Pediatr Nephrol
DOI 10.1007/s00467-015-3298-9
EDUCATIONAL REVIEW
The path to chronic kidney disease following acute kidney injury:
a neonatal perspective
Swasti Chaturvedi 1 & Kar Hui Ng 1,2 & Cherry Mammen 3
Received: 30 May 2015 / Revised: 30 November 2015 / Accepted: 8 December 2015
# IPNA 2016
Abstract The risk of acute kidney injury (AKI) in hospital-
ized critically ill neonatal populations without primary renal
disease continues to be high, in both term and premature in-
fants. Observational studies have revealed high rates of chron-
ic kidney disease (CKD) in survivors of neonatal AKI. Pro-
posed mechanisms underlying the progression of CKD fol-
lowing AKI include nephron loss and hyperfiltration, vascular
insufficiency and maladaptive repair mechanisms. Other fac-
tors, including prematurity and low birth weight, have an in-
dependent relationship with the development of CKD, but
they may also be positive effect modifiers in the relationship
of AKI and CKD. The large degree of heterogeneity in the
literature on AKI in the neonatal population, including the use
of various AKI definitions and CKD outcomes, has hampered
the medical community’s ability to properly assess the rela-
tionship of AKI and CKD in this vulnerable population. Larg-
er prospective cohort studies with control groups which utilize
recently proposed neonatal AKI definitions and standardized
CKD definitions are much needed to properly quantify the
risk of CKD following an episode of AKI. Until there is fur-
ther evidence to guide us, we recommend that all neonates
with an identified episode of AKI should have an appropriate
* Cherry Mammen
cmammen@cw.bc.ca
1
Khoo Teck Puat-National University Children’s Medical Institute,
National University Health System, Singapore, Singapore
2
Department of Paediatrics, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore, Singapore
3
Division of Paediatric Nephrology, Department of Paediatrics,
British Columbia Children’s Hospital, 4480 Oak Street,
Vancouver, BC, Canada V6H3V4
longitudinal follow-up in order to identify CKD at its earliest
stages.
Keywords Acute kidney injury . Outcomes .
Chronic kidney disease . Neonate . Prematurity
Introduction
Over the past decades, there has been a major epidemiological
shift in paediatric acute kidney injury (AKI) etiology. Previ-
ously, the most commonly reported causes of AKI in children
were related to primary kidney diseases, such as haemolytic
uremic syndrome and post-infectious glomerulonephritis
[1–7]. More recently, the most common causes of paediatric
AKI are related to systemic illnesses or their treatments in
hospitalized patients without primary renal disease [5, 8, 9].
Recent research has further highlighted that AKI is not just a
marker of illness severity in children, but that it has a direct
independent association with poor outcomes including mor-
tality, ventilation requirements and hospital length of stay [2,
10–18].
Neonates, most commonly defined as infants aged
<28 days, are at a particularly high risk of AKI during hospi-
talization due to several factors, including a naturally low
glomerular filtration rate (GFR) in the first weeks of life, tu-
bular immaturity, an increased susceptibility to reduced renal
perfusion and disturbed glomerular vasoregulation (vasomo-
tor nephropathy), the increased risk of renal vein and artery
thrombosis with frequent use of umbilical vascular access
catheters and a high exposure to nephrotoxins, such as ami-
noglycosides and non-steroidal anti-inflammatory drugs
[19–22]. A high incidence of AKI has recently been docu-
mented in several neonatal populations, including term and
near-term infants with perinatal asphyxia (15.6–38 %) [23,

24], premature infants with very low birth weight (VLBW;
<1500 g) and extremely low birth weight (<1000 g) (12.5–
39.8 %) [25–27] as well as neonates requiring cardiac surgery
for congenital heart disease (62–64 %) [11, 15].
Historically, AKI was thought of as a completely reversible
syndrome, with the underlying notion that survivors of an
AKI episode return to their pre-morbid renal function. How-
ever, over the past several years, a plethora of data from ex-
perimental animal and human studies has suggested that AKI
more than likely results in permanent kidney damage [28–32].
Depending on the severity and site of injury, the phenotype of
chronic kidney dysfunction may be in the form of hyperten-
sion, proteinuria, tubular dysfunction, a reduced GFR or even
hyperfiltration at its earlier stages [33, 34]. In adults, a recent
systematic review revealed that patients with a single episode
of AKI had a significantly higher risk of developing chronic
kidney disease (CKD) [pooled adjusted hazard ratio (HR) 8.8;
95 % confidence Interval (CI) 3.1–25.5)] and end-stage renal
disease (ESRD) [HR 3.1; 95 % CI 1.9–5) than patients with-
out AKI [30]. Several adult studies have demonstrated a dose–
response relationship between AKI and CKD, including a
higher risk of CKD with increasing severity of AKI and also
with repeated episodes of AKI [35–37]. In children, it is al-
ready known that there is a considerable risk of long-term
renal sequelae associated with AKI caused by intrinsic kidney
diseases, such as Henoch–Schonlein purpura or haemolytic
uremic syndrome [4, 38]. The increased risk of CKD in sur-
vivors of AKI in older children without primary renal disease
has also been highlighted in recent observational studies, with
high proportions of CKD incidence ranging from 10.3 to 69 %
[31, 39–43].
This review will focus on the long-term renal outcomes of
AKI in neonatal populations without primary renal disease
and includes the following: (1) the pathophysiology and
mechanisms underlying the progression of AKI to CKD; (2)
a review of the literature supporting the link between neonatal
AKI and CKD; (3) the various issues surrounding the defini-
tion of neonatal AKI and CKD; (4) discussion of the need for
larger prospective studies and long-term renal surveillance on
all survivors of neonatal AKI.
A detailed summary of eight longitudinal studies from
1978–2014 which describe the long-term renal outcomes of
neonatal AKI in both premature and term/near term infants is
given in Table 1. The proportion of patients who developed
CKD outcomes, including reduced GFR (<60 ml/min/
1.73 m2), mildly reduced GFR (60–90 ml/min/1.73 m2),
hyperfiltration (GFR > 150 ml/min/1.73 m2), proteinuria and
hypertension is listed for each individual study. In studies that
included both neonates and older patients, neonatal data were
extracted from the individual studies when available or
through contact with the study authors. Figure 1 provides an
illustrated schematic of the pathway of CKD following neo-
natal AKI which includes the various causes of AKI in this
Pediatr Nephrol
vulnerable population and several potential effect modifiers
that may promote the development of CKD following an
AKI episode, including prematurity, low birth weight
(LBW), hypertension and childhood obesity.
AKI to CKD pathophysiology
Nephron loss, endothelial injury, vascular insufficiency, inter-
stitial inflammation and fibrosis, cell cycle disruption and
maladaptive repair mechanisms have all been implicated as
important regulators of CKD progression in patients who ex-
perience an episode of AKI [29, 44]. Remnant kidney models
suggest that nephron loss leads to glomerular hypertrophy and
hyperfiltration in the remaining nephrons which in turn trigger
tubulointerstitial fibrosis, arteriosclerosis and eventual
glomerulosclerosis [45, 46]. Inflammation after AKI also
leads to interstitial immune cell infiltration. Animal models
of acute tubular necrosis show an initial neutrophil infiltrate
followed by monocytic–lymphocytic infiltration at later stages
[47, 48]. These inflammatory cells further exacerbate injury
and promote ongoing fibrosis. Various AKI animal models
have also demonstrated endothelial injury in the acute phase
and reduced vascular density [49, 50]. Diminished vascular
density leads to tissue hypoxia and the activation of hypoxia-
inducible pathways that can promote further downstream in-
flammation and fibrosis [51, 52]. The repair processes that
become active after injury involve growth factors and prolif-
erative signaling cascades which work in a coordinated and
integrated manner for appropriate cell repair and regeneration
[47]. Maladaptive repair processes, such a cell cycle dysfunc-
tion and epigenetic changes, can derange normal repair and
regeneration processes and push the tissue towards the path of
fibrosis and further damage [53, 54].
Association of AKI and CKD in premature infants
Premature infants [<37 weeks gestational age (GA)] admitted
to a neonatal intensive care unit (NICU) setting represent a
highly prevalent and growing population across the world.
Currently, 15 million children are born premature annually,
with premature births accounting for approximately 11 % of
births worldwide [55]. In the USA, a 21 % increase in preterm
birth rates has been observed between 1980 and 2000, and
similar trends have been observed in other nations [55–57].
Despite the occurrence of this increased number of high-risk
premature births, an improvement in survival has also been
observed in the USA, with infant mortality rates declining by
over 30 % in babies born at >24 weeks GA between 1985–
1988 and 1995–2000 [58]. Those born as early as 25 weeks
gestation are now reported to have a >80 % chance of survival
[58, 59]. Outside of the high risk of AKI caused by several
Table 1 Summary of studies on long-term renal outcomes following neonatal acute kidney injury

