Pediatric Nephrology (2022) 37:2037–2052

https://doi.org/10.1007/s00467-021-05346-8

EDUCATIONAL REVIEW

Acute kidney injury in pediatrics: an overview focusing

on pathophysiology
Ana Flávia Lima Ruas1 · Gabriel Malheiros Lébeis1 · Nicholas Bianco de Castro1 · Vitória Andrade Palmeira1 ·
Larissa Braga Costa1 · Katharina Lanza1 · Ana Cristina Simões e Silva1

Received: 15 May 2021 / Revised: 13 October 2021 / Accepted: 14 October 2021 / Published online: 30 November 2021
© The Author(s), under exclusive licence to International Pediatric Nephrology Association 2021

Abstract
Acute kidney injury (AKI) is defined as an abrupt decline in glomerular filtration rate, with increased serum creatinine and
nitrogenous waste products due to several possible etiologies. Incidence in the pediatric population is estimated to be 3.9 per
1,000 hospitalizations, and prevalence among children admitted to intensive care units is 26.9%. Despite being a condition
with important incidence and morbimortality, further evidence on pathophysiology and management among the pediatric
population is still lacking. This narrative review aimed to summarize and discuss current data on AKI pathophysiology in the
pediatric population, considering all the physiological particularities of this age range and common etiologies. Additionally,
we reported current diagnostic tools, novel biomarkers, and newly proposed medications that have been studied with the aim
of early diagnosis and appropriate treatment of AKI in the future.

Keywords Acute kidney injury · Pediatrics · Epidemiology · Pathophysiology · Perspectives

Introduction Several validated classification systems assess diagnos-

Acute kidney injury (AKI), formerly known as acute kidney
failure, is defined as an abrupt decline in glomerular filtra-
tion rate (GFR), ranging from minor loss of kidney func-
tion to complete failure [1]. The condition is characterized
by an increase in serum creatinine (Scr) and nitrogenous
waste products, and the inability of the kidney to regulate
body volume and hydroelectrolyte homeostasis [1]. These
kidney alterations can be caused by inadequate organ perfu-
sion, arterial or venous obstruction, kidney cell injury (e.g.,
acute tubular necrosis, rapidly progressive glomerulonephri-
tis, exposure to nephrotoxic drugs), or acute obstruction to
urine flow [1, 2].
AKI is clinically diagnosed by the decrease in urine out-
put and/or the accumulation of urea and creatinine in the
blood, due to the loss of the kidney’s excretory function.
* Ana Cristina Simões e Silva
acssilva@hotmail.com
1
Interdisciplinary Laboratory of Medical Investigation,
Department of Pediatrics, Faculty of Medicine,
Federal University of Minas Gerais (UFMG), Alfredo
Balena Avenue, Number 190, 2nd floor, Room #281,
Belo Horizonte, MG 30130100, Brazil
tic criteria for AKI, all based on urine output and Scr. In
addition, widely available biomarkers in clinical practice
are neither specific nor sensitive, hampering the identifi-
cation of AKI at early stages, especially in public health
systems of developing countries [3, 4]. Although functional
and histological alterations may be reversible, the condition
is associated with high morbimortality rates, demanding a
prompt approach to avoid a worse prognosis [1, 3]. Pediatric
patients in particular have increased morbimortality rates
during hospitalization and a higher probability of developing
future chronic kidney disease (CKD) [5–7].
The prevalence of AKI varies widely, ranging from < 1%
in high-income countries to 66% in low-to-middle-income
countries [8]. The diversity of diagnostic tools, unequal
access to basic sanitation, and presence of endemic diseases
favor the expressive variation in prevalence [8, 9]. Suther-
land et al. [10] showed an incidence of 3.9 per 1,000 pediat-
ric hospitalizations in a large North American cohort study
[10]. The multicenter AWARE study showed an incidence of
26.9% in pediatric patients admitted to intensive care units
(ICUs) [7]. Goldstein et al. showed a 31% incidence of AKI
in admissions of non-critically ill children with high expo-
sure to nephrotoxic medications [11]. Bresolin et al. reported
a 46% incidence of AKI in Brazilian pediatric patients

