Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6

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Seminars in Fetal & Neonatal Medicine

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Review

Chronic kidney disease in the neonate: etiologies, management,

and outcomes
Jason Misurac*
Pediatric Nephrology, University of Iowa Children's Hospital, Iowa City, IA, USA

s u m m a r y
Keywords: Neonatal chronic kidney disease (CKD) occurs with an estimated incidence of 1 in 10,000 live births,
Chronic kidney disease whereas the incidence of neonatal end-stage renal disease (ESRD) is about 7.1 per million age-related
Etiology
population. The most frequent etiologies are renal hypoplasia/dysplasia, posterior urethral valves, and
Neonate
Preterm
other congenital anomalies of the kidney and urinary tract. Other etiologies include polycystic kidney
disease, cortical necrosis, and renal vascular thrombosis. Management of CKD focuses primarily on
replacing renal functions such as erythropoietin, 1,25-hydroxylation of vitamin D, electrolyte homeo-
stasis/excretion, and, in ESRD, waste product removal. Nutrition and growth monitoring are of utmost
importance, with the majority of ESRD infants requiring gastrostomy tube for nutrition. Outcomes of
neonates (<31 days) started on dialysis continue to improve, with large cohort studies showing 2e3-year
survival rates of 79e81%. As in other neonatal disciplines, the gestational age and size limits for safe
provision of dialysis continue to decrease.
© 2016 Elsevier Ltd. All rights reserved.

1. Etiologies of neonatal chronic kidney disease
Neonatal chronic kidney disease (CKD) may broadly be defined
as a decrease in kidney function which manifests in the neonatal
period and is longstanding or is expected to be longstanding. The
incidence of neonatal CKD is difficult to ascertain, as there have
been few systematic studies. Wedekin et al. retrospectively
analyzed all neonates at a single center with serum creatinine
>100 mmol/L (1.13 mg/dL), dividing them into acute kidney injury
(AKI) and CKD cohorts. During ~5 years of study, 49 infants with
CKD were identified, for an incidence of 1 in 10,000 live births in
the geographical area of the study [1]. More data are available
regarding incidence and etiologies of neonatal end-stage renal
disease (ESRD), the most severe presentation of neonatal CKD. The
ANZDATA registry showed an incidence of ESRD of 7.1 per million
age-related population in infants aged 0e2 years, consistent with
rates reported elsewhere [2,3]. A study of the North American Pe-
diatric Renal Trials and Collaborative Studies (NAPRTCS) database
identified the causes of ESRD in the modern era (2000e2012)
among 98 neonates aged <31 days: (i) renal dysplasia in 28%, (ii)
* Address: 200 Hawkins Dr, 4019 BT, Iowa City, IA 52242, USA. Tel.: þ1 319 356
7249.
E-mail address: jason-misurac@uiowa.edu.
obstructive uropathy in 21%, (iii) reflux nephropathy in 3%, and (iv)
other causes in 46% [4]. Etiologies of ESRD in neonates from a
combined database study representing 40 countries and 264 pa-
tients showed that the most frequent causes of neonatal ESRD
were: (i) congenital anomalies of the kidney and urinary tract
(CAKUT) in 55%, (ii) cystic kidney disease in 13%, (iii) cortical ne-
crosis in 11%, and (iv) congenital nephrotic syndrome in 6% [3].
Preterm neonates are at a higher risk of CKD for several reasons.
First, they are born with a smaller complement of nephrons. Renal
development begins at 5 weeks of gestation, with the first per-
manent nephrons appearing at about 9e10 weeks. However, >60%
of glomeruli form in the third trimester, and nephrogenesis pla-
teaus at 36 weeks [5,6]. Furthermore, nephrogenesis does not
continue normally after preterm birth. Sutherland et al. demon-
strated this by examining kidney tissue collected at autopsy from
28 preterm neonates with postnatal survival ranging 2e68 days.
The estimated gestational age ranged 24e35 weeks, and these
kidneys were compared to 32 stillborn controls matched to post-
conceptional age [7]. The preterm kidneys demonstrated acceler-
ated postnatal renal maturation with a much higher proportion of
abnormal glomeruli compared to kidneys from the stillborn infants
[7]. Providing further evidence that nephron endowment is lower
in preterm neonates, Hughson et al. showed that birth weight was
directly correlated to number of glomeruli many years later in au-
topsy study of teens and adults without kidney disease [8].

