Short-Term Gestation, Long-Term Risk: Prematurity and

Chronic Kidney Disease

AUTHORS: J. Bryan Carmody, MD, and Jennifer
abstract R. Charlton, MD, MSc
Thanks to remarkable advances in neonatal intensive care, infants University of Virginia, Department of Pediatrics, Division of
Nephrology, Charlottesville, Virginia
who once had little chance for survival can now enter adulthood. Yet
KEY WORDS
the consequences of premature birth or low birth weight (LBW) on Chronic kidney disease, premature infants, low birth weight,
nephrogenesis, final nephron number, and long-term kidney function acute kidney injury, nephron, secondary FSGS, proteinuria
are unclear. This review focuses on the theory, experimental evidence, ABBREVIATIONS
and observational data that suggest an increased risk of chronic AKI—acute kidney injury
kidney disease (CKD) for infants born prematurely. Many premature CKD—chronic kidney disease
ESRD—end-stage renal disease
and LBW infants begin life with an incomplete complement of imma- FSGS—focal segmental glomerulosclerosis
ture nephrons. They are then exposed to a variety of external stress- GFR—glomerular filtration rate
ors that can hinder ongoing kidney development or cause additional LBW—low birth weight
nephron loss such as hemodynamic alterations, nephrotoxic medica- Dr Carmody participated in the research drafting and editing of
the manuscript; Dr Charlton formulated the study concept and
tions, infections, and suboptimal nutrition. Acute kidney injury, in
participated in the research, drafting and editing of the
particular, may be a significant risk factor for the development of manuscript; and both authors approved the manuscript as
CKD. According to Brenner’s hypothesis, patients with decreased submitted.
nephron number develop hyperfiltration that results in sodium re- www.pediatrics.org/cgi/doi/10.1542/peds.2013-0009
tention, hypertension, nephron loss, and CKD due to secondary focal doi:10.1542/peds.2013-0009
segmental glomerulosclerosis. Because the risk of CKD in premature Accepted for publication Mar 25, 2013
and LBW infants has not been accurately determined, there are no Address correspondence to Jennifer Charlton, MD, MSc,
evidence-based recommendations for screening or management. Yet Department of Pediatrics, University of Virginia, Box 800386,
with the first generation of infants from the surfactant era only now Charlottesville, VA 22908. E-mail: [email protected]
reaching adulthood, it is possible that there is already an unrecog- PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
nized epidemic of CKD. We suggest individualized, risk-based assess- Copyright © 2013 by the American Academy of Pediatrics
ments of premature and LBW infants due to the increased risk of CKD FINANCIAL DISCLOSURE: The authors have indicated they have
and call for additional research into the long-term risk for CKD these no financial relationships relevant to this article to disclose.
infants face. Pediatrics 2013;131:1168–1179 FUNDING: No external funding.

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 STATE-OF-THE-ART REVIEW ARTICLE

Improving survival for the smallest, hypertension,10 insulin resistance,11 and hypertension and proteinuria.14,16–18 These
most vulnerable infants is among the coronary artery disease.12 processes eventually cause nephrons
great success stories in pediatrics. The Nephrologist Barry Brenner first applied to become sclerotic and senescent.
advances in neonatal intensive care in Barker’s theory to the development of This in turn leads to additional decline
the past 50 years have been nothing less CKD. Building on the observation that in nephron number and greater hyper-
than remarkable: according to the most human nephron number is widely vari- filtration in remnant nephrons, culmi-
recent data from the Vermont Oxford able (ranging from 200 000 to 2 million nating in more rapid nephron dropout
Network, ∼90% of infants born weigh- per kidney13), Brenner hypothesized and perpetuating renal injury in a vicious
ing 501 to 1500 g survive to NICU dis- that either a congenital or acquired re- cycle14,19 (Fig 1).
charge, and ∼60% of survivors leave duction in nephron number could ex-
the NICU without any major neonatal plain why some individuals are more LATE GESTATION IS CRITICAL FOR
morbidity.1 It is clear that today, many susceptible to hypertension and CKD.14 NEPHROGENESIS
infants who in another era would have
Brenner proposed that persons with Although nephrogenesis in humans
died within a matter of hours are now
a decreased complement of nephrons begins around 9 weeks gestation,20,21
surviving to adulthood.
can initially maintain a normal glo- 60% of nephrons are formed during the
The long-term consequences of pre- merular filtration rate (GFR) as in- third trimester (Fig 2).22 The entire
maturity or low birth weight (LBW) are dividual nephrons enlarge to increase nephron complement of the human
less clear. Although there has been a the total surface area available for re- kidney is determined by 36 weeks’ ges-
great deal of research into the neuro- nal work.15 Over time, however, this tation,23 and these nephrons must last
developmental outcomes of premature adaptive response becomes harmful. for a lifetime because nephrons do not
infants,2–4 the impact of prematurity or Increased glomerular surface area have the ability to regenerate24; even in
LBW on other organ systems is less well leads to sodium retention and systemic healthy persons, the number of func-
understood. There is now evidence from hypertension, and glomerular hyper- tional nephrons gradually declines over
both the basic science and the clinical filtration disrupts renal autoregulatory time, leading to the age-dependent de-
arenas to suggest that premature and mechanisms, generating intraglomerular cline in GFR seen in older adults.25
LBW infants who survive the NICU still
face serious risks to their long-term
kidney health. Here, we review the the-
ory, experimental evidence, and obser-
vational data that suggest an increased
risk of chronic kidney disease (CKD) for
premature and LBW infants and argue
for increased surveillance of these
patients.