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admitted to ICUs [12]. Several studies showed that AKI was
also associated with a longer length of hospitalization and
comprised an independent risk factor for higher mortality
rates [7, 13]. Sutherland et al. reported increased in-hospital
mortality in pediatric patients admitted to the ICU with AKI
than in those without the condition [10]. The AWARE study
reported that severe AKI was associated with higher 28-day
mortality rates (11% vs. 2.5%) [7]. Bresolin et al. found a
12-fold higher in-hospital mortality rate compared to ICU
patients without AKI (36.2%) [12].
AKI has been associated with an increased need for kid-
ney replacement therapy, mechanical ventilation, and extra-
corporeal support [7, 10]. Risk factors for AKI in the neona-
tal group include low birth weight, low APGAR score, use
of mechanical ventilation, and antenatal corticosteroids [5].
Studies showed that neonates present higher mortality rates,
longer hospitalization length, and higher odds of develop-
ing CKD compared to older pediatric patients [5, 10, 14].
Indeed, Mammen et al. reported a 10.3% prevalence of CKD
in pediatric patients in 1–3 years after experiencing an AKI
episode [15]. Assessing and preventing AKI in the pedi-
atric population is particularly important, as the mortality
rates and long-term outcomes are concerning. This narrative
review aims to summarize and discuss current data on AKI
pathophysiology in the pediatric population. In addition, we
report current diagnostic tools, novel biomarkers, and newly
proposed medications.
From physiology to pathophysiology
Kidney physiology within the pediatric age range presents
several particularities that should be addressed before dis-
cussing AKI pathophysiology. GFR is known to depend
on multiple factors, including the filtration barrier surface
area, water permeability, hydrostatic and oncotic pressures
in the Bowman capsule, glomerular lumen, and the balance
between these factors [16, 17]. Studies showed that kidney
development is only completed after birth, with the glomer-
ular and tubular function continuing to develop until the
second or third year of life. Indeed, GFR as a parameter of
kidney maturation seems to be correlated with gestational
age among preterm newborns, who present lower GFR than
full-term newborns [16, 18–20]. Any intrauterine growth
restriction, antenatal glucocorticoids administration, or pre-
maturity itself may compromise kidney growth and reduce
the number of nephrons. Low nephron number makes all
hemodynamic changes more abrupt, favoring AKI onset [5].
Full-term newborns have a GFR around 15–25 mL/
min/1.73 m at birth, reaching values close to adults
(110–120 mL/min/1.73m2) in the second or third year of
life. During this period, newborns and infants are more
prone to AKI and drug nephrotoxicity [17, 21]. Filtration
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Pediatric Nephrology (2022) 37:2037–2052
capacity experiences a significant increase during the first
days postpartum, followed by a gradual elevation until the
first to the second year of life [16, 18–20]. The postnatal
transition of plasma flow is also an important contributor to
the raising of GFR. The elevation in cardiac output percent-
age direct to the kidneys, from 3% in fetal life to 20% after
kidney development, leads to constant alterations in kidney
perfusion pressure, systemic arteriolar resistance, and local
vascular resistance. All these changes are due to neurohu-
moral regulation, mostly mediated by prostaglandins and the
renin-angiotensin system (RAS). Therefore, medications that
modulate these molecules frequently have an exacerbated
response, especially in newborns [19, 21].
Tubular function development also takes place after birth.
Kidney tubules participate in the hydroelectrolytic and acid-
basic balance of the organism, and its immaturity is associ-
ated with high urinary loss of glucose, electrolytes, amino
acids, and low molecular weight proteins, in addition to a
reduced erythropoietin production [22]. The ability to con-
centrate urine is also deficient in neonates due to shorter
loops of Henle and low capacity to generate corticomedul-
lary solute gradient, only reaching the maximum osmolality
values of 1,200 mosmol/kg around the second year of life
[23–25]. From the second or third year of life to the begin-
ning of puberty, kidney function remains almost constant
with values similar to adult ranges. These particularities
must be kept in mind to properly understand the pathophysi-
ological pathways of the AKI etiologies in pediatric patients.
AKI is a multifactorial and incompletely understood
condition that encompasses both direct injury to the kidney
and acute functional impairment [26]. Possible etiologies
for AKI vary within countries and age groups and its con-
sequences are not well defined [26]. It is not yet known if
the type and intensity of the injury or the anatomic affected
part and the subsequent response time of the kidney change
is according to different etiologies or if the kidney has a
single stereotyped response apart from the etiology [26, 27].
In addition, it is still a matter of debate if the genes activated
during the disease course are a consequence of the intrin-
sic mechanisms of the kidney or are induced by secondary
effects such as the recruitment of immune cells [26, 27].
However, the pathophysiological mechanisms probably fol-
low a common homeostatic pathway triggered by kidney
ischemia [1, 14, 28] interplayed by tubular injury, vascular
insult, and consequent inflammatory response [26, 29]. This
common pathway is didactically subdivided into 4 stages:
initiation, extension, maintenance, and recovery, as shown
in Fig. 1 [2].
The ischemic event deflagrates the initiation phase, char-
acterized by a fast and intense decrease in GFR [30]. Once
adenosine triphosphate (ATP) is depleted, the impairment
of actin filaments of the cytoskeleton initiates the AKI in the
kidney proximal tubule cells, compromising tubular function
Pediatric Nephrology (2022) 37:2037–2052
Fig. 1  Acute kidney injury (AKI) pathophysiology from a tubular
cell perspective. The AKI general pathophysiology is divided into 4
stages: Initiation (1A, 1B); extension (2); maintenance (3); recovery
(4). Different mechanisms of AKI cause ischemia (1A), an event that
leads to a decrease of the glomerular filtration rate (GFR) and conse-
quent renal tubular cell lethal injuries: apoptosis and necrosis (1B).
The hypoxia also stimulates inflammatory response that is clinically
and cell to cell interaction, leading to cell apoptosis or necro-
sis [2]. In highly injured kidney sites, the apoptosis makes
the basement membrane the only remaining part between
the peritubular interstitium and the glomerular filtrate and
also causes an accumulation of cellular waste in the kidney
lumen that obstructs and elevates the intratubular pressure,
interfering with the filtrate flow. Therefore, the inflammatory
response is stimulated, provoking additional injury [26, 31].
Following initiation, the extension phase is marked by
persistent hypoxia, inflammatory response, and some level
of cell reperfusion [2, 28]. In extension, GFR drops more
slowly, and microvascular/endothelial cell injury is estab-
lished in the corticomedullary junction of the kidney [2,
28]. At this site, the dissipated glomerular filtration pressure
may cause alteration of vascular smooth muscle tone and
endothelial cell permeability, losing vascular autoregulation
[32]. There is an enhanced vascular response to vasocon-
strictors, including angiotensin II, prostaglandin H2, throm-
boxane A2, leukotrienes C4 and D4, and endothelin-1, and
an impaired response and production of vasodilators like
nitric oxide, bradykinin, and acetylcholine [33, 34]. Both
alterations are worsened with interstitial edema and reduc-
tion of blood flow [33].
At the same time, the inflammatory response stimu-
lated in the initiation phase also proceeds. The Toll-like
receptors (TLRs) stimulate the release of cytokines and
chemokines [35, 36]. Cytokines upregulate the expression
of leucocytes integrins, intercellular adhesion molecule-1
(ICAM-1), and vascular cell adhesion molecule (VCAM),
2039
characterized by the slower GFR decrease (2). When GFR is stable
and the repair on tubular cells and capillary starts to happen, it is
considered the “maintenance” phase (3). After some time, the tubu-
lar and capillary structure is restored, featuring the last disease stage,
in which GFR starts rising and the kidney function is progressively
restored (4)
enhancing leukocyte adherence to endothelial cells in kid-
ney tissue [37]. Once activated, leukocytes produce pro-
inflammatory cytokines that determine severe alterations
in proximal tubular epithelial cells and cell–matrix adhe-
sion, leading to cell release to the lumen [38]. The comple-
ment system also potentiates leukocyte–endothelial inter-
actions and mediates even more kidney tissue injury [39].
Together, these alterations further decrease GFR [28, 40].
After dropping, GFR stabilizes in a lower range, which
defines the maintenance phase [2]. Tubule cells start dedif-
ferentiating and repairing to restore the functional integ-
rity of the nephron. These cells migrate to cover exposed
areas of the basement membrane and proliferate as an
attempt to restore cell number and tubule integrity [2].
During this phase, kidney function improves and makes
possible the last phase, recovery [41].
The recovery phase is initiated by the normalization of
blood flow and cellular homeostasis. Recovery cells are
undergoing differentiation, restoring epithelial polarity,
and normalizing their function [41]. The chance of recov-
ery is directly linked to the extension, cause, and duration
of AKI, corroborating the importance of early diagnosis
and treatment [2]. In severe cases, chronic hypoxia sets in
caused by an inhibition of the angiogenesis, probably by
T-regulatory cells [42]. Hence, AKI does not undergo a
complete repair and remains with tubulointerstitial inflam-
mation, proliferation of fibroblasts, and excessive deposi-
tion of extracellular matrix, leading to CKD [43, 44].
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2040 Pediatric Nephrology (2022) 37:2037–2052