First author, Study population/ AKI definition Number Age at Number (%) of patients with renal abnormalities at follow-up Remarks
year Study design of patients follow-up
with GFR <60 GFR 60–90 GFR > 150 Proteinuria Hyper-tension
Pediatr Nephrol

follow-up ml/min/ ml/min/ ml/min/

1.73 m2 1.73 m2 1.73 m2 a

Anand, 1978 Full-term (n = 7) and Peak BUN ≥40 mg/dl and/or 9 1–57 months 2 (22 %) 2 (22 %) 0 NK 3 (33 %) -Urine concentration defect
[101] premature infants SCr ≥1.8 mg/dl and either (n = 4; 44 %). -Bilateral
(n = 4) with AKI/ (1) UO ≤10 ml/kg/24 h × papillary necrosis or corti-
Retrospective cohort ≥24 h OR (2) haematuria cal scarring & atrophy
and/or proteinuria (n = 4, 44 %)
-GFR: timed urinary CrCl
Mocan, 1991 Full-term infants with Not specifically defined 16 2.5-16.7 (median 4 (25 %) 2 (13 %) 1 (6 %) 2 (13 %) 3 (19 %) -Urine concentration defect
[104] RVT (n = 16)/ -Oliguria (n = 13) 11.4 years) (n = 7; 44 %)
Retrospective cohort -Elevated BUN (n = 16) -GFR: timed urinary CrCl or
-Acute PD (n = 4) EDTA clearance
-Proteinuria: timed urine
protein excretion
Shaw, 1991b Full term infants with Requirement of acute 5 1.3–5.5 0 2 (40 %) 1 (20 %) 2 (40 %) NK -Urine concentration defect
[41] cardiac surgery dialysis (median 3.8 (n = 1; 20 %) -Proteinuria:
related AKI (n = 5)/ years) tubular protein by
Retrospective cohort electrophoresis
-GFR: DTPA scan
Marks, 2005 Full-term & preterm Not specifically defined 38 0.5–20.2 (median 11 (29 %) NK NK NK 13 (34 %) -ESRD (n = 3, 8 %)
[105] infants with RVT -Acute renal failure (n = 24) 3.7 years) -GFR: Schwartz formula.
(n = 43) -Acute PD (n = 2)
Median 38 weeks GA/
Retrospective cohort
Polito, 1998 Full-term neonates SCr >1.5 mg/dl × 24 h and 6 6.5–19 years 4 (66 %) 1 (17 %) 0 4 (66 %) 1 (17 %) -ESRD (n = 1; 17 %)
[102] with AKI (n = 6)/ UO < 1 ml/kg/h × 24 h -Urine concentration defect
Retrospective (n = 2; 33 %)
cohort - GFR: Schwartz formula
- Proteinuria: urinalysis
-High urinary NAG
excretion (n = 4; 67 %)
- US: renal atrophy/small
kidneys (n = 3, 50 %)
Abitbol, 2003 Preterm infants SCr >2 mg/dl × 48 h and/or 20 3.2–18.5 8 (40 %) 1 (5 %) 0 9 (45 %) 2 (10 %) -ESRD (n = 5; 25 %)
[61] (ELBW) with AKI UO <0.5 ml/kg/h × 24 h (mean 7.5 - US: loss of renal mass
(n = 20)/ after third day of life years) (n = 12; 60 %)
Retrospective cohort
Mammen, Term infants (PICU) AKIN definition 30 1–3 years 0 7 (23 %) 4 (13 %) 5 (17 %) 1 (3 %) -GFR: DTPA scan (n = 10;
2012c [31] with AKI (n = 30) (SCr and UO criteria) 33 %); Schwartz formula
Cardiac surgery- (n = 20; 67 %)
related AKI - Proteinuria: first morning
(n = 25)/ urine ACR >30 mg/g × 2
Prospective cohort
 Pediatr Nephrol

-Only longitudinal study with

tetraacetic acid; ELBW, extremely low birth weight; ESRD, end-stage renal disease; GFR, glomerular filtration rate (in ml/min/1.73 m2 ); IQR, interquartile range; KDIGO, Kidney Disease Improving
ACR, Albumin creatinine ratio; AKI, acute kidney injury; CrCl, creatinine clearance; DTPA, diethylenetriaminepentaacetic acid; ECMO, extracorporal membrane oxygenation; EDTA Ethylenediamine-
physiological and haemodynamic stressors imposed by an of-

associated with CKD as

- Only history of AKI was

- Proteinuria: Urine PCR

-GFR: Schwartz formula
ten hostile extra-uterine environment, premature infants are

defined by KDIGO
often born with a reduced nephron mass as nephrogenesis

control group
normally ceases at 36 weeks GA, with the majority of neph-

(p = 0.004)