FETAL ORIGINS OF ADULT DISEASE

David Barker is credited with the ob-
servation that many “adult” diseases
may in fact have their origins in fetal
life.5,6 To survive in a stressful or
nutrient-poor environment, a fetus
must make “choices” about how to use
scarce resources in a way that max-
imizes the likelihood of survival in early
life, even at the expense of greater
susceptibility to chronic illnesses and
increased mortality in adulthood. This FIGURE 1
kind of developmental programming According to Brenner’s hypothesis, reduced nephron number (oligonephropathy) leads to hyper-
filtration, hypertension, and proteinuria, which perpetuate renal damage and lead to glomerulo-
among LBW infants7,8 has been associ- sclerosis and CKD.16,150 Infants born prematurely have additional risk factors for nephron loss such as
ated with problems including obesity,9 nephrotoxins and hemodynamic alterations.

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 studied models of FSGS for 80 years,33
and more recent techniques of experi-
mental podocyte depletion also generate
clinical FSGS in a dose-dependent man-
ner.34,35 Notably, some animal studies
suggest that the presence of hyperten-
sion is essential for the development of
glomerulosclerosis36,37 and that lesions
can be avoided if glomerular hemody-
namic changes are prevented.38

FIGURE 2 EVIDENCE FROM ANIMAL MODELS

Late gestation is critical for nephrogenesis in both humans (A) and mice (B). Data adapted from
Hinchiffe22 and Cebrián.151 In rats and mice, nephrogenesis con-
tinues for 5 to 7 days postnatally, yet
premature birth alone still has a pro-
Because there is no mechanism to as- width and more mature glomeruli com- foundeffecton nephrogenesis.Miceborn
sess nephrogenesis in a living infant, pared with gestational controls at simi- 1 to 2 days prematurely develop a CKD
data on human kidney development in lar postconceptional ages, suggesting phenotype by the time they are 5 weeks
an extrauterine environment is limited early cessation of nephrogenesis or ac- old, with hypertension, albuminuria, and
to autopsy studies.26–28 Although such celerated postnatal renal maturation. reduced nephron number.39 In other
studies are prone to selection bias, Preterm infants also had increased rodent studies, reduced nephron num-
their findings suggest that although glomerular volume (potentially indica- ber can be induced by prenatal protein
nephrogenesis in infants born pre- ting glomerular hyperfiltration), and up restriction or vitamin A deprivation,
maturely continues postnatally, it may to 13% of their glomeruli were histo- perinatal exposure to gentamicin, or
be altered.27,28 logically abnormal, with dilation of antenatal exposure to steroids.40–43
Rodriguez et al27 performed an autopsy Bowman’s space and a shrunken glo- A closerapproximation of the NICU is the
study of 56 premature infants with merular tuft. baboon model of prematurity in which
birth weight ,1000 g and found no animals are delivered prematurely
evidence of postnatal glomerulo- FROM THE NICU TO FSGS and maintained under conditions that
genesis after 40 days. Additionally, Fewer layers of larger glomeruli with approximate those encountered by hu-
when stratified by occurrence of acute more histologic abnormalities suggest man infants (including mechanical ven-
kidney injury (AKI), defined as a sus- that premature infants leave the NICU tilation and exposure to nephrotoxins
tained serum creatinine of .2 mg/dL, with a reduced number of functional such as gentamicin44 and nonsteroidal
those infants who experienced AKI had nephrons, a risk factor for focal seg- antiinflammatory drugs for patent duc-
significantly lower radial glomerular mental glomerulosclerosis (FSGS). It is tus arteriosus closure45). Analogous to
counts, or layers of glomeruli. If pre- now clear that all forms of FSGS are human studies, premature baboons con-
mature infants have only 40 days from diseases of the podocyte.29 Although the tinued to develop nephrons postnatally,
birth to complete nephrogenesis, then pathologic findings of FSGS can be in- and although there was no alteration
those born at 23 to 24 weeks may only duced by immunologic mechanisms in total glomerular number, a high per-
develop nephrons until 29 to 30 weeks, (primary FSGS), genetic mutations, centage of nephrons had histologic ab-
in contrast to continuing nephro- viruses, systemic diseases, certain normalities.44
genesis until 36 weeks, as in normal drugs, and obesity can all cause
gestation. podocyte dysfunction or injury, leading PREMATURITY: AN
The developing nephrons in premature to secondary FSGS.30–32 Reduced UNDERRECOGNIZED RISK FACTOR
infants seem particularly vulnerable to nephron mass is also a well-described FOR CKD
maldevelopment and dysfunction in an cause of secondary FSGS. The subtotal To date, there have been no prospective,
ex utero environment. Sutherland et al28 or five-sixths nephrectomy model, in population-based studies to confirm
performed an autopsy study including which experimental rats have 1 kidney the association between prematurity or
60 infants and found that premature removed and two-thirds of the second LBW and CKD. Although it is difficult to
infants had reduced nephrogenic zone kidney ablated, has been among the best- disentangle the effects of confounders