http://dx.doi.org/10.1016/j.siny.2016.09.003
1744-165X/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
2 J. Misurac / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6
Second, preterm neonates are frequently exposed to nephro-
toxic medications and other risk factors for AKI. Exposure to
nephrotoxic medications interrupts and impairs nephrogenesis by
causing AKI. Indeed, in-vitro evidence has shown that gentamicin
has direct effects on reducing nephron endowment in rats [7,9]. It is
increasingly recognized that AKI frequently leads to increased risk
of later development of hypertension, proteinuria, and CKD. This
occurs through pro-fibrotic healing pathways during AKI recovery.
Finally, CKD is more prevalent in preterm neonates because
prenatal kidney disease leads to a higher risk of preterm delivery.
This may be related to oligohydramnios and the associated increase
in risk for preterm delivery, or to the various syndromic causes of
CKD in children, which often have extra-renal manifestations that
may themselves make preterm delivery more likely.
The increased risk of CKD in the preterm neonate is neatly
summed up by two recent studies. The first, a systematic review,
compiled observational studies which examined the link between
birth weight and the development of CKD defined as albuminuria,
low estimated glomerular filtration rate (GFR <60 mL/min/1.73 m2),
or end-stage renal disease (ESRD). There was a significant associ-
ation between low birth weight and risk of CKD at 20e50 years of
age, with overall odds ratio of 1.73 (95% confidence interval
1.44e2.08) [10]. Thus, preterm delivery in itself is a risk factor for
CKD development. Second is an analysis from the Chronic Kidney
Disease in Childhood (CKiD) study, demonstrating that 17% of the
cohort with CKD had a history of low birth weight, compared with
8% in the general population. Additionally, 40% of these children
with CKD were hospitalized in the neonatal ICU immediately after
birth [11].
1.1. Congenital etiologies of neonatal CKD
1.1.1. Cystic kidney disease and renal ciliopathies
1.1.1.1. Autosomal dominant polycystic kidney disease. Autosomal
dominant polycystic kidney disease (ADPKD) is caused by a mutation
in either PKD1 or PDK2 [12]. Penetrance is near 100%, but disease
severity is widely variable due to gene, allele, and gene modifier
effects. Severe ADPKD can present in neonates or in utero and can
even mimic autosomal recessive polycystic kidney disease (ARKPD)
in its presentation [13]. However, most patients with ADPKD present
as young adults, and the progression to ESRD is much slower than
ARPKD [12]. The overall incidence is ~1 in 1000, making ADPKD the
most prevalent heritable kidney disease [12]. Family history is pos-
itive in about 90% of patients, with a presumed de-novo mutation
rate of 10%. The cysts in ADPKD arise from any part of the nephron,
and range in size from microscopic to very large. Cyst formation is
thought to occur following random somatic loss of heterozygosity,
and more cysts appear gradually over time. The prevalence of hy-
pertension in children with ADPKD is 20%, and may be present from
early in childhood, even with normal renal function [14]. Negative
imaging (ultrasound, magnetic resonance imaging, etc.) does not
rule out ADPKD, and routine imaging or genetic testing is not
currently recommended due to the lack of accepted disease-specific
treatment [13,15].
1.1.1.2. Autosomal recessive polycystic kidney disease. Autosomal
recessive polycystic kidney disease (ARPKD) is a genetic disorder
caused by a mutation in the polycystic kidney and hepatic disease 1
gene (PKHD1), located on chromosome 6p21 [12]. ARPKD is often
identified during the prenatal and neonatal periods due to strikingly
large, poorly functioning, echogenic kidneys. Kidney size is
typically þ2 to þ4 standard deviations above the normal for gesta-
tional age, in contrast to the normal or small echogenic kidneys seen
with mutations of hepatocyte nuclear factor 1b (HNF1b) [16,17].
Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
ARPKD occurs at a frequency of 1 in 10,000 to 1 in 40,000 live births,
and affects males and females equally [12].
The cysts in ARPKD are not generally visible on ultrasound or
gross examination of the kidneys, and are all similar in size. They
arise exclusively from the collecting tubules, and they affect all of
the collecting tubules [17]. Over time, larger cysts may develop.
The severity of ARPKD ranges from ESRD at birth with severe
pulmonary hypoplasia and congenital hepatic fibrosis to mildly
decreased kidney function with gradual but inexorable progression
to ESRD [12,18]. Overall, 14% reached ESRD by 5 years of age, 29% by
10 years, and 58% of patients reached ESRD by 20 years of age.
Whereas ARPKD was once considered a uniformly fatal disease, 70%
of patients now survive beyond the newborn period, and mortality
in the neonatal period is most usually due to pulmonary disease
[12]. More than 80% of those patients who survive the neonatal
period survive beyond 10 years of age [18].
There are no known disease specific treatments to slow the
progression of cyst formation in ARPKD. Hypertension is a common
feature: one series of patients showed that angiotensin-converting
enzyme (ACE) inhibitors were used in 82% (18/22) of patients with
ARPKD, and three or more antihypertensive drugs were required in
32% (7/22) [18]. Unilateral or bilateral nephrectomy may be needed
due to impingement of the abdominal compartment on the dia-
phragm in patients with pulmonary hypoplasia or to allow space
within the peritoneum for peritoneal dialysis. However, manage-
ment of an anephric infant with ARPKD and pulmonary hypoplasia
is very challenging, so the decision to proceed with nephrectomy
must be carefully considered. Portal hypertension due to hepatic
fibrosis occurs in about half of patients who survive the neonatal
period, and early involvement of hepatology is important in pa-
tients with hepatomegaly or other signs of hepatic involvement
[12].
1.1.1.3. Other renal ciliopathies. There has been substantial and
growing interest in the role of cilia in the pathogenesis of certain
kidney diseases since the 1999 discovery that proteins from Cae-
norhabditis elegans (nematode worm) genes PKD-2 and LOV1
localize to the worm's flagellum [19,20]. Further work demon-
strated that many of the genes implicated in various forms of her-
itable cystic kidney disease have products which localize to or
interact with the primary cilia on renal epithelial cells [19]. The
following heritable kidney diseases are now considered cil-
iopathies: ADPKD, ARPKD, juvenile nephronophthisis, Joubert
syndrome, BardeteBiedel syndrome, oro-facial digital syndrome
type I, Jeune syndrome, and MeckeleGruber syndrome [19]. A
detailed review of these syndromes is beyond the scope of this
article, but the importance of cilial function is illustrated by the
multi-organ impact of almost all of these syndromes.
1.1.2. Renal dysplasia
Renal dysplasia falls within the larger category of congenital
anomalies of the kidneys and urinary tract (CAKUT). Genetic de-
fects, lower urinary tract obstruction, and certain teratogens/drugs
may cause renal dysplasia, but it is most often idiopathic [21]. By
definition, dysplastic kidneys are deficient in normal renal tissue
(nephrogenic zone, glomeruli, collecting ducts). Dysplastic kidneys
have been characterized as having primitive tubules with sur-
rounding metaplastic cartilage and stroma, dysmorphic vessels,
and cysts [21,22]. Multicystic dysplastic kidney (MCDK) is a severe
form of renal dysplasia in which the kidney is comprised of mul-
tiple cysts with no functional renal tissue [21].
CAKUT are mostly considered polygenic or non-heritable.
However, recent genetic studies of CAKUT cohorts have identified