Finally, it is important to mention that ongoing growth,
greater kidney reserve, and high kidney regenerative poten-
tial are important factors related to AKI in pediatric patients.
Additionally, the underlying and unique comorbidities of
pediatric patients should also be considered [41, 45]. How-
ever, in both adult and pediatric patients, AKI etiologies
are traditionally divided into three groups, according to the
anatomical site of the initial alteration and the main mecha-
nism: prekidney, kidney, and postkidney [1]. More recently,
authors proposed a new classification, in which prekidney
causes are called AKI functional change, while the kidney
causes are termed kidney damage [46]. Table 1 summarizes
the classification, pathophysiology, and common etiologies
of AKI in pediatric patients.
Functional causes of AKI
The main mechanism of functional AKI is the decreased
kidney perfusion pressure leading to a transitory ischemic
event without lethal ischemic damage to parenchyma cells
[47]. The counterregulatory kidney response to all func-
tional causes is the concentration of urine and reabsorption
of sodium, which, in turn, can increase intravascular volume
and normalize kidney perfusion. This process contributes to
oliguria [48]. Once the disruption is not solved as usually
occurs, the profound functional ischemia may result in lethal
damage to the kidney [28]. The main causes of the functional
AKI are decreased true intravascular volume (hypovolemia)
or decreased effective intravascular volume [1].
Vomiting, hemorrhaging, diarrhea, poor water intake,
burns, excessive sweating, and excessive diuresis may cause
hypovolemia. All these causes result in dehydration, which
reduces the cardiac output and consequent decreased kidney
perfusion. Hypovolemia comprises a common etiology of
AKI in newborns, since tubular immaturity hampers fluid
management and the physiological lower kidney blood flow
(KBF) worsens the condition [5]. The effective intravascular
volume impairment, a result of lower arterial pressure, may
have two physiological explanations: diminished cardiac
output or decreased intravascular volume without decreased
total body fluid [2]. Impaired cardiac output comes from any
cardiac disorder that causes congestive heart failure (HF) or
decreased cardiac output. This is also a common pediatric
reason for AKI. It is usually related to perioperative com-
plications in infants who undergo either cardiac or vascular
surgery, once these procedures encompass cardiac dysfunc-
tion and stress with cardiopulmonary bypass effects [49].
Altered intravascular volume not linked to reduced total
body fluid may be diminished due to decreased vascular
resistance or kidney vasoconstriction [28]. Decreased vas-
cular resistance due to peripheral vasodilatation is a possible
consequence of sepsis, anaphylaxis, vasodilator medications,
or autonomic neuropathy [49]. Kidney vasoconstriction
could be a result of medications or hydroelectrolytic dis-
turbance, such as hypercalcemia [36, 50]. Rare cases, such
as pulmonary tuberculosis associated with hypercalcemia,
were described in pediatric AKI as a cause of vasoconstric-
tion, but were also related to dehydration, nephrocalcino-
sis, diabetes insipidus, and injured kidneys [40]. In both
scenarios, three compensatory mechanisms are naturally
triggered to vasodilate the afferent arterioles and offset the
situation: intrarenal vasodilatory prostaglandins liberation,
myogenic autoregulation, and the classical RAAS axis acti-
vation that leads to further vasoconstriction of the efferent
arteriole enhancing hydrostatic pressure and, consequently,
improving GFR [51]. All these compensatory mechanisms
are important to avoid permanent kidney injury [2].
Recently, the decreased KBF as a causative step for AKI
has been questioned [52]. Experimental and clinical stud-
ies have shown that changes in kidney microcirculation and
local inflammation seem to be more important than a global
reduction of KBF for the development of AKI [52–54].
Although blood flow for the kidneys is considered high,
most of the oxygen consumed for ATP production is to sup-
port active sodium transport (TNa), while the basal meta-
bolic rate accounts for only a small percentage of oxygen

Table 1  Acute kidney injury classification, pathophysiology, and common etiologies in pediatric patients
Classification Etiology

Functional injury Hypovolemia: vomiting, hemorrhaging, diarrhea, poor water intake, and burns
Cardiorenal syndrome type 1
Surgery (cardiac and non-cardiac)
Sepsis
Kidney injury Loss of eNOX function or vascular lesion (hypertension, thrombosis, and kidney thrombosis)
Acute tubular injury (caused by drugs, other toxins, or hypoxic insults)
Uric acid nephropathy, tumor lysis syndrome, other exogenous and endogenous toxins
Interstitial nephritis (caused by drugs, infection, or other diseases) and glomerulonephritis
Kidney hypoplasia/dysplasia
Postkidney injury Obstruction in a solitary kidney, bilateral ureteral obstruction, and urethral obstruction