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 STATE-OF-THE-ART REVIEW ARTICLE

such as socioeconomic status in ret- tional ages of 22 to 30 weeks, and pre- authors even to suggest that the rising
rospective studies, a systematic review sented at an average age of 32 years incidence of AKI may be partly re-
of 31 cohort or case-control studies with nephrotic-range proteinuria, hypo- sponsible for the nationwide increase
found a 70% increase in adulthood CKD albuminemia, and lack of edema without in CKD and ESRD.61 A recent meta-
for LBW infants.46 Although this meta- other risk factors for secondary FSGS. analysis of adult trials found a sub-
analysis excluded studies consisting stantial, exposure-dependent risk of
exclusively of extremely LBW or very CKD after AKI, with patients who expe-
premature infants, other more inclusive AKI AS A RISK FACTOR FOR CKD rienced more severe AKI developing
studies have shown similar results. A Acute kidney injury in the NICU is CKD and ESRD more frequently.62 Al-
national registry-based study including common. Although its overall incidence though there are inherent risks in ex-
all infants born in Norway from 1967 to is difficult to determine given the lack of trapolating the results of adult studies
2004 found an overall relative risk of 1.7 multicenter studies and variable defi- to pediatric patients, it seems likely that
for the development of end-stage renal nitions of AKI, it is clear that smaller and nephron loss would have even greater
disease (ESRD) for infants with birth sicker infants most commonly experi- effects on future health for a newborn
weight ,10th percentile compared with ence AKI (Table 1). Yet because the infant than for an older adult.
those with weights from the 10th to 90th majority of pediatric patients with AKI Moreover, the limited number of pedi-
percentile.47 are discharged from the hospital with atric studies have found similar results.
Clinical signs of oligonephropathy a normal serum creatinine,55 the long- Pediatric patients with AKI due to
among patients born prematurely may term significance of their renal injury diarrhea-associated hemolytic-uremic
be detectable in childhood.48,49 Two may not be appreciated. syndrome,63 meningococcal sepsis,64
recent case series (each including 50 It was long taught that AKI is reversible.56 and cardiac surgery65 all have an in-
infants born at ,30–32 weeks’ gesta- This may be true for AKI caused purely creased long-term risk of CKD. Beyond
tion) found that children born pre- by volume depletion, but it is now clear these specific populations, a recent
maturely had smaller kidneys and that intrinsic forms of AKI cause cumu- single-center PICU study found that
higher blood pressure compared lative and irreversible damage. In ani- 10.3% of all patients with AKI (defined
with term controls, even though their mal models of acute tubular necrosis, by Acute Kidney Injury Network crite-
GFR remained normal.50,51 Microalbu- renal regeneration is not complete: ria66) subsequently developed CKD
minuria, an early indicator of kidney there is permanent reduction in vascu- (GFR ,60 mL/min/1.73 m2) within the
disease and a risk factor for future lar density and compromised oxygen next 1 to 3 years.67 An additional 46.8%
cardiovascular morbidity,52 is also com- delivery.57,58 Regeneration of tubular of this cohort were deemed “at risk”
mon among children aged 8 to 11 years epithelial cells can result in sustained for CKD based on the presence of hy-
who were born prematurely or with fibroblast activation, leading to pro- pertension, reduced GFR (60–90 mL/
LBW.53 gressive fibrosis even after the initial min/1.73 m2), or hyperfiltration (GFR
The first series of premature infants insult has subsided.59,60 .150 mL/min/1.73 m2).
who developed secondary FSGS was There is now ample epidemiologic These studies have been criticized for
recently reported.54 These 6 patients evidence associating AKI with the epidemiologic flaws that prevent the
were all very premature, with gesta- development of CKD, leading some determination of causation; that is, it