Global Outcomes; NAG, N-acetyl-beta-glucosaminidase; NK, not known; PCR, protein creatinine ratio; PD peritoneal dialysis; SCr, serum creatinine; UO, urine output; US, ultrasound
rons forming in late gestation at a time when preterm infants
Remarks

have already been delivered [22]. Along with increased long-

term survival trends seen in all preterm GA groups due to
advances in obstetrical and neonatal care, these factors place
GFR > 150 Proteinuria Hyper-tension

the premature infant at a potentially higher risk of CKD, es-

32 (19 %)

pecially after an AKI episode, compared to older children and

adults.
Number (%) of patients with renal abnormalities at follow-up

In a landmark autopsy study involving 56 extremely pre-

mature infants weighing ≤1000 g and ten full-term infants as
20 (12 %)

controls, glomerulogenesis was assessed by measuring radial

glomerular counts (RGC) [60]. For analysis, preterm infants
were initially divided into two groups, namely, those surviv-
1.73 m2 a

19 (11 %)

ing for <40 and >40 days, respectively, and each group was
ml/min/

then further divided into those with AKI, defined as a maxi-

mum elevation of serum creatinine (SCr) of ≥2.0 mg/dl
(≥176.8 μmol/l), or not. RGC were significantly decreased
GFR 60–90

in all preterm infants as compared to term controls and corre-

1.73 m2
ml/min/

lated with gestational age (r = 0.87, p < 0.001). Active

9 (5 %)

glomerulogenesis, characterized by the appearance of primi-

tive BS-shaped bodies^ close to the renal capsule was absent in
GFR <60

preterm infants surviving for >40 days and term infants but
1.73 m2
ml/min/

present in premature infants surviving for <40 days, suggesting

that the kidney continues to form in premature infants postna-
0

tally, but with limited potential. Glomerular counts and glomer-

(IQR 5.2–12.1

ular size of those with AKI were significantly less and appeared
Median 8.2
of patients follow-up

abnormal with cystic dilatation of Bowman’s capsule (Fig. 2).

years)
Age at

These findings suggest that postnatal glomerulogenesis is im-

paired from the effects of AKI. The cystic dilatation of the glo-
merular capsule also suggests possible ischaemic injury that
follow-up
Number

could lead to glomerular sclerosis and nephron loss if these

with

169

patients survived. In those who survived longer without AKI,

larger glomeruli were seen compared to all other groups, sug-
gesting that even premature infants without significant AKI may
Neonatal data extracted through direct contact with authors

be prone to the effects of glomerular hyperfiltration and CKD.

In a long-term paediatric follow-up study of premature in-
Paediatric RIFLE
AKI definition

fants with AKI, Abitbol et al. evaluated 20 patients with a

(SCr criteria)
definition

history of extreme prematurity (mean GA 25 weeks); patients

Neonatal data extracted from journal article

with renal and urogenital abnormalities were excluded [61].

AKI was diagnosed based on a SCr level of >2.0 mg/dl
(176.8 μmol/l) for at least 48 h and/or oliguria of <0.5 ml/
ECMO (n = 169),
Study population/

Prospective cohort

kg/h for >24 h after the third day of life. This study identified a
AKI (n = 62)/
Term infants on

large proportion of patients (85 %) with either a reduced esti-

Study design

Indicating hyperfiltration

mated GFR (eGFR) of <75 ml/min/1.73 m2 (n = 9) or an ele-

vated urine protein:creatinine ratio (PCR) of >0.2 mg/mg
Table 1 (continued)

(n = 15) in a median follow-up period of 6.6 years. An elevat-

ed SCr of >0.6 mg/dl (53 μmol/l) and urine PCR of >0.6 mg/
Zwiers, 2014
First author,

mg at 1 year of age were the strongest predictors for CKD

[106]

progression in this cohort. Five patients (25 %) developed

year

ESRD. The histomorphometry of the kidney from one of these

b
a

c
Pediatr Nephrol
Fig. 1 Schematic diagram revealing the multiple causes of neonatal
acute kidney injury (AKI) (green) and the various factors which
potentially contribute to the development of chronic kidney disease
(CKD) following an AKI episode (purple and blue)
patients who developed ESRD at age 5 years was compared to
that of the kidney from a full-term age-matched child with
primary focal segmental glomerulosclerosis (FSGS) and to
that of a kidney from a healthy child without renal disease
[62]. Lower RGC as well as a larger Bowman’s space and
mesangial area were seen in the child with a history of prema-
turity (24 weeks) and AKI compared to the control patients. In
this study, obesity seemed to be a significant effect modifier in
premature infants, as a body mass index (BMI) of >85th per-
centile at 3 years of age was associated with an increased risk
of renal dysfunction progression [61].
Fig. 2 Renal autopsy tissue from extremely preterm infants surviving
≥40 days with acute kidney injury (AKI) (a) and without AKI (b),
compared with a full-term infant with normal renal function (c). Preterm
infants with AKI (a) show cystic dilatation of Bowman capsule (arrows),
some cystically dilated tubules and smaller glomerular tuft areas than
Risk of CKD and hypertension in premature infants
without AKI
In another informative autopsy study, Sutherland and col-
leagues analysed 28 premature infants surviving from 2–68
days without a documented history of AKI at 24–35 weeks
GA [63]. Accelerated postnatal glomerular maturation was
observed in all preterm infants, but up to 13 % of glomeruli
from the premature infants showed abnormalities, including a
dilated Bowman’s space and a larger cross-sectional area of
the renal corpuscle suggestive of renal hyperfiltration. Abnor-
mal glomeruli were only present in the outer cortex, suggest-
ing that it is the newer glomeruli formed in the extra-uterine
environment that are unlikely to be fully functional and may
be at risk of further damage from AKI episodes.
Several paediatric case–control studies have also examined
CKD in premature infants without a documented episode of
AKI. Kwinta et al. followed 78 infants with a median GA of
27 weeks and 38 full-term age-matched controls with a medi-
an age of 6.7 years [64]. These authors reported that cases had
significantly higher serum cystatin C levels (0.64 vs. 0.59 mg/
l) and smaller kidneys, as assessed by ultrasonography, than
the controls (renal volume: 81 vs. 113 ml, respectively), sug-
gesting that kidney growth may be stunted after preterm birth.
In the same study, analysis of 12-h pooled urine samples re-
vealed that 6.4 % (n = 5) of the study subjects had
microalbuminuria versus none in the control group [64].
Rodriguez-Soriano et al. followed 40 children with a history
of prematurity (mean GA 27 weeks) at a mean age of 8.6 years
and compared them with 43 age-matched controls [65]. Over-
all, only one study subject demonstrated a reduced eGFR of
<90 ml/min/1.73 m2 (Schwartz equation), but plasma urea and
creatinine values for the study subjects were significantly
higher than those for the controls. Specifically, 12.5 %
(n = 5) of those with a history of prematurity had
microalbuminuria [urine albumin:creatinine ratio (ACR)
>30 mg/g] versus none in the control group [65]. Lastly,
those without AKI (b). Large glomeruli (glomerulomegaly) are clearly
present in b, indicating potential hyperfiltration. Formation of new
glomeruli (glomerulogenesis) was not seen in those neonates surviving
for ≥40 days (a–c). Figures are adapted from Rodriguez et al. [60] with
permission.