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Pediatric Nephrology (2022) 37:2037–2052
consumption [55]. Therefore, kidney oxygen demand is
closely related to the glomerular filtration rate and tubular
reabsorption [53, 54]. In an animal study of endotoxemia,
the relationship between partial pressure of oxygen ­(PO2)
and tissue oxygen tension remained the same in both cor-
tex and outer medulla due to an increase in oxygen extrac-
tion, despite a decrease in the KBF and urine output [54].
Another study also demonstrated that the inhibition of the
Na transport in the thick ascending limb of Henle and proxi-
mal tubule with specific diuretics increases the ­PO2 in the
medulla and cortex. This finding shows how important tubu-
lar transportation and the related oxygen consumption are
for kidney tissue oxygenation [53]. It was also shown that
increased kidney capillary permeability occurs before the
decrease in KBF [56]. Alterations in KBF are preceded by
reduced perfusion of cortical microcirculation, peritubular
capillary leakage, and reactive nitrogen species generation
[57]. Taken together, these experimental data support that
cell injury may not be directly associated with the global
reduction of KBF. However, more studies are necessary to
clarify the sequence of events related to the development
of AKI.
Cardiorenal syndrome type 1
Cardiorenal syndrome (CRS) is a condition that affects both
heart and kidneys, in which one induces the other’s dysfunc-
tion or injury [58, 59]. CRS is divided into five subtypes that
comprise chronic and acute conditions [59]. Type 1 CRS
(CRS-1), also named acute cardiorenal syndrome, has as its
most frequent etiologies acute HF, acute coronary syndrome,
and cardiac surgery [58].
The pathophysiology of CRS-1 comprises an acute HF
leading to kidney hypoperfusion and reduced GFR [60]. A
different pathway for the CRS-1 pathophysiology is through
increased central venous pressure (CVP) affecting kidney
vein and kidney perfusion [60]. Mechanisms including the
activation of the RAS and the sympathetic nervous system
(SNS) with an increased inflammatory status have also been
postulated [60]. CRS-1 may be reversed with appropriate
management, such as careful use of diuretics, with both kid-
ney and cardiac functions returning to normal status [60].
Concerning the relationship between cardiovascular dis-
ease and kidney involvement among the pediatric popula-
tion, a prospective cohort study highlighted myocarditis and
congenital heart disease as the most frequent cardiac disor-
ders associated with CRS-1 [61]. The same study showed
an overall incidence of CRS of 27.7% over 1 year, with a
six-time increase in the risk of mortality among affected
children [61]. Moreover, Price and Goldstein found that
hospitalized children with decompensated HF are likely to
develop a decrease in kidney function during the period of
hospitalization [62].
2041
Cardiac and non‑cardiac surgery
Cardiac surgery is one of the most common causes of AKI
in the ICU, occurring in 10 to 50% of pediatric patients fol-
lowing surgery for congenital heart disease [62]. In addition,
the development of AKI after these surgeries is associated
with longer hospitalization periods and higher mortality
rates [62]. AKI is a risk factor for death in patients follow-
ing cardiac procedures, whereas, in turn, the major risk fac-
tor for operative and long-term mortality in this scenario is
previous kidney dysfunction [63].
There are different pathways to explain kidney injury
following cardiac surgery, which include low cardiac out-
put after the procedure [62, 63], remaining cardiovascular
lesions, use of nephrotoxic drugs, and aggressive postop-
erative diuresis. All of these factors can result in kidney
ischemia–reperfusion injury [62]. The cardiopulmonary
bypass (CPB) used in these procedures may also induce
AKI through hypoperfusion due to a lower and nonpulsatile
flow with hemodilution, decreasing the capacity of carrying
oxygen and resulting in hypothermia [63]. CPB can also trig-
ger an inflammatory response that leads to afferent arteriolar
constriction [63]
Major non-cardiac surgeries are also associated with AKI,
which may also lead to CKD and death [64, 65]. As almost
20% of children from low-income countries are likely to
need surgery, it can be inferred that exposure to major sur-
gery is an important factor to be considered as a cause of
AKI in this population [65]. Even though cardiac surgery is
an established risk factor for the development of AKI, the
role of other surgeries in this scenario is still not yet settled
in the literature [65].
Sepsis
Sepsis comprises a clinical syndrome characterized by a
systemic inflammatory response, immune dysregulation,
and microcirculatory disturbance, with high incidence and
significant mortality rates [66, 67]. Since 60% of patients
with sepsis develop AKI [22], sepsis is considered the most
common risk factor for this complication [66]. Indeed,
Alobaidi et al. found that sepsis was responsible for 26 to
50% of AKI cases, with severity being directly proportional
to its incidence [66]. Sepsis-associated AKI (SA-AKI) is
more severe than the non-septic AKI, probably due to the
higher inflammatory response [66]. Additionally, SA-AKI
patients are more likely to need mechanical ventilation,
hemodynamic support, and an increased amount of fluid for
resuscitation [66].
Although its pathophysiology is not clarified, it
appears to have specificities that differ from other AKI
etiologies [66, 67]. As with other causes of AKI, hypop-
erfusion and ischemic injury are believed to be the basis
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2042
of SA-AKI pathophysiology [67]. Therefore, the most
accepted mechanism to explain SA-AKI is a decrease
in global KBF leading to tubular epithelial cell death
or acute tubular necrosis (ATN) [66, 67]. This theory,
however, is no longer considered the only pathway for
SA-AKI development [66]. In addition to ischemia–rep-
erfusion injury, the other proposed mechanisms include
inflammation, alterations in microcirculation, and meta-
bolic reprogramming [67].
The pathogen recognition by immune cell receptors
triggers a pro-inflammatory cascade that promotes dys-
regulated inflammatory response and organ dysfunction
in the context of sepsis [67]. The exposition of kidney
tubular cells to components of the pathogen, such as the
pathogen-associated molecular patterns, may increase
oxidative stress and lead to mitochondrial injury [67].
Inflammation and the formation of reactive oxygen spe-
cies (ROS) associated with changes in nitric oxide and
nitrosative stress are also believed to characterize kidney
tissue hypoxia [66].
In terms of microcirculatory dysfunction, sepsis
decreases capillary density and produces the replace-
ment of capillaries with continuous flow for those with
intermittent and stop flow [67]. Endothelial injury, auto-
nomic nervous system response, and thrombotic micro-
angiopathy also contribute to microcirculatory alterations
[67]. Moreover, the constriction of the afferent arteriole
combined with the dilation of the efferent arteriole can
explain the reduction of GFR and intraglomerular pres-
sure [67].
Metabolic alterations in SA-AKI are considered an
attempt to preserve cell integrity [66, 67]. These changes
include optimization of the energy consumption sparing it
from non-vital functions, such as cell replication [67]. The
neutralization of factors responsible for apoptosis and the
reprogramming of substrate use are also metabolic changes
of SA-AKI [67].
Kidney causes of AKI
AKI may also be caused by intrinsic kidney disease, which
comprises a broad spectrum of lesions affecting different
structures of the kidneys, including tubules, glomeruli,
interstitium, and intrarenal blood vessels [1, 28, 68].
The main causes of intrinsic kidney diseases are ATN,
due to ischemia or nephrotoxicity; uric acid nephropathy
and tumor lysis syndrome; idiopathic and drug-induced
interstitial nephritis; glomerulonephritis; intrarenal blood
flow damage caused by vascular lesions, such as hemolytic
uremic syndrome (HUS) and thrombosis; and hypoplasia
and dysplasia with or without obstructive uropathy [1, 68].
These causes are discussed below.
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Pediatric Nephrology (2022) 37:2037–2052
Acute tubular injury
ATN is considered an important cause of AKI in neonates,
children, and adolescents and is associated with tubular
injury, mainly due to ischemia and nephrotoxicity [1].
Ischemia The molecular pathway in which ischemia results
in vasoconstriction and tubular necrosis is not entirely com-
prehended. Alterations in the vascular tone due to changes
in the cytoskeleton, endothelin, and nitric oxide concentra-
tions; ATP depletion; inflammatory response; and produc-
tion of ROS and nitrogen molecules are considered to play
an important role in this process [1].
The endothelial nitric oxide synthase (eNOS) is responsi-
ble for the production of nitric oxide, a vasodilator. Studies
suggest that eNOS loses its normal function following the
ischemic injury [1]. In addition, inducible nitric oxide syn-
thase (iNOS), which participates in the production of ROS
and nitrogen molecules, has its activity increased following
the event [1]. The response to ischemic/hypoxic processes
leads to ATP depletion and, consequently, disruption of the
cytoskeleton and generation of ROS, contributing to injury
[1]. The systemic inflammatory response also leads to kid-
ney dysfunction through increased levels of cytokines and
also of ROS [1]. The interstitium, vasculature, and glomeruli
may also suffer in ATN [28]. The congestion of outer med-
ullary peritubular capillaries may contribute to the exac-
erbation of the tubular injury during the extension phase,
as well as the accumulation of leukocytes in the vasa recta
[28]. Collapsation of the glomerular tuft as a consequence
of hypoperfusion may also occur [28].
Endogenous toxins Nephrotoxic injury occurs due to
direct insult by the cytotoxic effects from both exogenous
and endogenous toxins and due to the precipitation of crys-
tals and metabolites [69]. In the case of endogenous toxins,
cytotoxic agents such as myoglobin in the context of rhab-
domyolysis may act directly on kidney tubular epithelial or
endothelial cells, causing vasoconstriction and precipitation
of metabolites and crystals into the tubular lumen [3, 28].
Serum uric acid (SUA) has been strongly associated with
the development of AKI as well [33]. This molecule acts as
an antioxidant in the extracellular environment and prooxi-
dant in the intracellular, and its crystallization is frequently
associated with gouty arthritis and nephrolithiasis [70].
However, high SUA levels, but not enough to precipitate,
have been linked to hypertension, CKD, and AKI [70]. The
association between AKI and SUA is not fully understood,
although it is proposed that elevated SUA levels can induce
vasoconstriction, alter kidney autoregulation, and activate
inflammatory cascade [70]. Uric acid crystals may lead to
tubular luminal obstruction, which contributes to decreased
GFR, therefore causing increased intrakidney pressure [70].
Pediatric Nephrology (2022) 37:2037–2052
Decreased kidney perfusion results in oxidative stress and,
therefore, vascular and tubular injury. Consequently, there
is activation of the proinflammatory cascade with increased
levels of cytokines and chemokines impairing endothelial
function [70].
In the neonatal population, however, SUA as a cause of
AKI is rare, due to its excretion through dilute urine, lower-
ing the possibility of precipitation [71]. Hyperuricemia is
also uncommon among children, generally resulting from
decreased excretion, overproduction, or both [71]. Therefore,
circumstances with high cell turnover and rapid cell prolif-
eration, including leukemias and lymphomas, as well as cell
death in tumor lysis syndrome (TLS), are the most common
causes of increased SUA in the pediatric population [71].
TLS, for instance, occurs in certain oncological patients due
to the massive breakdown of tumor cells spontaneously or
induced by cytoreductive chemotherapy [72]. The intracel-
lular contents released during this event cause hyperurice-
mia, hyperkalemia, and hyperphosphatemia and can lead to
hypocalcemia, which may produce different injuries, includ-
ing AKI [72]. The acute increase of SUA, in this scenario,
may cause uric acid crystal deposition in the tubules and
contribute to the sequelae of injury. The precipitation of
calcium phosphate crystals due to hyperphosphatemia may
also occur [72]. A higher risk of nephropathy was found in
pediatric patients with acute lymphocytic leukemia, B-cell,
and non-Hodgkin’s lymphoma [71].
Interstitial nephritis Acute interstitial nephritis (AIN)
leads to interstitial damage due to inflammatory infiltrate
and edema in this region, causing an acute impairment of
kidney function [28, 73]. AIN may be the result of drug reac-
tion, infection, anti-tubular basement membrane (anti-TBM)
disease, sarcoidosis, systemic diseases, including systemic
lupus erythematosus (SLE) and malignancies, or idiopathic
causes [3, 28, 73].
The leading cause of AIN is drug reaction, followed by
infection-related and idiopathic forms [73]. Medications
more frequently associated with AIN include methicillin and
other penicillin analogs, cimetidine, sulfonamides, cephalo-
sporins, rifampin, non-steroidal anti-inflammatory (NSAID)
drugs, and proton pump inhibitors [1, 28, 73]. AIN caused
by infection is more commonly associated with bacterial ill-
nesses, mostly leptospirosis and legionella [28]. Rarely, AIN
may be associated with pyelonephritis and viral illnesses,
including hantavirus infection [28]. The AIN episode begins
with the expression of endogenous and exogenous nephrito-
genic antigens processed by tubular cells [73]. Medications
and specific microbial antigens are also believed to evoke
immune reactions due to their interstitial deposition [73].