TABLE 1 Recent Estimates of AKI Incidence in Various Neonatal Populations

Study Study Population AKI Definition Number of Infants AKI Incidence
Viswanathan et al 141
Extremely LBW (,1000 g) Serum creatinine $1.5 mg/dL 472 12.5%
or urine output ,1 mL/kg/h
Koralkar et al142 Very LBW (,1500 g) AKIN66 229 18%
Selewski et al143 Asphyxiated newborns undergoing AKIN 96 38%
therapeutic hypothermia
Kaur et al144 Infants $34 wk gestation with asphyxia AKIN 36 41.7%
(Apgar ,7 at 1 min after birth)
Blinder et al145 Infants ,90 d old with congenital heart AKIN 430 52%
disease undergoing surgery
Gadepalli et al146 Infants with congenital diaphragmatic hernia RIFLE147 68 71%
requiring extracorporeal membrane
oxygenation
AKIN, Acute Kidney Injury Network; RIFLE, risk, injury, failure, loss, end-stage renal disease.

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could be argued that patients who are cal judgment to make an individualized to renal sodium retention and elevated
predisposed to the development of CKD risk assessment for each patient to blood pressure.14 Currently the Ameri-
may also be predisposed to the de- provide the best care to NICU graduates. can Academy of Pediatrics recom-
velopment of AKI.68 However, for pedia- Follow-up recommendations are pre- mends measuring blood pressure at
tricians caring for premature infants sented in Fig 3. health maintenance examinations be-
who have suffered AKI, this distinction is A careful review of the neonatal history ginning at 3 years among healthy chil-
likely academic. Whether AKI in fact is an essential first step for primary dren.73 However, because nearly half of
leads independently to CKD or simply care physicians to identify infants who extremely preterm infants have a sys-
identifies a subgroup of infants already require the closest follow-up. Note should tolic blood pressure .90th percentile
at risk for CKD, the implications for the be made of the infant’s birth weight, for their age and gender by age 2.5,74
child are the same, and the long-term gestational age, weight-for-age classifi- we argue that all premature infants
implications of AKI in the NICU ought not cation, and any history of AKI. Un- should be considered a high-risk group
be ignored. fortunately, discharge summaries may in whom blood pressure screening
not provide all of these details. A sys- should occur at earlier visits.
PRACTICE AND POLICY tematic review of pediatric and adult Careful assessment of linear growth at
IMPLICATIONS: WHAT ARE discharge summaries found that signifi- every well-child check is also important.
PEDIATRICIANS TO DO? cant errors and omissions were com- Although growth must be interpreted
Worldwide, almost 13 million infants mon.70 Communicating an infant’s history within the context of the patient’s ge-
are born prematurely each year,69 but of AKI to pediatricians may be particularly netic potential, nutritional status, and
there is currently no mechanism to poor: at our institution, only 21 of 155 neonatal history, practitioners should
identify the infants most at risk for (13.5%) of infants who experienced AKI by be alert to the possibility that abnor-
developing CKD due to congenital or the Acute Kidney Injury Network criteria mal growth may reflect CKD. Children
acquired low nephron number and no from 2008 to 2011 had AKI listed on their with CKD can have impaired linear
guidelines for screening or follow-up NICU discharge summary.71 growth even when the GFR is only mild
from the American Academy of Pediat- Hypertension may be a clinical indica- to moderately impaired,75,76 and both
rics or other professional association. tor of low nephron number72 because LBW and SGA status were risk fac-
Pediatricians must therefore use clini- decreased filtration surface area leads tors for impaired linear growth in

FIGURE 3
Follow up strategies for NICU graduates. In the absence of high-quality evidence, physicians must make an individualized risk assessment of each patient and
balance the risks and benefits of any screening strategy. IUGR, intrauterine growth retardation; SGA, small for gestational age.