a number of single genes which may lead to CAKUT [23,24]. This fits
with the observations that some CAKUT segregate in family cohorts,
 J. Misurac / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6
that CAKUT are present in syndromes affecting multiple organs,
and that monogenic mutations in mouse models may result in
CAKUT [23]. Multiple genes have been implicated in CAKUT,
including hepatocyte nuclear factor 1b (HNF1b) (previously called
TCF2), SALL1, PAX2, CHD1L, ROBO2, EYA1, RET, BMP7, CDC5L, GATA3,
SIX2, and SIX5 [16,24,25].
HNF1b has received much recent attention, and cohort studies
have found that up to 30% of patients with CAKUT have mutations
in HNF1b, depending on patient selection [26]. There is strong
rationale to support the role of HNF1b in renal development based
on in-vitro experiments and on the findings of the cohort studies.
HNF1b is expressed in the ureteric bud and the metanephric
mesenchyme during development [27]. In a mouse model, lack of
renal expression of HNF1b resulted in smaller than normal kidneys,
with early postnatal lethality compatible with death due to severe
renal failure. During development, fetal mice had defective S-sha-
ped body formation, enlargement of Bowman's capsule with some
glomerular cysts, and tubular dysgenesis [27]. Normal development
was seen in podocytes and glomerular cells of this mouse model
[27]. In humans, HNF1b mutations are implicated in a wide range of
CAKUT, including vesicoureteral reflux, multicystic dysplastic kid-
ney, posterior urethral valves, and renal hypo/dysplasia [24]. The
fetal kidneys often appear echogenic, but are not characteristically
enlarged [16,26]. This echogenicity can lead to confusion with
ARPKD, but the normal kidney size and lack of rapid kidney
enlargement after birth differentiates HNF1b renal disease from
ARPKD [16].
HNF1b mutations may cause disease limited to the kidneys and
urinary tract, but can also cause extra-renal disease. One well-
known extra-renal manifestation of an HNF1b mutation is dia-
betes, as seen in the syndrome of renal cysts and diabetes (RCAD,
also known as MODY5) [26]. However, the clinical phenotype of
HNF1b mutations can also include other extra-renal manifestations
such as hypomagnesemia, hyperuricemia, hyperparathyroidism,
and uterine abnormalities [26,28].
1.1.3. Obstructive uropathy
1.1.3.1. Posterior urethral valves. Bladder outlet obstruction sec-
ondary to posterior urethral valves (PUVs) represents one of the
most common causes of ESRD in the neonate. It occurs exclusively
in boys, and can present with variable severity of renal dysfunction
[29]. One important predictor of long-term kidney function is renal
reserve at birth [29,30]. Odeh et al. analyzed renal outcomes in 75
boys with PUV [29]. Of these, 16/75 (21%) had progression to end-
stage renal disease after a mean follow-up of 64 ± 39 months,
consistent with other reports of end-stage renal disease prevalence,
which range from 13 to 42% [31e33]. Assessment of renal echo-
genicity, cortical medullary differentiation, and total parenchymal
area in the Odeh study was shown to be predictive of long-term
renal outcomes. In addition, the predictive value of serum creati-
nine at one year of age dichotomized at 80 mmol/L (0.9 mg/dL) was
validated in this group (P < 0.001) [29].
Long-term kidney function is also impacted by ensuring
adequate drainage of the bladder, and maintaining a low bladder
pressure. Patients with PUV often have thick-walled high-pressure
bladders with poor compliance. Despite successful valve ablation,
the thick-walled bladder may put pressure on urinary drainage, and
may lead to decline of renal function over time [34,35]. Early
ablation of the valves along with adequate bladder drainage and
cycling is the mainstay of treatment in uncomplicated PUV.
1.1.3.2. Other forms of urinary tract obstruction. While ureter-
opelvic junction obstruction and ureterovesical junction obstruc-
tion are relatively frequent forms of urinary tract obstruction, they
do not typically cause CKD unless bilateral. Neurogenic bladder (e.g.
Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
3
due to myelomeningocele) may lead to CKD, but generally not in
the neonatal period.
Prune-belly syndrome (PBS) consists of intra-abdominal crypt-
orchidism (in males), megaureter and megacystis, and redundant
abdominal wall with muscular deficiency. It is suggested that de-
ficiencies in mesoderm during the 6th to 10th weeks of develop-
ment may explain the abnormalities seen in prune-belly syndrome
[36]. The theory most widely held is that transient lower urinary
tract obstruction occurring at a specific point in fetal development
results in massive dilation of the lower ureteral tract. This causes
abdominal distention, resulting in destruction of the abdominal
musculature [37]. Renal hypoplasia or dysplasia are widely seen in
PBS, and additional associations include intestinal malrotation or
atresia [37]. Less frequent causes of lower urinary tract obstruction
include anterior urethral valves/diverticulum, obstructing ureter-
ocele, and megalourethra, among others [36].
1.2. Acquired causes of neonatal CKD
1.2.1. Acute kidney injury
Acute kidney injury (AKI) is covered elsewhere in this issue, but
it is important to note that recovery from AKI is often incomplete,
as detailed above, due to interruption of nephrogenesis along with
decreased nephron endowment in preterm neonates. Thus, AKI can
be an important acquired cause of CKD in the neonate.
1.2.2. Renal vascular thrombosis
Neonatal coagulation is immature by comparison to coagulation
in older infants and children; development progresses according to
postnatal and postconceptual age, with an acceleration of matu-
ration occurring after preterm birth [38]. Whereas the balance of
pro and anticoagulant factors in the healthy neonate does not
predispose to clotting at baseline, this balance is less stable and is
easily altered by maternal, genetic, infectious, and iatrogenic fac-
tors [38].
1.2.2.1. Renal vein thrombosis. The incidence of symptomatic renal
vein thrombosis (RVT) has been estimated to be 2.2 per 100,000
live births [39]. Risk factors include maternal diabetes, cho-
rioamnionitis, neonatal polycythemia, inherited thrombophilia,
congenital heart disease, male sex, birth asphyxia, hypertonic
dehydration, sepsis, and prolonged venous cannulation, among
others [38e40].
The clinical features of RVT include gross hematuria (48e56%),
palpable abdominal/flank mass (45e62%), and thrombocytopenia
(48e80%) [38,41]. This classic triad is only present in 22% of pa-
tients with RVT, so a higher index of suspicion in patients at high
risk is needed [41]. RVT is most often unilateral (70% of cases), but
long-term CKD is more prevalent with bilateral RVT [38]. Hyper-
tension may be seen but is less common in RVT than with renal
arterial thrombosis (RAT). The thrombosis may extend to the IVC,
and larger clots portend a worse prognosis. Whereas conventional
angiogram is the most sensitive test to detect RVT or RAT, Doppler
ultrasound is more widely used as it is less invasive and more
portable to the patient's bedside.
Choice of treatment depends on local practice patterns and
expertise, along with the consensus decision of an interdisciplinary
team. In many cases, the use of aggressive thrombolytic agents or
anticoagulants is reserved for more severe or bilateral cases of RVT
[38]. The benefit of restoring blood flow through thrombolytic
agents or anticoagulants must be balanced with the substantial risk
of bleeding, including intraventricular hemorrhage [38]. Whether
specific therapy is initiated or not, frequent renal ultrasound to
monitor for change is recommended.
4 J. Misurac / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6