In some cases, drugs inducing the AIN episode may attach
to the TBM or mimic an antigen commonly present in the
2043
TBM, inducing an immune response against this antigen
[73].
The AIN episode initiates when the protective mecha-
nisms are surpassed, leading to cell-mediated immunity,
causing hypersensitivity and cytotoxicity, marked by
inflammatory cellular infiltrates of T lymphocytes and mac-
rophages [73]. These cells release cytokines, increase the
production of interstitial fibroblasts, amplify the process, and
enhance the infiltration of inflammatory cells, possibly lead-
ing to interstitial fibrosis with loss of kidney tubules [3, 73].
Glomerulonephritis Glomerular damage in AKI may be
caused by severe glomerulonephritis (GN) [28]. GN may
occur due to systemic disease, including SLE, or due to pri-
mary kidney disease, resulting in rapidly progressive glo-
merulonephritis (RPGN) [28, 74]. RPGN is an entity charac-
terized by hypertension, edema, hematuria, and rising levels
of blood urea nitrogen and creatinine, which may evolve to
kidney failure within weeks or months [1, 74, 75].
RPGN is more frequent among older children and adoles-
cents [1]. The condition is clinically associated with crescen-
tic glomerulonephritis (CresGN), a glomerular disorder that
comprises different immunopathological mechanisms [75,
76]. In children, immune-complex crescentic glomerulone-
phritis is the most common CresGN [76]. Approximately
half of the children with CresG progress to kidney failure
[75]. In this regard, poststreptococcal acute GN (PSAGN),
one of the immune-complex CresGN, represents an impor-
tant cause of acute kidney failure in children [76, 77]. In
this insult, there is an immune reaction to components of
the glomerulus and streptococcal parts deposited in the glo-
merulus [77].
Pathogenesis of GN is mainly explained by the immune
response to exogenous antigens, when caused by infections,
and also the immune complex circulation and deposits in the
glomeruli, which induces inflammation [77–79]. The reac-
tion to these complexes results in the activation of innate and
adaptive immune systems, along with the release of inflam-
matory mediators, causing glomerular injury [79]. While
antibodies lead to trapping and in situ formation of immune
complexes, the generation of antigen-specific T and B cells
is directed to the antigens fixed in the glomerulus, mediating
tissue damage [79]. Activation of complement components
by antibodies is also part of immunopathology and contrib-
utes to the glomeruli damage [78, 79].
Vascular lesions Vascular damage in AKI is a result of an
injury to intrarenal vessels, decreasing kidney perfusion and
GFR [28]. Causes of vascular damage include hypertension
[28], kidney artery and kidney vein thrombosis and corti-
cal necrosis, preeclampsia/eclampsia, thrombotic thrombo-
cytopenic purpura (TTP), and hemolytic uremic syndrome
(HUS) [1, 28]. Cortical necrosis and kidney vein thrombosis
13
2044
are more frequent in neonates, while HUS is more com-
monly found in young children [1].
Considering injuries associated with AKI, cortical necro-
sis is frequently related to hypoxic/ischemic insults, mostly
due to perinatal anoxia, placenta abruption, twin-twin/twin-
mother transfusion, and consequent activation of the coagu-
lation cascade [1]. On the other hand, HUS is a condition
characterized by the triad of thrombocytopenia, anemia, and
AKI, classically associated with the production of Shiga
toxin by E. coli, although other causes include invasive S.
pneumoniae infections, drug exposure, hypertension, auto-
immune diseases, malignancy, and genetic alterations of the
alternative complement pathway/coagulation cascade (called
atypical HUS) [80]. HUS caused by E. coli infection is con-
sidered a childhood disease, initiated by the attachment of
the Shiga toxin to endothelial and kidney tubular cells, lead-
ing to ribosomal inactivation and cell death [80]. Moreover,
the toxin is also proinflammatory and prothrombotic, there-
fore increasing the secretion of the von Willebrand factor
and the activation of the complement pathway [80].
Vein thrombosis (RVT) is the most common non-cathe-
ter-related thrombosis among children, mostly newborns and
those of younger age [81]. The consequence of the occlusion
depends on the extension of the thrombus, the presence of
collateral circulation, and the acuteness of the event [81].
The development of RVT is related to a combination of
endothelial damage, stasis of the blood flow, and hypercoag-
ulability [81, 82]. RVT can also happen as a consequence of
dehydration that causes volume depletion leading to reduc-
tion of blood flow [81, 82]. Other causes include septicemia,
shock, and newborns with diabetic mothers [81]. RVT is
commonly associated with nephrotic syndrome [81, 82].
Kidney hypoplasia/dysplasia Kidney hypoplasia or dys-
plasia is an important cause of AKI in neonates [1]. The for-
mation of the human kidneys begins at the fifth gestational
week and perturbations during these events result in congen-
ital anomalies of the kidney and the urinary tract (CAKUT)
[83]. Kidney dysplasia and kidney hypoplasia are common
causes of CAKUT [83]. Undifferentiated and metaplastic tis-
sues in the kidney characterize dysplasia, while hypoplasia
may be defined as a kidney with a significant nephron deficit
[83, 84]. These alterations are generally diagnosed at the
time of birth or during infancy [84].
In such disorders, mutations of the genes usually
expressed in the kidney may be identified, leading to dereg-
ulated cell proliferation and programmed cell death [84,
85]. Moreover, an important cause of hypoplasia and dys-
plasia is exposure to maternal drugs in utero, interfering
with nephrogenesis [1]. Medications such as angiotensin-
converting enzyme inhibitors, angiotensin receptor block-
ers, and NSAID drugs have been related to these conditions
[1]. Kidney dysplasias may be divided into obstructive and
13
Pediatric Nephrology (2022) 37:2037–2052
non-obstructive [85]. Obstructive uropathy can lead to AKI
if it affects a solitary kidney or both ureters, or if it occurs
at the urethra level [1]. Examples of obstructive uropathy
include posterior urethral valves, bilateral ureteropelvic
junction obstruction, or bilateral obstructive ureteroceles [1,
83]. Obstruction can lead to hydronephrosis with compres-
sion and fibrosis of the medulla [85]. While common causes
of obstructive dysplasia are related to increased hydrostatic
pressure in the kidney pelvis, non-obstructive dysplasia
seems to be mediated by transforming growth factor (TGF)
[85].
Postkidney causes of AKI
The postkidney mechanism of AKI comprises an acute
obstruction of the urine flow by obliterating one or both
ureters at any level, although there is usually a pre-existing
cause of reduced kidney function [28, 86]. This obstruction
elevates the intratubular pressure locally, but the augmenta-
tion is transmitted back to the proximal tubules, counteract-
ing the high intraglomerular pressure that drives glomeru-
lar filtration. Hence, there is a reduction in the GFR [87].
Additionally, there is kidney blood flow impairment, once
the increase in the intratubular pressure induces secondary
kidney vasoconstriction and inflammatory processes, which
may lead to the previously mentioned ischemic events [28,
87]. The main etiologies of postkidney AKI in children are
kidney calculi, clots, neurogenic bladder, urinary retention
as a medication consequence, and any septic, nephrotoxic,
or ischemic injury in a patient with non-treated obstructive
CAKUT, such as posterior urethral valve [88].
Drug‑induced AKI
Nephrotoxicity is a common etiology of AKI in pediatric
patients, particularly in those hospitalized [89, 90]. Medica-
tions associated with tubular injury include amphotericin B,
chemotherapy, contrast media, acyclovir, and acetaminophen
[1]. Acetaminophen, for instance, causes a reversible and
dose-related injury associated with lysosomal dysfunction
[1] and has an increased risk after a long period of admin-
istration [89].
The interstitium is also affected by drug reactions, being
responsible for two-thirds of acute interstitial nephritis
(AIN) episodes [35]. Drugs associated with such injury
include antimicrobial agents, including penicillin analogs,
sulfonamides, cephalosporins and rifampin, and NSAID
drugs [1, 20, 35]. The pathophysiology of AIN is associ-
ated with the immunological process of exogenous antigens
exerted by tubular cells [35]. These toxins can bind to the
tubular cells’ basement membrane or mimic one of their
Pediatric Nephrology (2022) 37:2037–2052
antigens, thus inducing the immune response associated with
the lesion [35].
Maternal exposure to medications that directly interfere
with the kidney and urinary tract during embryogenesis,
such as angiotensin-converting enzyme inhibitors, angio-
tensin receptor blockers, and NSAIDs, is also associated
with different anomalies, including kidney dysplasia or
hypoplasia [1].
The hemolytic uremic syndrome (HUS), an association
between microangiopathic hemolytic anemia, thrombocy-
topenia, and AKI, may be induced by genetic mutations,
infections, autoantibodies, and drug toxicity, although it is
mostly associated with E. coli toxin production [42]. The
drugs most frequently associated with HUS are calcineurin
inhibitors (ciclosporin and tacrolimus), quinine, vascular
endothelial growth factor inhibitors, quetiapine, chemo-
therapeutics, antiplatelet agents, and drugs of abuse, such
as cocaine [42]. HUS caused by drug exposure shares the
same pathophysiological characteristics as those caused by
Shiga toxin, which include a prothrombotic and proinflam-
matory state on the endothelium surface [42].
Considering the importance of nephrotoxic AKI among
children, the Nephrotoxic Injury Negated by Just-in-Time
Action (NINJA) systematic screening program was cre-
ated to assess AKI in non-critically ill children exposed
to nephrotoxic medications [91]. The AKI rate doubled in
children receiving three or more nephrotoxic drugs when
compared to those treated with two or fewer [92]. The imple-
mentation of this monitoring program led to a decrease of
64% in AKI rates, pointing out the possible avoidability of
adverse events due to nephrotoxic drug administration [90,
93].
Diagnosis and management
Current practice
Diagnosis of AKI is based on the individualized interpreta-
tion of clinical findings and laboratory parameters of kid-
ney function [3]. Clinical signs include accelerated mani-
festations of kidney parenchyma damage by significantly
increased serum levels of waste nitrogenous compounds,
notably urea and creatinine, which can be associated with
a reduction of urinary output [3]. However, small increases
in serum creatinine are associated with higher mortality,
possibly indicating the limitation and low sensitivity of this
parameter in early stages of AKI [3]. As previously men-
tioned, AKI is a condition that needs immediate interven-
tion due to its rapid progression and significant morbidity
and mortality. For this reason, several diagnostic tools have
been proposed aiming to detect AKI as early as possible [7].
2045
Currently, the most frequently used criteria to define and
classify AKI in the pediatric population are pRIFLE, AKIN,
and KDIGO. These classification scores share laboratory
parameters, although with some specificities [54, 59]. All
have been validated and consolidated in the scientific lit-
erature as capable of predicting morbidity and mortality in
adults [60, 61], but with important constraints. A compari-
son between different criteria for AKI diagnosis and classi-
fication is summarized in Table 2. Strong evidence indicates
that an effective variation of kidney function biomarkers,
SCr included, is only observed after important damage of
kidney tissue [3]. Limitations of the SCr are even more
expressive in the pediatric population, after children have
presented low SCr levels. Even if this parameter increases
significantly, it may still be within the normal range [14].
Kidney angina index
As an alternative to the various biomarkers and criteria for
AKI, the concept of the kidney angina index was developed
in 2010 to classify patients according to their pretest prob-
ability of developing severe AKI — stage 2 or 3 according
to KDIGO [94]. Patients should be evaluated 3 days after
ICU admission based on clinical and laboratory criteria [95].
The kidney angina index is summarized in Table 3. The kid-
ney angina index is fulfilled when the multiplied score of
risk and injury is equal to or greater than 8, though greater
scores are also related to greater risks of developing severe
AKI [96]. According to a multicenter cohort study, a kidney
angina index below 8 has a high negative predictive value
(92–99%) and a high positive predictive value for day-3
AKI, outperforming those of KDIGO-1 and with similar and
often superior parameters compared to KDIGO-2 and 3 [95].
Perspectives on pharmacological treatment
Traditionally, AKI treatment aims to reduce or cease kid-
ney lesions and to provide support, with rigorous control
of hemodynamics, hydroelectrolytic, and acid–base distur-
bances. In recent years, novel drugs have been proposed
to interrupt specific pathways of kidney lesion, potentially
reducing damage extension and avoiding further injuries.
Mechanisms addressed by these new treatment options
interfere with microvascular alterations in nephron blood
flow, production of ROS, inflammation, and cycle cell arrest,
along with apoptosis.
Exogenous angiotensin II is proposed to raise intra-
glomerular pressure by efferent arteriole constriction and
aldosterone release in the context of inflammation and
RAS dysfunction when the angiotensin type 1 receptor and
angiotensin II itself could be downregulated [97, 98]. This
molecule could increase GFR to maintain adequate kidney
perfusion, avoiding ischemic events in the tubular epithelial
13
 2046

