pocalin concentrations ⬎50 ␮g/mL predict
AKI in children after CPB with high sensi-
tivity and specificity (62).
Diagnostic Adjuncts. Other real-time mo-
dalities are being tested for AKI diagnosis. Min-
ute-to-minute variations in somatic near-
infrared spectroscopy numbers may be
correlative with low perfusion states, including
pediatric emergency department patients with
hypovolemia (65, 66). Imaging modalities such
as blood oxygen level-dependent magnetic reso-
nance imaging have been used in adults to de-
termine changes in renal parenchymal oxygen-
ation (67). Adult urine PO2 levels, assumed to
mirror changes in renal oxygenation, have been
correlated to AKI (68).
AKI is clearly a major contributor to over-
all morbidity and mortality in hospitalized pa-
tients. Although stratification strata continue to
advance as epidemiologic tools, biomarker re-
search seeks to deliver intensivists real-time and
sensitive tests of even subtle kidney injury, in-
jury that may have more consequences than
simply signaling the kidney’s own death knell.

342 Pediatr Crit Care Med 2011 Vol. 12, No. 3

Table 6. Quality biomarkers currently undergoing study for acute kidney injury (58)

Etiology Established Acute Kidney Injury Early Detection Prediction of Severity

Cardiopulmonary bypass Serum cystatin C Serum/urine NGAL, urine interleukin-18

Intensive care unit Serum cystatin C Urine NGAL, serum cystatin C Serum cystatin C
Nephrotoxin Urine NGAL
Pediatric cardiopulmonary bypass Urine NGAL, kidney injury Urine NGAL, interleukin-18
molecule-1, L-FABP
Pediatric intensive care unit Urine NGAL Urine interleukin-18, cystatin C
Hemolytic uremic syndrome Urine NGAL

NGAL, neutrophil gelatinase-associated lipocalin.

High-performing biomarkers for acute kidney injury based on performance in high-quality individual trials in which outcome measure was either
sensitivity or specificity of the test (⬎0.75), area under the receiver-operating characteristic curve (⬎0.75), or likelihood ratio (⬎2). Adapted with
permission from Parikh et al (58).