Table 1
Outcomes and complications of peritoneal dialysis in extremely (ELBW) and very (VLBW) low birth weight infants.

Publication Age (days) at Birth Dialysis Access method Complications Survival

dialysis start weight (g) duration

Stojanovic et al. [52] 4 470 1d 24G IV cannula None reported No

Macchini et al. [53] 20e34 630e1097 3 d e long term Straight Tenckhoff-2, Leak (2/3) 67% (2/3)
Broviac-1
Yu et al. [54] 6e32 630e1430 2e10 d 14G Arrow Vascath with Peritonitis-2, Leak-2, 10/16 survived to 60 days post
manually added side-holes Hernia-1, Hemo- dialysis
peritoneum-1
Sizun et al. [55] 4e41 640e700 51e136 h 16G venous catheter or 20G Leak, hyperglycemia, and PD None (3/3 survived dialysis
chest tube catheter malfunction but died from extra-renal
causes)
Nakamura et al. [56] 6.2 ± 5.2 701 ± 118 7.1 ± 6.9 d 10F J-VAC drain or Tenckhoff Leak, hyperglycemia, and PD 9/14 weaned off PD, 3/14
straight catheter catheter malfunction survived to discharge
Kanarek et al. [57] 3 710 30 h Adult PD catheter cut down None Yes
and flame-sealed
Harshman et al. [49] 5 830 16 d 8.5 Fr, 8 cm Cook PD catheter Hypotension Yes
Milliner et al. [48] 2 850 1d Trocar catheter “Vygon 0.8 Catheter malfunction Yes
cm”
Rainey et al. [50] 8 930 14 w Tenckhoff PD catheter Peritonitis, hernias, catheter Yes
malfunction

IV, intravenous; PD, peritoneal dialysis.