13
Table 2  Comparison of different criteria for acute kidney injury (AKI) diagnosis and classification
Creatinine definition Estimated CCI Urine output
AKIN KDIGO RIFLE pRIFLE KDIGO, AKIN, and pRIFLE
RIFLE

Stage 1 ≥ 0.3 mg/dL increase Stage 1 ≥ 0.3 mg/dL increase Risk ≥ 1.5-fold increase Risk eCCl decreased by 25% < 0.5 mL/kg/h for > 6 h < 0.5 mL/kg/h for 8 h
OR ≥ 1.5-fold increase within 48 h OR from baseline SCr
from baseline SCr 1.5–1.9 times baseline OR decrease in
within 48 h within 7 days GFR ≥ 25%
Stage 2 ≥ twofold increase from Stage 2 2.0–2.9 times baseline Injury ≥ twofold increase Injury eCCl decreased by 50% < 0.5 mL/kg/h for 12 h < 0.5 mL/kg/h for 16 h
baseline SCr within 7 days from baseline SCr
OR decrease in
GFR ≥ 50%
Stage 3 ≥ threefold increase Stage 3 ≥ 3 times baseline Failure ≥ threefold increase Failure eCCl decreased by 75% < 0.3 mL/kg/h for 24 < 0.3 mL/kg/h for 24 h
from baseline SCr OR within 7 days OR from baseline SCr OR OR eCCl < 50 mL/ hOR anuria for > 12 h OR anuric for 12 h
increase to ≥ 4.0 md/dL increase to ≥ 4.0 mg/ increase to ≥ 4 mg/ min/1.73 ­m2
with an acute increase dL with an acute dL OR decrease in
of > 0.5 mg/dL OR increase of > 0.5 mg/ GFR ≥ 75%
initiation of KRT dL OR initiation of
KRT