Iacobelli et al. compared renal function in 48 premature in-
fants (mean GA 29.7 weeks) at a mean age of 7.2 years with
46 age-matched controls born at term [66]. Microalbuminuria
(urine ACR >20 mg/g) was found more frequently in the study
subjects than in the controls (8.3 vs. 2.1 %, respectively), but
the difference was not found to be statistically significant.
eGFR (Schwartz) was reported as Bnormal^ in all study sub-
jects, but the reported mean GFR values in the study subjects
were elevated (149 ± 40 ml/min/1.73 m2), indicating potential
hyperfiltration injury [66]. Severe hypotension requiring ino-
tropic support during the neonatal period was also significant-
ly associated with albuminuria, suggesting that AKI may have
had a role in the development of CKD in this group of patients
[66].
Individuals born preterm may also be at an increased risk of
developing hypertension due to several factors, including
interrupted angiogenesis, impaired endothelial function and
reduced arterial elasticity [67–69]. A meta-analysis of ten ob-
servational studies showed that former preterm or VLBW in-
fants had a modestly higher systolic blood pressure than full-
term infants (pooled estimate increase of 2.5 mmHg) at a
mean age of 17.8 years [70]. A paediatric study involving
24-h ambulatory blood pressure monitoring (ABPM) in 41
children with a mean age 8.8 years who were born premature-
ly did not reveal any significant daytime blood pressure dif-
ferences compared to those born at term [71]. However, noc-
turnal systolic blood pressure was significantly higher in the
preterm children, and a lack of nocturnal dipping was more
prevalent in this group than in the controls. These subtle ab-
normalities in blood pressure regulation found in preterm chil-
dren may be progressive over time, as a recent 24-hour ABPM
study performed on 50 young adults revealed significantly
higher daytime systolic blood pressures in those with a history
of prematurity compared to controls [72].
Preterm birth also predisposes children to the development
of metabolic syndrome, beginning with early insulin resis-
tance and the subsequent development of hyperinsulinemia,
dyslipidemia and obesity [73–76]. Outside of the risk of dia-
betes, obesity appears to be a significant effect modifier of
CKD progression in those born premature. Abitbol and col-
leagues showed that in children with proteinuric kidney dis-
ease, obese patients who were born premature had a signifi-
cantly increased risk of renal demise during childhood com-
pared to obese children born at term and non-obese patients
born preterm (HR 2.4; 95 % CI 1.1–7.1) [77]. Renal biopsy
revealed glomerulomegaly in all obese patients, representative
of glomerular hyperfiltration, and 41 % of patients with a
history of prematurity and obesity had findings consistent
with FSGS. Concomitant with the present-day ongoing global
obesity epidemic [78], the numbers of children and adoles-
cents with obesity-related glomerulopathy is likely to increase,
especially in survivors of the NICU with a prior history of
prematurity and/or AKI.
Pediatr Nephrol
Risk of CKD and hypertension in LBW infants
Another aspect unique to the neonatal population is the poten-
tially increased risk of CKD and hypertension in infants born
with LBW, defined by the World Health Organization as a
birth weight of <2500 g. LBW is not only the result of prema-
turity, but it is also associated with intra-uterine growth restric-
tion (IUGR) and a complex interplay of genetic, nutritional,
social and obstetric factors. The prevalence of IUGR is ap-
proximately 20–30 % in premature infants and up to 50 % in
term small for gestational age infants, defined as a birth weight
of <10th percentile for age [79–81].
Barker first proposed the concept of developmental origins
of health and disease and proposed a causal association be-
tween IUGR and premature birth with the future development
of hypertension, cardiovascular complications and metabolic
diseases [82, 83]. The BBarker’s hypothesis^ has subsequently
been confirmed by multiple epidemiological and experimental
studies [70, 72, 84–86]. In 1988, Brenner et al. first proposed
the Bhyperfiltration theory^ and hypothesised that individuals
with a reduced nephron endowment as a result of LBW are at
increased risk of hypertension, CKD and accelerated age-
related glomerulosclerosis [87–89].
The human kidney contains on average 900,000 glomeruli,
but with wide individual variation [90, 91]. Birth weight has
been found to correlate with nephron endowment independent
of GA. A landmark study by Manalich et al. performed a post-
mortem analysis of 35 infants born at term (>36 weeks GA),
18 of whom had LBW, and observed that birth weight was
directly related to glomerular number and was inversely relat-
ed to glomerular size [92]. An autopsy study of 56 adults
without kidney disease suggested that every 1 kg increase in
birth weight leads to an average increase of 260,000 additional
nephrons [93]. Reduced nephron mass is postulated to lead to
hyperfiltration via intra-renal vasodilatation, elevated glomer-
ular capillary pressure, increased plasma flow per nephron and
an increased single-nephron GFR [94]. This compensatory
increase in GFR is accompanied by an increase in endothelial
and mesangial cells and mesangial matrix expansion [46, 95].
The podocytes, however, are unable to proliferate, leaving
gaps in the filtration barrier, which in turn leads to proteinuria
and further glomerulosclerosis through activation of pro-
fibrotic pathways [46, 89]. Unfortunately, there is no com-
monly agreed-upon GFR threshold to define hyperfiltration,
with values ranging from 125 to 175 ml/min/1.73 m2 reported
in the literature [43]. We have chosen a GFR threshold of
150 ml/min/1.73 m2 in order to identify patients with potential
hyperfiltration in studies analysed in this review (Table 1).
In the last decades, the Brenner hypothesis has been strong-
ly supported by the results from a number of clinical studies
worldwide. In a meta-analysis of 27 studies, LBW (<2500 g)