Frequently occurring themes include the importance of dialysis catheter choice and placement, high mortality (especially in patients with multi-organ disease), and the short-
term nature of most reported courses of dialysis in ELBW and VLBW infants.

1.2.2.2. Renal arterial thrombosis. Renal arterial thrombosis (RAT)
is considered less prevalent than renal vein thrombosis, though
estimates of its incidence have not been rigorously assessed. By
far the most important risk factor for RAT is prolonged use of a
femoral or umbilical arterial catheter, but other risk factors
include low birth weight, prematurity, sepsis, catheter type, and
catheter location [42]. AKI is rare, unless the thrombus involves
both kidneys. However, CKD and chronic hypertension may be
late sequelae of RAT, whether unilateral or bilateral. RAT pre-
vention methods include removing arterial lines as soon as they
are not needed, using an end-hole single-lumen catheter, and
placement of the catheter tip above the origin of the renal ar-
teries and celiac axis, at the level of the T6eT9 thoracic verte-
brae [38].
Hypertension is the most usual presenting feature of RAT, and a
high index of suspicion in patients with femoral or umbilical arte-
rial lines is important. Proteinuria or microscopic hematuria may be
seen, though gross hematuria is rare.
2. Management of neonatal CKD
Chronic kidney disease management is highly dependent on the
severity of the CKD, and ranges from simple long-term surveillance
for mild CKD to renal replacement therapy for ESRD. Both phar-
macological management and renal replacement therapy are
covered elsewhere in this issue.
Briefly, pharmacological management of CKD centers around:
(1) drugs to replace missing endogenous renal products (erythro-
poietin, calcitriol), (2) drugs to mimic the homeostatic functions of
the kidney (phosphorus binders, potassium binders, alkali sup-
plementation, sodium supplementation), and (3) administration of
vitamins/minerals which are poorly absorbed or utilized in CKD
(vitamin D, iron, B vitamins, vitamin C). Other drugs are used for
specific indications, such as hypertension.
Choice of chronic renal replacement therapy is heavily weighted
towards peritoneal dialysis in the neonatal population because the
process and equipment scale down to neonate size much better
than hemodialysis (HD) or continuous renal replacement therapy
(CRRT). That said, there are some compelling primary indications
for HD or CRRT in neonates, of which hyperammonemia is most
important.
2.1. Nutrition and growth monitoring
In the first year of life, growth velocity is the highest of any age
besides fetal life, at 25 cm/year. This growth is driven primarily by
genetic potential and nutritional intake, not by the growth hormone
axis. For a number of reasons, most neonates with CKD lack sufficient
appetite and oralemotor skills to take in sufficient calories for
appropriate growth. This has been attributed to the uremic milieu,
including higher circulating levels of cytokines and alterations in
amino acid balance [43,44]. Therefore, gastrostomy or nasogastric
feeding tubes are an essential component of the nutritional man-
agement of almost every infant on dialysis, and for many with CKD.
Gastrostomy tube may be preferred due to a lesser incidence of oral
aversion and lower risk for tube displacement into the lungs [45].
Updated nutritional guidelines from KDOQI (Kidney Disease
Outcomes Quality Initiative) recommend that infants with CKD
receive caloric intake equal to that recommended for chronologic
age, with adjustments based on changes in weight and length
[45,46]. Protein intake in CKD should be 1e1.4 age-appropriate
normal intake, and for patients on peritoneal dialysis, protein
intake should be higher still at 1.8 g/kg/day for the first 6 months of
life [45]. This is due to the losses of protein in peritoneal dialysis
effluent, which may be 0.25 g/kg/day [47].
Sodium losses also occur across the peritoneal membrane, and
neither breastmilk nor formula has sufficient sodium to replace
these losses. Thus, infants on peritoneal dialysis generally require
3e5 mEq/kg/day of sodium intake, both to maintain normal serum
sodium and to maintain a positive sodium balance, which is
essential for growth [1,45]. In addition, sodium supplementation
may be required in patients with mild or moderate CKD with high
urine output or with tubular dysfunction (frequently in patients
with renal dysplasia/CAKUT) [46].
Dietary intake and growth percentiles (height, weight, BMI)
should be monitored at least monthly for infants on dialysis, and
every 1e3 months for infants with other CKD, depending on
severity and their growth pattern [46].
3. Outcomes
Outcomes of neonatal CKD have been infrequently studied. The
previously mentioned study by Wedekin et al. of neonates with

Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
 J. Misurac / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6
moderate to severe CKD found that 21 out of 49 patients received
dialysis (median age of 65 days at dialysis start). Overall survival was
74% (36/49) at a median of 2.9 years of follow-up [1]. Of those who did
not survive, four died after parental refusal of dialysis due to severe
extra-renal comorbidities. With these patients removed, 5-year
estimated patient survival was 83% [1]. Eleven of the 13 deaths
were associated with extra-renal malformations (heart, liver, and
lung hypoplasia, among others) [1]. Importantly, this study exam-
ined the impact of CKD on family life. It was shown that moderate to
severe CKD in the neonate has a large influence on multiple spheres
of family life: work, family time, free time, and time for other children
all were highly influenced by the child's disease [1].
3.1. Survival of neonates with ESRD
An international study combining multiple databases examined
264 children who started dialysis within the first month of life from
2000e2011 [3]. Outcome over a median of 7 months of follow-up
showed that 83% (219/264) children survived, with estimated 2-
year survival of 81% and estimated 5-year survival of 76%. Of the
45 children who died, the cause was missing/unknown in 18 (40%),
infection was the proximate cause in 16 (36%), cardiac arrest in four
(9%), pulmonary hypoplasia/edema in four (9%), and other in three
(7%) [3]. Secondary effects of ESRD were present in the majority of
children, including poor growth (63%), hypertension (57%), and
anemia (55%). A NAPRTCS study compared outcomes between ne-
onates (aged 31 days) starting dialysis in the prior era
(1992e1999) to the modern era (2000e2012) [4]. They found that
overall 3-year survival was 79% in the modern era versus 69% in the
prior era. The primary renal diagnosis influenced the risk of mor-
tality in that neonates with polycystic kidney disease had the
highest risk of death [4]. Infection and cardiopulmonary disease
were the overall leading causes of death [4]. The survival during the
initial course of dialysis and the overall survival have both
improved markedly, and rates of successful renal transplantation
have increased: 68% of dialysis terminations in the neonatal group
were for renal transplant [4]. Whereas neonates with ESRD have a
higher risk of overall mortality than infants started on dialysis
between 32 and 365 days of age, this is likely due to an increased
frequency of comorbidities in the neonatal group [4]. These studies
confirm that overall survival is improving for neonates with ESRD,
and that dialysis for these patients is far from a futile therapy.
Less information is available about the safety and long-term
outcomes of peritoneal dialysis in preterm neonates, especially
VLBW (<1500 g birth weight) and ELBW (1001e1500 g birth weight).
Although not performed universally, there are multiple case reports
of successful short-term peritoneal dialysis in these patients. In 1987,
Millner et al. reported short-term peritoneal dialysis in an 850 g birth
weight neonate. Peritoneal dialysis successfully reduced serum po-
tassium from 10 to 5 mmol/L, and was discontinued after 24 h. The
patient survived and was doing well at the most recent follow-up
(age 9 months) [48]. In 2014, Harshman et al. reported successful
short-term dialysis in an ELBW infant (birth weight 830 g) with oligo-
anuric AKI. Dialysis was performed for 16 days, and the patient sur-
vived with residual CKD at 16 months of age (estimated GFR 61 mL/
min/1.73 m2) [49]. Finally, Rainey et al. reported successful long-term
dialysis in a neonate born 930 g at 29þ5 weeks estimated gestational
age, and started on peritoneal dialysis at 7 days of age. The patient
received peritoneal dialysis successfully for 14 weeks, and did well in
long-term follow-up [50]. Still others have reported dialysis in VLBW
patients as a bridge to transplant [51]. Common themes in these re-
ports of peritoneal dialysis for ELBW and VLBW infants include the
importance of dialysis catheter choice and placement, high mortality
(especially in patients with multi-organ disease), and the short-term
nature of most courses of dialysis (Table 1).
Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
5
Practice points
 Chronic kidney disease in the neonate is generally pre-
natally diagnosed and is most often due to congenital
anomalies of the kidney and urinary tract.
 Outcomes are steadily improving in the treatment of ne-
onates with ESRD: 3-year survival in neonates initiated on
dialysis at <31 days of age is about 80%.
Research directions
 Cohort studies to evaluate incidence, severity, and out-
comes in neonates with CKD.
Conflict of interest statement
None declared.
Funding sources
None.
References