Legend: The diagnoses and classifications are given due to the presence of any of the described changes: creatinine level alterations for acute kidney injury network (AKIN); kidney disease
interventions, goals and outcomes (KDIGO); risk, injury, failure, lesion, end-stage kidney disease (RIFLE); estimated creatinine clearance for pediatric RIFLE (pRIFLE); and urine output for all
Abbreviations: eCCl estimated creatinine clearance, SCr serum creatinine, GFR glomerular filtration rate, KRT kidney replacement therapy
Pediatric Nephrology (2022) 37:2037–2052
Pediatric Nephrology (2022) 37:2037–2052
Table 3  Renal angina index for stratifying risk of acute kidney injury
Risk strata Risk criteria
Admission to ICU
Solid organ or stem-cell transplantation
Mechanical ventilation and/or vasoactive sup-
port
Injury strata Serum creatinine relative to FO accu-
baseline mulation
(%)
Decrease or no change <5
Less than 50% increase 5 to 10
50% to less than 100% increase 11 to 15
More than 100% increase > 15
Abbreviations: ICU, intensive care unit; FO, fluid overload
cells and subsequent functional loss [30, 56]. Although some
evidence was demonstrated in animal models, current data
in humans seem inconclusive [98].
As an example of antioxidant drugs, alpha-lipoic acid
neutralizes ROS and restores inactivated natural antioxi-
dants, such as vitamin C, with promising results in animal
studies [99, 100]. Selenium supplementation is proposed to
reduce cellular oxidative damage in animal models. How-
ever, human data are ambiguous [101, 102]. Propofol is
associated with increased kidney protection when compared
to sevoflurane. Experimental studies showed antioxidant
properties for propofol. In humans, propofol was associated
with reduced AKI incidence when chosen as the main anes-
thetic drug in surgical procedures [103–105].
Genetic modifiers have been proposed as a treatment
option for AKI due to their capacity of altering the cell cycle
arrest and apoptosis that lead to ATN [106]. The small inter-
fering ribonucleic acid I5NP inhibited p53 in kidney tubules
and improved tubular injury in mice [107]. However, human
studies are still missing.
Potential biomarkers for AKI
Considering the intrinsic limitations of currently used
kidney biomarkers, which only get augmented after sig-
nificant kidney damage, the search for new biomarkers has
increased in the past two decades [57]. In this regard, stud-
ies have evaluated the urinary levels of tissue inhibitor of
metalloproteinases 2 (TIMP-2), insulin-like growth factor
binding protein 7 (IGFBP7) [108–110], liver fatty-acid-
binding protein (L-FABP) [111, 112], kidney injury
molecule-1 (KIM-1) [113, 114], neutrophil gelatinase-
associated lipocalin (NGAL) [115–117], and interleukin
(IL)-18 [118, 119] and the capacity of these molecules
to show early increases in response to kidney damage. In
2014, the United States Food and Drug Administration
2047
approved the use of TIMP-2/IGFBP7, known commer-
Score
cially as NephroCheck, as a diagnostic tool for AKI [56].
Although several studies have shown that these molecules
1
can be used as predictors of AKI in pediatric patients, the
3 results should be interpreted with caution, as the studies
5 were mainly carried out in situations of cardiopulmonary
bypass [120]. Findings on these biomarkers are summa-
rized in Table 4.
Score
1
2 Conclusion
4
8 Although AKI is a condition with significant incidence and
important morbimortality, large epidemiological studies
with the pediatric population are scarce. Current data have
established a general pathophysiological pathway to explain
the disease, but more substantial information in specific
etiologies is needed to better manage and develop novel
treatment options. Diagnostic tools are diverse and limited
to labile biomarkers at present, hampering a standardized
analysis and classification in the pediatric population. Sev-
eral biomarkers and drugs have been tested as options for
early diagnosis and more tailored treatment of AKI. How-
ever, few significant advances have occurred in clinical prac-
tice to date. Further understanding of its physiopathological
mechanisms is needed to properly manage pediatric patients
with AKI.
Key summary points
Acute kidney injury is defined by abrupt decline in glo-
merular filtration rate secondary to functional, kidney, and
postkidney etiologies.Glomerular filtration rate experiences
a fast decrease in the initiation phase, followed by a slow
reduction in extension phase, an augmentation in mainte-
nance, and a stabilization in the recovery phase of AKI.
Acute kidney injury is defined by abrupt decline in glo-
merular filtration rate secondary to functional, kidney, and
postkidney etiologies.
Glomerular filtration rate experiences a fast decrease in
the initiation phase, followed by a slow reduction in exten-
sion phase, an augmentation in maintenance, and a stabiliza-
tion in the recovery phase of AKI.
AKI is responsible for important morbimortality rates
among the pediatric population, mostly due to kidney imma-
turity and increased susceptibility to drug toxicity and accu-
mulation of waste products.
The search for sensible, specific, and rapidly increasing
biomarkers for AKI includes promising studies on NGAL,
KIM-1, IL-18, and L-FABP.
13
 2048