was associated with an increased risk of hypertension [odds
ratio (OR) 1.21; 95 % CI 1.13–1.31] compared to those with a
Pediatr Nephrol
birth weight of >2500 g [86]. Mean systolic blood pressure in
those with LBW was increased by 2.28 mmHg (95 % CI
1.24–3.33).
A systematic review of 31 case–control or cohort studies,
excluding studies primarily consisting of very premature or
VLBW infants, revealed that individuals with LBW are at a
70 % greater risk of developing CKD, which was defined as
albuminuria, a low eGFR or ESRD [96]. A large registry-
based study from Norway revealed a higher risk for the devel-
opment of ESRD in infants with a birth weight of <10th per-
centile compared to those with birth weights of >10th percen-
tile (relative risk 1.7; 95 % CI 1.4–2.2) [97]. The clinicopath-
ological link between LBW and the future development of
FSGS was highlighted in a comprehensive report on six adults
(mean age 32 years, mean birth weight 1054 g) [98]. In all
patients, renal biopsy revealed FSGS in a minority of glomer-
uli, with a predominance of peri-hilar lesions, mild foot pro-
cess effacement and glomerulomegaly, all suggestive of a sec-
ondary FSGS process; no other risk factors for secondary
FSGS were present [98].
Even though it is difficult to disentangle the effects of pre-
maturity and LBW on the development of CKD outcomes as
they both often co-exist, recent studies have highlighted that
IUGR may have an independent effect on CKD development
in those born premature. A prospective study of a large cohort
of young adults (n = 422) born very premature (GA
<32 weeks) showed that the birth weight standard deviation
score (SDS) was negatively associated with SCr concentration
and microalbuminuria and positively associated with GFR at
19 years of age [99]. A separate cohort study of 50 children
born premature (mean GA 27.3 weeks) and followed-up for a
mean of 7.3 years found that GFR, as measured by inulin
clearance, was >90 ml/min/1.73 m2 in all patients [100]. How-
ever, inulin clearance was significantly lower in the 23 IUGR
patients (mean GFR 107 ml/min/1.73 m2) than in the 11 chil-
dren with normal birth weight for GA and with normal post-
natal growth (mean GFR 125 ml/min/1.73 m2). This study’s
novel finding was that those with extrauterine growth restric-
tion, defined as a low weight or height at discharge (<−2 SDS
for corrected age), also had significantly lower inulin GFR
values (mean 107 ml/min/1.73 m2) than those with normal
postnatal growth and without IUGR [100]. This result indi-
cates that an early deficit in protein-calorie intake may repre-
sent an important risk factor for long-term renal impairment in
those born premature and emphasizes the pivotal role of nu-
trition in the early days of extrauterine life.
Risk of CKD in term and near-term infants following
AKI
Several studies have followed term or near-term infants, i.e.,
without the effects of prematurity, after an episode of AKI in
childhood and have also found a significant percentage with
CKD (Table 1). In one of the earlier studies examining the
long-term renal consequences of AKI related to perinatal as-
phyxia, Anand et al. described nine survivors of AKI during a
follow-up period ranging from 23 to 57 months and found that
44 % (n = 4) had reduced eGFR of <90 ml/min/1.73 m2 as
measured with endogenous creatinine clearances from timed
urine collections [101]. Of the nine survivors, 33 % (n = 3) had
persistent hypertension. Reduced urine concentrating ability
following 12–16 h of fasting was found in all four patients in
whom it was measured, indicating potential tubulointerstitial
injury. Excretory urograms in those with reduced GFR re-
vealed extensive cortical scarring and atrophy as well as renal
papillary necrosis [101]. In a separate cohort study, six full-
term neonates with AKI mostly related to perinatal asphyxia
were followed for a minimum of 5 years. AKI was defined as
a SCr concentration of >1.5 mg/dl (130 μmol/l) or oliguria of
<1 ml/kg/h sustained for 24 h [102]. Of the six full-term neo-
nates, five (83 %) were identified with a reduced eGFR of
<90 ml/min/1.73 m2, while one patient was found to have
hypertension. One of these children developed ESRD and
required chronic dialysis at the age of 6 years. Markers of
tubulointerstitial damage were again identified, including a
reduced urinary concentrating ability following administration
of desmopressin in 33 % of patients (n = 2) and elevated uri-
nary excretion of N-acetyl-beta-glucosaminidase in 67 % of
patients (n = 4).
In one of the earliest studies of long-term outcome of in-
fants with reno-vascular accidents in the newborn period,
Stark et al. followed three infants ranging from 8 months to
2 years of age. Although AKI was not specifically identified,
all three neonates likely suffered from an acute renal insult
with significant rises in blood urea nitrogen values upon pre-
sentation (>40 mg/dl, or >14.3 mmol/l) [103]. All three pa-
tients had either a reduced creatinine clearance of <90 ml/min/
1.73 m2 or an abnormal creatinine level for age, while two of
the infants had findings consistent with tubular damage, in-
cluding reduced phosphate reabsorption, tubular proteinuria,
urine concentration defects and impairment in distal tubular
acidification [103]. An evaluation of 16 patients with renal
vein thrombosis (RVT) in the neonatal period or early infancy
at a median follow-up duration of 12 years revealed that 81 %
of patients (n = 13) developed oliguria and 25 % (n = 4) re-
quired acute peritoneal dialysis [104]. All patients had elevat-
ed plasma urea levels of ≥15 mmol/l (or ≥42 mg/dl) upon
presentation, indicating AKI, but SCr values were unavail-
able. At follow-up, 63 % of patients (n = 10) were identified
with renal abnormalities including eGFR of <90 ml/min/
1.73 m2 (n = 6), hypertension (n = 3), hyperfiltration with an
eGFR of 193 ml/min/1.73 m2 (n = 1) or an abnormal urinary
concentrating ability following a 12-h overnight fast (n = 7).
More recently, Marks et al. evaluated 38 of 43 eligible patients
with neonatal RVT at a median age of 3.7 years [105]. Clinical