Management
Development of management parameters
in AKI is limited by the multifactorial etiology
of the disease process and by the paucity of
prospectively validated data. Thus, although
universally based on limiting future injury,
patient management is quite heterogeneous.
Maintaining Renal Perfusion. To limit
ischemic injury, attempts are made to modu-
late renal perfusion pressure and to optimize
renal preload. The use of renal vasodilators to
increase renal perfusion has not demonstrated
improved outcomes. Adult studies of low-dose,
or “renal-dose,” dopamine have failed to show
benefit and actually may even be harmful (69,
70). Low-dose dopamine in children has not
been effective at improving outcomes either
(6, 71). Fenoldopam, a selective dopamine ag-
onist, increases renal blood flow and may re-
duce mortality and the need for renal replace-
ment therapy (RRT) in adults (72) but has not
significantly improved AKI outcomes in chil-
dren (73, 74).
No consensus exists regarding the appro-
priate balance of fluids, diuresis, and dialysis
to use in AKI. In response to hypoperfusion,
many patients may receive total fluid doses to
reach central venous pressure and mean arte-
rial pressure targets that result in total body
water overload (75, 76). Intravenous fluids are
medicines prescribed and administered like all
other drugs, and warning signs of “overdose”
should be heeded before every dose. A study of
⬎3,000 adult patients revealed a link between
positive fluid balance and mortality in AKI
(77). The Prospective Pediatric Continuous
Renal Replacement Therapy Registry Group
(Prospective Pediatric CRRT), studying a sam-
ple of 116 children, retrospectively found in-
creased fluid administration to be indepen-
dently associated with mortality in children
started on CRRT (78).
Crystalloid or Colloid Infusions. In the
adult population, studies have compared albu-
min to saline (SAFE study [79]) and hydroxy-
ethyl starches to saline (SOAP study [80]) for
resuscitation. Neither demonstrated clear
benefit in colloid over crystalloid infusions.
There was no survival difference in ⬎7,000
patients between recipients of albumin or sa-
line (SAFE). Conflicting correlations between
AKI and the use of starches for resuscitation
during sepsis have been reported. There have
been no published studies relating type of fluid
used in pediatric resuscitation and AKI inci-
dence or outcomes.
Diuretics. Reducing fluid overload with di-
uresis can limit the use of renal replacement
therapy but has not been proven to improve
outcomes of AKI.
Adults. The use of diuretics in adults with
AKI has been associated with an increased risk
of death and has shown no benefit in recovery
of kidney function (81, 82). There is also no
evidence of a mortality benefit in using diuret-
ics to convert oliguric AKI into nonoliguric
AKI. Several trials involving recombinant
atrial natriuretic peptide have shown conflict-
ing results.
Pediatrics. Data regarding augmentation
of urine output in pediatric AKI using diuret-
ics are limited to bone marrow transplantation
and after bypass (74, 83). The use of natri-
uretic peptides has been attempted in patients
with AKI and cardiorenal syndrome (84).
Brain natriuretic peptide (nesiritide), de-
scribed in children with decompensated heart
failure, increases diuresis but its effect on iso-
lated AKI is not known (85).
Continuous RRT. Other than emergent di-
alytic therapy for electrolyte disturbance or
ingested toxins, controversies abound with re-
gard to the proper timing of initiation, dose,
route, and duration of continuous RRT
(CRRT) in AKI. Prospective adult data based
on blood urea nitrogen value cutoffs are het-
erogeneous for timing of initiation and out-
come. The mortality for adults started on
CRRT is nearly 60% in some studies (86 – 88).
In pediatrics, the percent fluid overload has been
used as an initiating trigger and is calculated as
follows: fluid overload ⫽ [(⌺ fluidIN ⫺ ⌺ fluid-
OUT)/admission weight] ⫻ 100.
Retrospective study of 21 children receiving
CRRT for AKI suggested that the degree of fluid
overload at time of CRRT initiation was signifi-
cantly lower in survivors than in nonsurvivors
(16.4% vs. 34%) (89). In a larger study of 113
children with multiple organ dysfunction syn-
drome started on CRRT, median percent fluid
overload was significantly lower in survivors
compared to nonsurvivors (7.8% vs. 15.1%), in-
dependent of severity of illness (90). Even more
recently, in 297 patients, percent fluid overload
was again significantly lower in survivors vs.
nonsurvivors (12.5% vs. 23.0%) (91). DiCarlo
(92) initiated CRRT for ten children with acute
respiratory distress syndrome after bone marrow
transplantation regardless of presence of AKI in
a prospective observational study, with an 80%
survival rate. The mortality for children started
on CRRT is 10% to 57.1% (Table 7). Although
Prospective Pediatric CRRT data suggest that
10% to 15% fluid overload is the signal for CRRT
or peritoneal dialysis initiation, this has yet to be
prospectively proven. Further, it has yet to be
demonstrated that children administered CRRT
for AKI have better outcomes than those without
such therapy.
RRT Dose and Modality. A large recent
study with meticulous documentation of ac-
tual doses received demonstrated no improve-
ment in kidney function or mortality outcome
in adults receiving high-intensity CRRT (35
mL/kg/hr) vs. low-intensity CRRT (20 mL/kg/
hr) or intermittent hemodialysis (87). The few
outcomes studies performed in pediatrics in-
vestigating the effects of RRT dosage and mo-
dality are retrospective. The Prospective Pedi-
atric CRRT in 2007 demonstrated no
difference in overall outcomes based on mo-
dality or dose of CRRT used (93). Although
another study showed some improvement in
outcome using convective CRRT modes for
bone marrow transplantation patients, many
centers only offer one mode of CRRT delivery,
and thus study applicability is limited.
Peritoneal Dialysis. Peritoneal dialysis can
be efficacious in fluid overload and offers ad-
vantages for younger children, including sim-
plicity, less invasiveness, and improved hemo-
dynamic tolerance (94). Peritoneal dialysis is
generally safe and effective in children after
CPB, with some investigators utilizing it as a
prophylactic therapy as well (95).
CRRT for Immunomodulation. CRRT has
been used in septic adults with the intention of
altering levels of circulating cytokines and in-
flammatory mediators (96, 97). Modifications of