13
Table 4  Current studies on potential urinary biomarkers for acute kidney injury in pediatric patients
Biomarker Characterization Study Conclusion Ref

TIMP-2/IGFBP7 Markers of cell-cycle arrest, released in response to non-injurious Gist et al., 2017 TIMP-2/IGFBP-7 can be used in infants to predict subsequent serum 108
noxious stimuli creatinine-defined AKI following cardiopulmonary bypass
Westhoff et al., 2015 TIMP-2/IGFBP7 has good diagnostic performance in predicting 109
adverse outcomes in neonatal and pediatric AKI
Dong et al., 2017 TIMP-2/IGFBP-7 alone is not suitable for predicting AKI among the 110
pediatric population
L-FABP Cytoplasmatic protein of kidney proximal tubules, upregulated in Ivanišević et al., 2013 L-FABP rises earlier than serum creatinine in children with AKI 111
continuous kidney lesion undergoing cardiopulmonary bypass
Portilla et al., 2008 L-FABP levels represent a sensitive and predictive early biomarker of 112
AKI after cardiac surgery in children
KIM-1 Transmembrane protein of proximal tubules epithelial cells, upregu- Genc et al., 2013 Serial KIM-1 measurements may be used as a non-invasive indicator 113
lated in continuous kidney lesion of kidney injury in premature newborns
Parikh et al., 2013 KIM-1 was not significantly associated with AKI in children after 114
adjusting for other kidney injury biomarkers
NGAL Bacteriostatic molecule produced by neutrophils that is related to Kuribayashi et al., 2016 Urinary NGAL elevated a day before alteration in serum creatinine, 115
kidney epithelium development being considered an earlier marker for AKI
Reiter et al., 2018 Plasma and urinary NGAL values are not good predictors of AKI in 116
pediatric patients undergoing cardiopulmonary bypass
Bellos et al., 2018 This metanalysis concluded that serum and urinary NGAL are highly 117
predictive for AKI in newborns with perinatal asphyxia
IL-18 Pro-inflammatory cytokine produced in proximal tubular cells Washburn et al., 2008 IL-18 rises prior to serum creatinine in non-septic critically ill chil- 118
dren
Li et al., 2012 IL-18 is an independent predictive biomarker of AKI in non-septic ill 119
neonates

Abbreviations: TIMP-2, Tissue Inhibitor of Metalloproteinases 2; IGFBP7, Insulin-like Growth Factor Binding Protein 7 (IGFBP7); L-FABP, Liver fatty-acid-binding protein; KIM-1, Kidney
Injury Molecule-1; NGAL, Neutrophil Gelatinase Associated Lipocalin; IL-18, Interleukin 18
Pediatric Nephrology (2022) 37:2037–2052
Pediatric Nephrology (2022) 37:2037–2052
Multiple choice questions (answers are
provided following the reference list)
1. What is the GFR change in each AKI pathophysiological
phase?
a) Initiation (slow GFR decrease), extension (fast GFR
decrease), maintenance (GFR stabilization), recov-
ery (GFR increase).
b) Initiation (slow GFR decrease), extension (fast GFR
decrease), maintenance (slow GFR increase), recov-
ery (fast GFR increase).
c) Initiation (fast GFR decrease), extension (slow GFR
decrease), maintenance (GFR stabilization), recov-
ery (GFR increase).
d) Initiation (fast GFR decrease), extension (slow GFR
decrease), maintenance (GFR increase), recovery
(GFR stabilization).
2. Considering the pathophysiology of Sepsis-associated
Acute Kidney Injury (SA-AKI), choose the correct
answer:
a) SA-AKI’s pathophysiology is similar to other AKI
etiologies, with hypoperfusion and ischemic injury
being the main mechanisms.
b) The most accepted mechanism associated with SA-
AKI is a decrease in global kidney blood flow, but
differently from other AKI causes, it does not lead
to Acute Tubular Necrosis.
c) There is more than one pathway for the development
of SA-AKI, including ischemia–reperfusion injury,
inflammation, alterations in microcirculation and
metabolic reprogramming.
d) Microcirculatory dysfunction is one of the mecha-
nisms associated with SA-AKI, through endothelial
injury, thrombotic microangiopathy and alteration
of the kidney blood flow with preserved capillary
density.
3. Which of the following causes of intrinsic kidney dis-
ease is not associated with drug-induced nephrotoxicity?
a) Acute Tubular Necrosis.
b) Acute Interstitial Nephritis.
c) Tumor Lysis Syndrome.
d) Rapidly Progressive Glomerulonephritis.
4. Which pregnancy-related event favours AKI onset in
neonatology?
a) Late term delivery.
b) Antenatal glucocorticoid administration.
c) Placental abruption.
2049
d) Use of centrally-acting anti-hypertensive agents.
5. Which parameter/condition is most widely used to deter-
mine AKI in hospitalized patients?
a) Reduction of urine output or anuria.
b) Increase in baseline serum creatinine (SCr).
c) Reduction of glomerular filtration rate (GFR).
d) Need for kidney replacement therapy.
Author contribution AFLR, GML, NBC, VAP, and LBC did the lit-
erature review and selected the main articles, defined the topics of
this review, and wrote the first draft. KL and ACSS conceptualized
the study, provided general supervision, and revised the manuscript.
ACSS submitted the final version of the manuscript, which is approved
by all authors.
Funding This study was partially supported by CNPq (National Coun-
cil for Scientific and Technological Development), grant 430246/2018–
8, and FAPEMIG (Research Support Foundation of Minas Gerais),
grant PPM-00435–18.
Declarations
Ethics approval Not applicable.
Conflict of interest The authors declare no competing interests.
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Multiple choice answers 1. c; 2. c; 3. d; 4. b; 5. b