presentations included AKI in 24 patients (56 %); 34 % of
patients (n = 13) had sustained hypertension, and 29 % of pa-
tients (n = 11) had a reduced eGFR of <70 ml/min/1.73 m2.
ESRD developed in 13 % of patients (n = 3) [105].
A prospective cohort study of children admitted to a pae-
diatric ICU with AKI, as defined by the Acute Kidney Injury
Network (AKIN) classification (SCr and urine output criteria),
included 30 term neonates with AKI mostly related to cardiac
surgery (85 %), whose unpublished data was extracted
through contact with the study authors [19]. At 1–3 years
following AKI, 16.6 % (n = 5) of the neonates with AKI were
identified with persistent albuminuria (first morning urine
ACR >30 mg/g), and 23 % (n = 7) had a mildly reduced
GFR of between 60 and 90 ml/min/1.73 m2. Four (13 %)
patients showed evidence of hyperfiltration with a measured
GFR of >150 ml/min/1.73 m2, while only one patient had
persistent hypertension during follow-up. Shaw et al. followed
11 survivors of cardiac surgery-associated AKI, of whom five
were neonates at the time of surgery, and found that 40 % of
neonates (n = 2) had a reduced eGFR of <90 ml/min/1.73 m2
at follow-up ranging from 1.3 to 5.5 years [41].
In another recent prospective cohort study, 169 children
previously treated with extra corporeal membrane oxygena-
tion (ECMO) in the neonatal period were followed up for a
median of 8.2 years. Of these children, 76 (45 %) developed
AKI as classified by the paediatric RIFLE (pRIFLE) score
[106]. Overall, 54 participants (32 %) had at least one sign
of CKD and/or hypertension. Of these 54 children, nine (5 %)
had a low eGFR of <90 ml/min/1.73 m2, but the GFR of all
were >60 ml/min per 1.73 m2. Proteinuria was seen in 20 of
the 169 children (12 %), with a median PCR of 0.26 mg/mg
(interquartile range 0.23–0.32 mg/mg), and 32 (19 %) children
had hypertension. Of the several variables analysed, including
diagnosis, age, use of vasopressors, ECMO duration and ox-
ygenation parameters, only a history of AKI was significantly
associated with CKD development (p = 0.004).
Strengths of neonatal AKI to CKD literature
As shown in Table 1, all eight observational studies have
revealed relatively high rates of CKD following neonatal
AKI. Five of the eight longitudinal studies revealed at least
20 % of patients with a GFR of <60 ml/min/1.73 m2 upon
follow-up. In the three studies that did not identify any patients
with a GFR of <60 ml/min/1.73 m2, a mildly reduced GFR
(60–90 ml/min/1.73 m2) was reported in an additional 5–40 %
of the respective study populations. The proportion of those
with hyperfiltration (GFR >150 ml/min/1.73 m2) ranged from
0 to 20 %, indicating that there may be a number of patients at
risk of progressive CKD without an apparent reduction in
GFR. In studies that measured urinary protein excretion, pro-
teinuria was identified in 12–66 % of patients. Lastly,
Pediatr Nephrol
hypertension was found in >10 % of patients in six of the eight
longitudinal studies. Even though the majority of studies were
retrospective in nature (n = 6), two more recent prospective
studies have also identified a number of patients with persis-
tent abnormalities, including a reduced GFR (5–23 %), pro-
teinuria (12–17 %), hyperfiltration (11–13 %) and hyperten-
sion (3–19 %) in their cohorts [31, 106]. In addition, one of
these studies utilized a control group without AKI and found
that children with RIFLE scores BInjury^ (eGFR decrease of
50 %) and BFailure^ (eGFR decrease of 75 %) had a higher
risk of developing CKD or hypertension than those without
AKI (OR 4.3; 95 % CI 1.6–12.1) [106].
Weaknesses of neonatal AKI to CKD literature
There is a significant degree of heterogeneity in the observa-
tional studies that have examined the long-term renal out-
comes of neonatal AKI including various study populations,
sample sizes, age at follow-up as well as definitions of AKI
and CKD (Table 1). In terms of the epidemiological compar-
ison of studies, this degree of heterogeneity makes it difficult
to properly assess the relationship between neonatal AKI and
the future development of CKD. In addition, most studies to
date have not followed a control population, which leads to
the inability to quantify a true risk estimate of CKD following
AKI. As the majority of studies have involved a retrospective
cohort design with smaller sample sizes, the risk of attrition or
loss-to-follow-up bias is also high, which can lead to either an
undererestimation or overestimation of the burden of CKD
outcomes.
Historically, the majority of neonatal studies have utilized
more strict definitions of AKI, including a sustained increase
in SCr levels of >1.5–2 mg/dl (133–177 μmol/l) and/or
prolonged oliguria, while only a few studies have used stan-
dardized and graded AKI classifications, including the
pRIFLE score and the AKIN definition [107–109]. Even
though most studies described in this review have found a
significant proportion of patients with CKD, thereby
supporting the link between more severe AKI and CKD, there
is a lack of published data on the long-term renal outcomes of
AKI of milder severity. Neonates with milder degrees of AKI
may also be at risk of CKD, especially with the presence of
other potential effect modifiers, including LBW and
prematurity.
In terms of CKD assessment, there has also been a wide
heterogeneity in the measurement of outcomes, which also
makes inter-study comparisons difficult. The majority of stud-
ies have estimated GFR using the Schwartz formula [31, 43,
106], but some have utilized timed creatinine clearance and
more accurate measured GFR techniques, such as ethylenedi-
aminetetraacetic acid (EDTA) and diethylenetramine-
pentaacetic acid (DTPA) clearance. Proteinuria quantification
Pediatr Nephrol
has ranged from timed urinary total protein excretion to spot
urine measurements of ACR or PCR, while some investiga-
tors have measured tubular protein excretion through urine
electrophoresis. Lastly, hypertension has been determined
mostly by casual office blood pressure readings, while only
few studies have used confirmatory 24-h ABPM.
Challenges of defining neonatal AKI
The unique physiology of the neonate complicates the inter-
pretation of our most commonly used clinical biomarker of
AKI—a change in the SCr concentration from baseline. Neo-
natal SCr levels are high in the first days of life and are reflec-
tive of a naturally low GFR and interference from maternal
creatinine levels. In more premature infants, the SCr level
often rises above maternal creatinine levels, potentially due
to tubular reabsorption of creatinine in the context of imma-
ture tubular function [110]. The role of potential AKI occur-
ring in the context of this early and appreciable rise of SCr in
premature infants is not known. SCr then declines at varying
rates over the first few weeks of life, with the slope of this
decline directly related to the GA of the infant [21, 22]. An-
other issue, which is common in the NICU setting, is that there
is a reluctance to measure SCr frequently in neonates due to
the concern for blood loss in infants who require multiple
sampling. Therefore, the true incidence of AKI in critically
ill neonates may be seriously underestimated as the rise of
creatinine may often be missed.
The use of urine output to define neonatal AKI also has its
specific issues. It is generally believed that neonates more
commonly have non-oliguric AKI compared to older patients.
However, there is a lack of sufficient knowledge regarding
normal urine output in critically ill neonates, and it is often
Table 2 Proposed neonatal acute kidney injury (AKI) definitions
Proposed classifications Categories
Modified Kidney Disease Stage 0 Stage 1
Improving Global Outcomes -No change in SCr or -SCr 1.5–1.9 × ref SCrc
(KDIGO) definition -Increase in SCr of in 7 days, or
<0.3 mg/dl -Increase in SCr of ≥0.3
-UO ≥0.5 ml/kg/h mg/dl in 48 h
-UO <0.5 ml/kg/h for 6–12 h
Neonatal RIFLE urine Risk
output criteriaa,b -UO <1.5 ml/kg/h for 24 h
ref, Reference; RRT, renal replacement therapy
a
RIFLE classification for acute kidney injury consists of three grades on increasing severity of AKI [Risk (R), Injury (I) and Failure (F)], and two
outcome classes [Loss (L) and End-stage kidney disease (E)]
b
For neonatal RIFLE, urine output (UO) reduction is not considered to be a criterion for the first 24 h of life. Total diuresis is measured in a 24-hperiod
and average UO is calculated (ml/kg/h)
c
Reference serum creatinine refers to the lowest previous serum creatinine value
difficult to measure hourly urine output as they often do not
have Foley catheters in place. Urine output in neonates may be
significantly higher than that in older hospitalized populations
with AKI due to several factors, including a higher total body
water content, immature tubular function and an inability to
concentrate the urine. Furthermore, newborns undergo early
postnatal weight loss as a result of contraction of the expanded
extracellular compartment (ECW) [111]. Although the exact
mechanisms responsible for ECW contraction are unclear, it is
generally believed to result from release of atrial natriuretic
peptide and resultant diuresis [112, 113]. Therefore, the com-
monly used Boliguria^ definition of <0.5 ml/kg/h may not be
an adequately sensitive marker of AKI in neonates. Bezerra
et al. performed a retrospective study of more than 300 neo-
nates admitted to a NICU and concluded that the oliguria
threshold level should be raised to 1.5 ml/kg/h due to its in-
dependent association with mortality [114]. With even higher
mortality rates associated with lower urine output thresholds
of <1 ml/kg/h and <0.7 ml/kg/h, these investigators have sug-
gested modifications to the original pRIFLE urine output
criteria, which are termed neonatal RIFLE or nRIFLE
(Table 2).
While there has been considerable progress in the valida-
tion of standardized creatinine-based AKI definitions in older
children and adults, including the RIFLE, pRIFLE, AKIN and
KDIGO (Kidney Disease Improving Global Outcomes) clas-
sifications [10, 107–109], these definitions have not been
widely used in neonatal populations until recently. Regardless
of the complexities surrounding the use of SCr in neonates,
there is general consensus that even a small increase in SCr of
0.3 mg/dl (26.5 μmol/l) or more (AKIN and KDIGO Stage 1)
is enough of a concern to signal an episode of AKI in this
population. Consequently, Jetton and Askenazi proposed a
neonatal AKI definition employing small modifications to
Stage 2 Stage 3
-SCr 2.0–2.9 × ref SCrc -SCr ≥3.0 × ref SCrc or
-UO <0.5 ml/kg/h for ≥12 h -SCr ≥2.5 mg/dl or
-UO <0.3 ml/kg/h for ≥24 h or
-Anuria for ≥12 h or
-Need for RRT
Injury Failure
-UO <1.0 ml/kg/h for 24 h -UO <0.7 ml/kg/h for 24 h
or anuric for 12 h