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 STATE-OF-THE-ART REVIEW ARTICLE

a prospective cohort of patients with all nucleated cells,85 is more easily in- children or adolescents, competing
mild to moderate CKD, independent of terpretable than creatinine because factors such as patient size, compen-
GFR.77 a single reference range can be used satory hypertrophy of remnant neph-
Assessments of the NICU graduate for any child over 1 year of age.86 Cys- rons, and additional nephron loss
should continue into adolescence, a time tatin C is a more sensitive marker of through injury make the relationship
when many children see their pediatri- mild renal impairment than creati- between kidney size and nephron
cian less frequently. Rapid growth in nine,87,88 and mild elevations are seen number less easily interpretable.99 Al-
puberty often unmasks renal dysfunc- in preterm infants at 12 to 36 months of though some studies have found
tion78 because abnormal kidneys may age compared with term control sub- smaller renal length or volume in
be unable to accommodate the de- jects.89 However, this test is expensive children born prematurely,100 the use
mands of increased growth. It is also and not readily available in all areas. of ultrasound or other imaging tech-
important that adolescent patients, Microalbuminuria (urine albumin/ niques is expensive and has yet to be
particularly those nearing transition to creatinine of 30–300 mg/g) is also an validated prospectively.
adult practitioners, be aware of their early indicator of CKD and represents
history of prematurity, understand their a therapeutic target for CKD progres- INTERVENTION AND EDUCATION
increased long-term risk for CKD, and sion.90 Standard urine dipsticks detect
Any recommendation for increased
receive counseling regarding modifi- only overt albuminuria, but targeted
population-based screening must be
able risk factors for CKD progression screening of premature or LBW infants
tempered by the acknowledgment that
(such as smoking,79 hypertension,80 or could result in earlier detection of CKD.
there is no specific therapy to slow or
obesity81). Such screening is already standard of
arrest the progression of CKD in chil-
Laboratory tests may be useful in specific care in certain other high-risk groups,
dren born prematurely or with a LBW.101
circumstances. Whereas an abnormal such as children with type 1 diabetes
However, there are nonspecific thera-
serum creatinine at NICU discharge or in mellitus91 and sickle cell disease.92
peutic targets for CKD progression
childhood carries an ominous prognosis, Unfortunately, the utility of micro-
such as hypertension,101,102 microalbu-
serum creatinine is not a sensitive in- albuminuria as a screening tool may be minuria,90 and dyslipidemia.90 In partic-
dicator of long-term CKD risk because hampered by a high false-positive rate ular, inhibition of the renin-angiotensin
increased tubular secretion can main- due to the prevalence of benign protei- system (RAS) has been shown to slow
tain a normal plasma creatinine until nurias (such as orthostatic proteinuria93 CKD progression in adults with pro-
25% to 50% of GFR has been lost.82 or exercise-induced proteinuria94) in the teinuria103 and hypertensive children
Pediatricians and neonatologists must pediatric population. For example, in aged 3 to 18104 and is standard of care in
therefore not be falsely reassured by the NHANES, 8.9% of adolescents had nephropathy related to diabetes.105,106
normal values. Additionally, the recogni- microalbuminuria, although the majority However, these medications must be
tion of mildly abnormal creatinine values of these had no other risk factors for used cautiously in children because
in children may be challenging. Although cardiovascular or renal disease.95 Find- their side-effect profile is not benign,
the average creatinine for a 2-year-old is ing elevated levels would therefore re- and they are a well-described cause of
0.3 mg/dL,83 values up to 0.6 mg/dL are quire additional testing to distinguish AKI, particularly with volume depletion
often reported as normal by reference true disease from benign proteinuria. or when given in combination with
laboratories.84 Yet these “normal” values Screening patients with imaging tech- other medications that decrease renal
can reflect significantly impaired GFR, as niques such as renal ultrasound is blood flow.107
demonstrated in Table 2. theoretically appealing because renal Even in the absence of targeted thera-
Cystatin C, a nonglycosylated basic volume at birth is a surrogate for pies for CKD progression, earlier
protein produced at a constant rate by nephron number.96–98 However, in older identification of patients with CKD could
provide the opportunity to improve
TABLE 2 Estimates of GFR With “Normal” Creatinine Values for a Hypothetical 2-Year-Old Child patient outcomes by addressing sys-
With Height 86.4 cm Using the Revised Schwartz Equationa
temic complications of CKD sooner.
Serum Creatinine (mg/dL) Estimated GFR (mL/min/1.73 m2) Interpretation148,150
Beyond the well-known complications
0.3 119 Normal of CKD such as anemia, poor growth,
0.4 89 Normal
0.5 71 Stage 2 CKD and renal osteodystrophy, many chil-
0.6 59 Stage 3 CKD dren with CKD have impaired neuro-
a GFR = 0.413 3 height(cm) / creatinine(mg/dL).148 cognitive function and reduced quality