[1] Wedekin M, Ehrich JH, Offner G, Pape L. Aetiology and outcome of acute and
chronic renal failure in infants. Nephrol Dial Transplant 2008;23:1575e80.
[2] Orr NI, McDonald SP, McTaggart S, Henning P, Craig JC. Frequency, etiology
and treatment of childhood end-stage kidney disease in Australia and New
Zealand. Pediatr Nephrol 2009;24:1719e26.
[3] van Stralen KJ, Borzych-Duzalka D, Hataya H, Kennedy SE, Jager KJ, Verrina E,
et al. Survival and clinical outcomes of children starting renal replacement
therapy in the neonatal period. Kidney Int 2014;86:168e74.
[4] Carey WA, Martz KL, Warady BA. Outcome of patients initiating chronic
peritoneal dialysis during the first year of life. Pediatrics 2015;136:e615e22.
[5] Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D. Human intra-
uterine renal growth expressed in absolute number of glomeruli assessed by
the disector method and Cavalieri principle. Lab Invest 1991;64:777e84.
[6] Carmody JB, Charlton JR. Short-term gestation, long-term risk: prematurity
and chronic kidney disease. Pediatrics 2013;131:1168e79.
[7] Sutherland MR, Gubhaju L, Moore L, Kent AL, Dahlstrom JE, Horne RS, et al.
Accelerated maturation and abnormal morphology in the preterm neonatal
kidney. J Am Soc Nephrol 2011;22:1365e74.
[8] Hughson M, Farris 3rd AB, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular
number and size in autopsy kidneys: the relationship to birth weight. Kidney
Int 2003;63:2113e22.
[9] Cullen LA, Young RJ, Bertram JF. Studies on the effects of gentamicin on rat
metanephric development in vitro. Nephrology 2000;5:115e23.
[10] White SL, Perkovic V, Cass A, Chang CL, Poulter NR, Spector T, et al. Is low birth
weight an antecedent of CKD in later life? A systematic review of observa-
tional studies. Am J Kidney Dis 2009;54:248e61.
[11] Greenbaum LA, Munoz A, Schneider MF, Kaskel FJ, Askenazi DJ, Jenkins R, et al.
The association between abnormal birth history and growth in children with
CKD. Clin J Am Soc Nephrol 2011;6:14e21.
[12] Dell KM. The spectrum of polycystic kidney disease in children. Adv Chronic
Kidney Dis 2011;18:339e47.
[13] Verghese P, Miyashita Y. Neonatal polycystic kidney disease. Clin Perinatol
2014;41:543e60.
[14] Marlais M, Cuthell O, Langan D, Dudley J, Sinha MD, Winyard PJ. Hypertension
in autosomal dominant polycystic kidney disease: a meta-analysis. Arch Dis
Child 2016 Jun 10 [Epub ahead of print].
[15] Grantham JJ. Therapy for polycystic kidney disease? It's water, stupid! J Am
Soc Nephrol 2008;19:1e7.
[16] Decramer S, Parant O, Beaufils S, Clauin S, Guillou C, Kessler S, et al. Anomalies
of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys.
J Am Soc Nephrol 2007;18:923e33.
[17] Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F,
et al. Clinical consequences of PKHD1 mutations in 164 patients with auto-
somal-recessive polycystic kidney disease (ARPKD). Kidney Int 2005;67:
829e48.
6 J. Misurac / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6
[18] Dell KM, Matheson M, Hartung EA, Warady BA, Furth SL. Chronic Kidney
Disease in Children S. Kidney Disease Progression in Autosomal Recessive
Polycystic Kidney Disease. J Pediatr 2016;171:196e201 e1.
[19] Dell KM. The role of cilia in the pathogenesis of cystic kidney disease. Curr
Opin Pediatr 2015;27:212e8.
[20] Barr MM, Sternberg PW. A polycystic kidney-disease gene homologue
required for male mating behaviour in C. elegans. Nature 1999;401:386e9.
[21] Winyard P, Chitty LS. Dysplastic kidneys. Semin Fetal Neonatal Med 2008;13:
142e51.
[22] Woolf AS. Evolving Concepts in Human Renal Dysplasia. J Am Soc Nephrol
2004;15:998e1007.
[23] Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene
causes of congenital anomalies of the kidney and urinary tract (CAKUT) in
humans. Pediatr Nephrol 2014;29:695e704.
[24] Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, et al.
Mutations in 12 known dominant disease-causing genes clarify many
congenital anomalies of the kidney and urinary tract. Kidney Int 2014;85:
1429e33.
[25] Heidet L, Decramer S, Pawtowski A, Moriniere V, Bandin F, Knebelmann B,
et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor
renal diseases. Clin J Am Soc Nephrol 2010;5:1079e90.
[26] Bockenhauer D, Jaureguiberry G. HNF1B-associated clinical phenotypes: the
kidney and beyond. Pediatr Nephrol 2016;31:707e14.
[27] Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler MC, et al. Hepatocyte
nuclear factor 1beta controls nephron tubular development. Development
2013;140:886e96.
[28] Oram RA, Edghill EL, Blackman J, Taylor MJ, Kay T, Flanagan SE, et al. Muta-
tions in the hepatocyte nuclear factor-1beta (HNF1B) gene are common with
combined uterine and renal malformations but are not found with isolated
uterine malformations. Am J Obstet Gynecol 2010;203:364 e1e5.
[29] Odeh R, Noone D, Bowlin PR, Braga LH, Lorenzo AJ. Predicting risk of chronic