the existing KDIGO classification [115] (Table 2). Due to the
issues of SCr declining over the first week(s) of life, for the
modified KDIGO neonatal AKI definition each SCr measure-
ment is compared with the previous trough value. In addition,
a SCr cutoff of 2.5 mg/dl (221 μmol/l) has been chosen to
define AKI stage 3 (severe AKI) as this value represents a
GFR of <10 ml/min/1.73 m2. In a National Institute of
Health-sponsored Neonatal AKI Workshop held in April
2013, both nephrologists and neonatologists agreed that this
was the best neonatal AKI definition to date and would need
to be further tested in larger cohorts. Following this successful
workshop, the National Kidney Collaborative was formed,
consisting of neonatologists and nephrologists from 23 sites
internationally, and has recently embarked on a large retro-
spective cohort study (AWAKEN—Assessment of Worldwide
AKI and Epidemiology in Neonates) to determine if this neo-
natal modified AKI definition adequately predicts outcomes
such as mortality, length of stay and discharge SCr.
Given the difficulties in defining AKI in neonates, recent
research has focused on identifying novel biomarkers to pre-
dict AKI hours or even days before a urine output reduction or
SCr increment can be seen [116]. Studies on AKI biomarkers
in neonates are limited and have mainly been performed in
specific populations at risk for AKI, such as VLBW babies,
asphyxiated newborns and children undergoing cardiac sur-
gery with cardiopulmonary bypass [117, 118]. Moreover, just
like SCr, several studies have now shown that many urinary
biomarker concentrations depend on GA age and birth weight
[119, 120]. The ability of immature tubules to reabsorb these
proteins is underdeveloped in preterm infants and can lead to
different values in this population. In recent AKI studies, the
most promising early non-invasive AKI biomarkers were
identified as: serum cystatin C, urinary interleukin-18 (IL-
18), serum and urinary neutrophil gelatinase-associated
lipocalin (NGAL), kidney molecule-1 (KIM -1), liver-type
fatty acid-binding protein (L-FABP), angiotensinogen, tissue
inhibitor of metalloproteinase-2, IGF-binding protein 7, osteo-
pontin (OPN) and beta-2 microglobulin [121]. For biomarker
use to become relevant in clinical practice in neonates, there is
a need for validation of these new biomarkers in larger neo-
natal populations with the development of AKI and CKD
prediction models.
Issues surrounding defining CKD
Given the wide heterogeneity of CKD outcomes reported in
the literature (Table 1), it would be prudent to use standardized
definitions of CKD in future prospective studies examining
the relationship between neonatal AKI and CKD. The 2012
KDIGO guidelines define CKD as a GFR of <60 ml/min/
1.73 m2 and/or the presence of markers of kidney damage
including albuminuria (urine ACR ≥30 mg/g), urinary
Pediatr Nephrol
sediment abnormalities, markers of tubular dysfunction (in-
cluding electrolyte abnormalities) or imaging abnormalities
for >3 months [122]. The role of hyperfiltration in the defini-
tion of CKD has not been discussed extensively in these
guidelines, and this is unfortunate considering hyperfiltration
is likely to be highly prevalent in neonates followed in child-
hood after AKI. Those with an eGFR between 60 and 90 ml/
min/1.73 m2 alone are considered to have a Bmildly reduced^
GFR, but are not considered as having CKD as per the
KDIGO definition.
In those children aged <2 years, the CKD criteria of <60 ml/
min/1.73 m2 does not apply as it is not until age 2 years that
one would expect to see body surface area-adjusted GFR
values comparable to those of an adult. However, age appro-
priate GFR and SCr values in those aged <2 years can be found
in a number of references [123–125]. As measured GFR tech-
niques, including inulin, iohexal, EDTA or DTPA clearance,
are often resource intensive and costly, it is recommended to
use paediatric-specific estimating equations in children, in-
cluding the Schwartz formula [126, 127]. However, it is im-
portant to note that the most recent estimating Schwartz equa-
tions based on enzymatic creatinine has not been validated in
those <1 year of age [126, 127]. Measured GFR scans can be
considered for those in whom SCr may not be as accurate (e.g.
patients with low muscle mass) to confirm low eGFR readings
or in those with suspected hyperfiltration (i.e. high eGFR and/
or low SCr for age).
For the assessment of albuminuria, a first morning urine
ACR is recommended to rule out orthostatic effects and
should be repeated if abnormal. Confirmation of albuminuria
can also be determined from an overnight urine collection for
timed albumin excretion rates. Normal urine ACR and albu-
min excretion rates in children of various ages can be found in
a recent comprehensive review [128]. The KDIGO guidelines
grade the degree of albuminuria from urine ACR measure-
ments as normal to mildly increased (ACR <30 mg/g), mod-
erately increased (ACR 30–300 mg/g) and severely increased
(ACR >300 mg/g). The urine protein:creatinine ratio can also
be used to quantify proteinuria in children, but this ratio does
not differentiate between tubular proteinuria and albuminuria,
both of which can be present following neonatal AKI [129].
Suggested CKD surveillance following an AKI
episode
According to the Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) system, the current
evidence of a significant risk of CKD following neonatal AKI
is largely based on smaller observational studies (Level C or
Low Evidence) [130]. Until there is further supporting evi-
dence to guide us, we recommend that all neonates identified
with an AKI episode should have longitudinal follow-up
Pediatr Nephrol
based upon the relevant results from the observational studies
highlighted in this review (Expert Opinion).
Unfortunately, there are no evidence-based guidelines to
suggest who should follow a neonate after an episode of
AKI, how often to follow them and what investigations are
necessary to screen for CKD in this population. The 2012
KDIGO AKI guidelines recommend evaluating patients at
least 3 months after AKI for resolution, new onset or worsening
of pre-existing CKD [108]. Since we are uncertain of the true
risk of CKD following neonatal AKI of varying severity, we
feel that further screening of all AKI patients for hypertension
and albuminuria at least annually is a non-invasive approach
where the overall benefits of identifying early modifiable risk
factors of CKD progression outweigh any risks of evaluation.
This should be accompanied by growth and BMI assessments
as well as counselling/education on healthy lifestyle habits at
every visit. Further evaluation of renal function with SCr and/
or cystatin C may be recommended for those with additional
CKD risk factors, including more severe AKI (KDIGO stages
2 and 3 or those requiring acute renal replacement therapy),
significant prematurity, LBW, IUGR or underlying renal struc-
tural abnormalities on ultrasound (Expert Opinion).
From a clinical perspective, one major concern is the lack
of recognition and recording of neonatal AKI events during
hospitalization. In a study of 66,526 preterm neonates, a coded
diagnosis of Brenal dysfunction^ and Brenal failure^ was only
found in 1.9 % of the population even though 15.1 % of the
neonates had a documented SCr of >1.3 mg/dl (114 μmol/l)
and another 2.5 % had SCr of >2 mg/dl (176.8 μmol/l) [131].
In a recent study of 455 VLBW infants which revealed an AKI
incidence of 39.8 %, AKI was recorded at discharge for only
13.5 % of AKI survivors, and no patient was referred to a
nephrologist for AKI follow-up [25]. This signifies that the
paediatric nephrology community needs to focus more on
improving AKI and CKD awareness and enhancing collabo-
ration with physicians caring for neonates at risk of AKI,
including intensivists, neonatologists and cardiac surgeons
as well as the general paediatricians who may be taking care
of these children for many years until adulthood.
Conclusions
The risk of AKI in critically ill neonates, both in term and
premature populations, continues to be high. This review
highlights that there may be an increased risk of CKD follow-
ing an AKI episode in neonates and that the presence of other
common variables, including prematurity, LBW and obesity
during childhood, may further increase the risk of CKD. Prop-
er longitudinal surveillance of neonates following an AKI
episode throughout childhood can potentially lead to earlier
identification of CKD and the initiation of therapy to limit
disease progression. Adoption of this strategy will be critical
as the long-term survival of hospitalized neonates continues to
increase. With several gaps identified in the current literature,
further prospective multi-center AKI studies with control pop-
ulations are much needed in order to properly study the long-
term consequences of AKI utilizing standardized definitions
of neonatal AKI and CKD.
Key summary points
1. Acute kidney injury (AKI) is a relatively common event
in hospitalized neonates, both in premature and term
infants.
2. Observational studies have shown high rates of chronic
kidney disease (CKD) in survivors of neonatal AKI; how-
ever, several gaps exist in the literature, including a large
degree of heterogeneity between studies.
3. Factors including prematurity and low birth weight have
an independent relationship with the development of
CKD, but they may also represent potential positive effect
modifiers in the relationship of AKI and CKD.
4. All neonates with an identified episode of AKI should
have serial follow-up throughout childhood in order to
identify early signs of CKD.
Multiple choice questions (answers are provided
following the reference list)
1. Which of the following mechanisms have been proposed
in the progression of CKD following an AKI episode?
a) Nephron loss leading to glomerular hyperfiltration
b) Tubulointerstitial fibrosis
c) Endothelial injury and reduced vascular density
d) Maladaptive repair mechanisms including cell cycle
disruption and epigenetic changes
e) All of the above
2. Which of the following renal pathology findings have not
been identified in premature infants with severe AKI
through prior autopsy studies?
a) Cystic dilatation of Bowman’s capsule
b) Podocyte effacement
c) Cystic dilatation of tubules
d) Lower glomerular counts compared to term infants
3. Outside of albuminuria and a reduced GFR, paediatric
observational studies have identified which of the follow-
ing abnormalities in survivors in neonatal AKI?
a) Tubular proteinuria
b) Urinary concentrating defects