Pediatr Crit Care Med 2011 Vol. 12, No. 3 343

Table 7. Mortality in pediatric renal replacement therapy since 2000

Mean
Authors Year n Age (yrs) Notable Etiologies Mortality Conclusions

Bunchman et al (117) 2001 226 6.2 ⫾ 0.9 CV shock 47 (20.8%) 104 (46%) Pressor requirement is significant
BMT 26 (11.5%)
Goldstein et al (89) 2001 21 8.8 ⫾ 6.3 Sepsis 11 (52.3%) 12 (57.1%) 16.4% FO in survivors vs. 34% in
nonsurvivors
CV shock 4 (19%)
Flynn et al (118) 2002 63 CV shock 27 (42.9%) 31 (49%) Peritoneal dialysis use can be effective
Sepsis 10 (15.9%)
DiCarlo et al (92) 2003 10 10.7 All patients had acute 1 (10%) Early initiation in BMT ⫹ acute respiratory
respiratory distress distress syndrome aids survival
syndrome
Foland et al (90) 2004 113 9.6 Orthotopic heart 44 (39%) 7.8% FO in survivors vs. 15.5% in
transplantation 18 nonsurvivors
(15.9%)
BMT 16 (14.2%)
Gillespie et al (119) 2004 77 5.1 ⫾ 5.7 ⬎10% FO has 3.02⫻ mortality risk than
⬍10% FO
Goldstein et al (78) 2005 116 8.5 ⫾ 6.8 Sepsis 47 (39.2%) 56 (48.3%) Greater fluid overload and central venous
pressure worsen outcome
CV shock 24 (20%)
Fernández et al (120) 2005 53 CV shock 22 (41.5%) 17 (32.1%) Prognosis depends on hemodynamics
Sepsis 8 (15.4%)
Hui-Stickle et al (1) 2005 77 5.5 ⫾ 6.7 31 (41.3%)
Flores et al (93) 2008 51 11.2 Only BMT patients 28 (55%) Ventilation and airway pressure worsen
(51/370) outcome
Hayes et al (121) 2009 76 5.8 BMT 12 (15.8%) 34 (44.7%) 7.3% FO in survivors vs. 22.3% in
nonsurvivors
Sepsis 9 (11.8%)
Sutherland et al (91) 2010 297 8.5 ⫾ 7.0 Sepsis 95 (32%) 128 (43.1%) 12.5% FO in survivors vs. 23.0% in
nonsurvivors
Oncologic 71 (23.9%)
Askenazi et al (51) 2010 2175 0–30 Neonates 863 (39.7%) Nonsurvivors (39.7%) received more
days administered continuous renal replacement therapy
extracorporeal than survivors (16.0%)
membrane
oxygenation who
died
Askenazi et al (51) 2010 816 Children 487 (58.9%) Nonsurvivors (58.9%) received more
administered continuous renal replacement therapy
extracorporeal than survivors (30.8%)
membrane
oxygenation who
died

CV, cardiogenic; BMT, bone marrow transplantation; FO, fluid overload at time of initiation.
Reported mortality in renal replacement therapy in select pediatric studies.

CRRT have not improved outcomes for such
patients. To date, literature does not support the
use of CRRT for sepsis without AKI.
In summary, few prospectively validated
data exist regarding the effect of CRRT on
outcomes. Although some data suggest that
early and aggressive CRRT initiation may be
beneficial in children with fluid overload, the
questions that need to be objectively addressed
are the definitions of “early” and “aggressive.”
We as practitioners must continually weigh
the inherent risks associated with initiating
RRT, including placement of large venous
catheters and creating significant hemody-
namic and thermal shifts in children with
unstable conditions, against the possible ben-
efits, which, to this point, have been only
retrospectively demonstrated.
Oxidative and Inflammatory Homeostasis.
The kidney has derangements in oxygen ho-
meostasis during AKI. Although prospective
study of CPB patients demonstrated that ane-
mia is independently associated with AKI, the
risks of increased volume and blood viscosity
must be balanced against the presumed bene-
fit of increased oxygen-carrying capacity.
Studies of N-acetylcysteine and dexametha-
sone therapies to limit oxidative and inflam-
matory damage in AKI after CPB showed con-
flicting results (98 –101). The use of
nephrotoxins such as aminoglycoside antimi-
crobials, nonsteroidal anti-inflammatory
drugs, radiocontrast media, antifungal agents,
and immunosuppressive drugs are associated
with high rates of AKI and must be diligently
constrained (102).
Nutritional Support. Nutrition in adult
AKI is important and minding macronutrient
and micronutrient requirements is vital to
outcome (50). Optimizing nutrition in pediat-
ric AKI patients can be challenging, and
Bunchman (10) recommends using a meta-
bolic cart to determine the amount of nutri-
tion necessary. CRRT may reduce fluid con-
cerns when optimal nutrition, using
renoprotective and anabolic formulas, is de-
sired. Recent large, prospective, randomized,
control trials suggest that tight glucose con-
trol increases overall mortality and also show
no difference in the number of adult patients
requiring RRT based on glycemic control
strategy (103). A prospective pediatric study
demonstrated morbidity improvements in
children receiving intensive insulin therapy,

344 Pediatr Crit Care Med 2011 Vol. 12, No. 3

but no effects on outcomes with AKI or dial-
ysis were seen (104).
CONCLUSIONS
The management of AKI in pediatrics
is complex and challenging. Our under-
standing and ability to detect renal dis-
tress and its possible autocrine and endo-
crine effects are in their infancy.
Biomarkers may improve our manage-
ment if early detection actually affects
outcomes. To date, therapy of AKI re-
volves around optimizing renal perfusion
pressure and oxygenation through a com-
bination of judicious fluid prescription,
inotropy, and RRT while attending to
proper nutrition and avoidance of addi-
tional nephrotoxins. However, pediatric
intensivists have limited consensus or
best-practice parameters to follow, as lit-
tle prospective evidence is available. Kid-
ney injury is likely incremental, more
temporally proximal than fluid overload
and anuric failure, and likely causes more
significant distal harm than previously
appreciated. The impact of AKI on criti-
cally ill children is significant and de-
mands prospective study if we are to find
effective therapies and improve out-
comes.
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