kidney disease in infants and young children at diagnosis of posterior urethral
valves: initial ultrasound kidney characteristics and validation of paren-
chymal area as forecasters of renal reserve. J Urol 2016;196:862e8.
[30] DeFoor Jr WR. Challenges in predicting renal outcomes in boys with posterior
urethral valves. J Urol 2016;196:639e40.
[31] DeFoor W, Clark C, Jackson E, Reddy P, Minevich E, Sheldon C. Risk factors for
end stage renal disease in children with posterior urethral valves. J Urol
2008;180:1705e8. discussion 8.
[32] Kibar Y, Ashley RA, Roth CC, Frimberger D, Kropp BP. Timing of posterior
urethral valve diagnosis and its impact on clinical outcome. J Pediatr Urol
2011;7:538e42.
[33] Klaassen I, Neuhaus TJ, Mueller-Wiefel DE, Kemper MJ. Antenatal oligohy-
dramnios of renal origin: long-term outcome. Nephrol Dial Transplant
2007;22:432e9.
[34] McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urody-
namic testing in myelodysplastic patients. J Urol 1981;126:205e9.
[35] Ghanem MA, Wolffenbuttel KP, De Vylder A, Nijman RJ. Long-term bladder
dysfunction and renal function in boys with posterior urethral valves based on
urodynamic findings. J Urol 2004;171:2409e12.
[36] Clayton DB, Brock 3rd JW. Lower urinary tract obstruction in the fetus and
neonate. Clin Perinatol 2014;41:643e59.
Please cite this article in press as: Misurac J, Chronic kidney disease in the neonate: etiologies, management, and outcomes, Seminars in Fetal &
Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.09.003
[37] Herman TE, Siegel MJ. Prune belly syndrome. J Perinatol 2009;29:69e71.
[38] Resontoc LP, Yap HK. Renal vascular thrombosis in the newborn. Pediatr
Nephrol 2016;31:907e15.
[39] Bokenkamp A, von Kries R, Nowak-Gottl U, Gobel U, Hoyer PF. Neonatal renal
venous thrombosis in Germany between 1992 and 1994: epidemiology,
treatment and outcome. Eur J Pediatr 2000;159:44e8.
[40] Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian
and international registry. Pediatrics 1995;96:939e43.
[41] Winyard PJ, Bharucha T, De Bruyn R, Dillon MJ, van't Hoff W, Trompeter RS,
et al. Perinatal renal venous thrombosis: presenting renal length predicts
outcome. Archs Dis Childh Fetal Neonatal Ed 2006;91:F273e8.
[42] Cohen RS, Ramachandran P, Kim EH, Glasscock GF. Retrospective analysis of
risks associated with an umbilical artery catheter system for continuous
monitoring of arterial oxygen tension. J Perinatol 1995;15:195e8.
[43] Mak RH, Cheung W, Cone RD, Marks DL. Leptin and inflammation-associated
cachexia in chronic kidney disease. Kidney Int 2006;69:794e7.
[44] Chazot C. Why are chronic kidney disease patients anorexic and what can be
done about it? Semin Nephrol 2009;29:15e23.
[45] Zaritsky JJ, Warady BA. Chronic kidney disease in the neonate. Clin Perinatol
2014;41:503e15.
[46] KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008
update. Executive summary. Am J Kidney Dis 2009;53:S11e104.
[47] Quan A, Baum M. Protein losses in children on continuous cycler peritoneal
dialysis. Pediatr Nephrol 1996;10:728e31.
[48] Millner M, Schweintzer G, Mutz I. Successful peritoneal dialysis in a prema-
ture infant with a birth weight of 850 gramsea case report. Klinische Padiatrie
1987;199:122e4.
[49] Harshman LA, Muff-Luett M, Neuberger ML, Dagle JM, Shilyansky J, Nester CM,
et al. Peritoneal dialysis in an extremely low-birth-weight infant with acute
kidney injury. Clin Kidney J 2014;7:582e5.
[50] Rainey KE, DiGeronimo RJ, Pascual-Baralt J. Successful long-term peritoneal
dialysis in a very low birth weight infant with renal failure secondary to feto-
fetal transfusion syndrome. Pediatrics 2000;106:849e51.
[51] Faas D, Klauwer D, Klaus G, Zerres K, Neuhauser C, Heckmann M. Long term
peritoneal dialysis in an anuric preterm infantea futile treatment? Klinische
Padiatrie 2012;224:76e9.
[52] Stojanovic V, Bukarica S, Doronjski A, Marinkovic S. Peritoneal dialysis in
neonates with extremely low body weight at birth: new modality of using IV
cannula for peritoneal access. Iranian J Pediatr 2013;23:718e20.
[53] Macchini F, De Carli A, Testa S, Arnoldi R, Ghirardello S, Ardissino G, et al.
Feasibility of Peritoneal Dialysis in Extremely Low Birth Weight Infants. J
Neonatal Surg 2012;1:52.
[54] Yu JE, Park MS, Pai KS. Acute peritoneal dialysis in very low birth weight
neonates using a vascular catheter. Pediatr Nephrol 2010;25:367e71.
[55] Sizun J, Giroux J-D, Rubio S, Guillois B, Alix D, Parscau LD. Peritoneal dialysis in
the very low-birth-weight neonate (less than 1000 g). Acta Paediatr 1993;82:
488e9.
[56] Nakamura S, Kon S, Iwanami N, Kemmochi M, Ishii M. Peritoneal dialysis for
extremely low birth weight infants. Kitasato Med J 2013;43:141e4.
[57] Kanarek KS, Root E, Sidebottom RA, Williams PR. Successful peritoneal dialysis
in an infant weighing less than 800 grams. Clin Pediatr 1982;21:166e9.