c) Supranormal GFR values indicating potential
hyperfiltration
d) Hypertension
e) All of the above
4. Which of the following statements is false in regards to
defining AKI in neonates
a) Defining AKI in neonates is challenging in the first
days of life due to the effects of maternal creatinine
and a naturally improving GFR
b) Existing long term follow-up studies have shown a
significant amount of hetereogenity in defining neo-
natal AKI
c) The recently proposed neonatal modified KDIGO
definition utilizes an absolute serum creatinine in-
crease of 0.3 mg/dl (26.5 μmol/l) to define AKI with-
in a period of 7 days
d) The recently proposed neonatal RIFLE urine output
criteria is based on a retrospective study that revealed
that Boliguria^ thresholds higher than >0.5 cc/kg/h
are associated with mortality
5. After an AKI episode in the neonatal period, which of the
following children would not be considered as having
CKD as per the KDIGO definition (2012):
a) A 5-year-old male with a reduced eGFR of 75 ml/
min/1.73 m2 with small kidneys on ultrasound for
age and size
b) A 10-year-old female with an albumin:creatinine ra-
tio of 50 mg/g on a first morning urine × 2 and an
eGFR of 90 ml/min/1.73 m2
c) A 14-year-old male with an elevated eGFR of
160 ml/min/1.73 m2 with no abnormalities on blood
work, urine tests or imaging.
d) A 3-year-old female with persistent hypertension
with a measured GFR of 90 ml/min/1.73 m2 and no
imaging, bloodwork or urine abnormalities.
e) c and d
Acknowledgements We thank Dr. Dimple Rajgor for her assistance in
reviewing and editing the manuscript.
Compliance with ethical standards
Conflicts of interest None
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Answers:
1. e
2. b
3. e
4. c
5. e