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of life. Subjects in the CKD in Chil- a normal nephron number despite their nephrogenesis in rodents limits the
dren (CKiD) reported decreased health- premature birth.119,120 utility of these models. Newer models
related quality of life compared with such as the premature mouse model39 or
healthy children, with lower scores in Nutrition fetal renal cell culture129 may enhance
physical, emotional, social, and school In rats, who continue nephrogenesis understanding of renal cell differentia-
domains.108 Additionally, 21% to 40% of postnatally, nutritional support after tion, proliferation, and apoptosis.
children with mild or moderate CKD birth can restore a normal nephron
have below average measures of IQ, endowment and prevent adult hyper- Acute Kidney Injury
academic achievement, attention reg- tension after uteroplacental insuffici- To evaluate the long-term effects of AKI,
ulation and executive functioning.109,110 ency.121 The potential benefit of improved it is imperative to validate and adopt
Early intervention in these areas could nutrition for human infants was sug- a consistent definition of AKI.130 The use
improve school performance and self- gested by a prospective cohort study of of serum creatinine–based definitions
esteem. premature infants with extrauterine of AKI is problematic because serum
At the very least, identification of growth restriction (growth value #10th creatinine is a measure of function, not
patients with early CKD would facilitate percentile of intrauterine growth ex- injury, and a rise in serum creatinine
education of the child and parents pectation based on postmenstrual age occurs only after as much as 50% of
about the treatments for CKD and allow at the time of discharge from the hos- kidney function has been lost.131 Iden-
the opportunity to provide counseling pital).50 Compared with infants with in- tification and validation of biomarkers
on avoiding risk factors that may ac- trauterine growth restriction or normal would allow earlier detection of AKI in
celerate its progression (such as neph- growth status, infants with extrauterine premature infants and permit gener-
rotoxic medications, recurrent urinary growth restriction had lower protein- alizability between single-center stud-
tract infections, dehydration, and coex- energy intake during their first week ies.132–134 Biomarkers including urine
isting urologic issues). Obesity in par- of life and lower GFR than at a mean of cystatin C, uromodulin, epithelial growth
ticular is a modifiable risk factor for CKD 7.6 years follow-up. However, there is factor, neutrophil gelatinase-associated
progression 111,112 and one for which also good epidemiologic evidence to lipocalin, and osteopontin predict AKI in
both primary care physicians and spe- suggest that too rapid “catch up” specific neonatal populations.135,136
cialists have an important role in man- growth for growth-restricted infants
agement.113 may be detrimental.122 NICU Management
Vitamin A is an important regulator of The role that NICU clinical management
RESEARCH HORIZONS cell proliferation and differentiation and strategies play in the development of
Nephrogenesis plays a critical role in the determination CKD is largely unexplored. However,
of nephron mass.123–125 Vitamin A de- NICU patients are commonly exposed to
A comprehensive discussion of the mo-
ficiency is also common in premature medications that impair nephrogen-
lecular mechanisms of nephrogenesis is
infants126 due in part to increased uri- esis137 (such as aminoglycoside anti-
beyond the scope of this review but has
nary losses of vitamin A.127 Although vi- biotics or prostaglandin synthetase
recently been reviewed elsewhere.114
tamin A supplementation appears to be inhibitors) and frequently experience
Although a number of genetic modifiers
beneficial in the lung, another branch- AKI. If these are independent risk factors
of nephrogenesis have been described,
ing organ that develops in late gesta- for CKD, avoidance of such medications
such as common variants in the PAX2115
tion, in protecting against chronic lung or efforts to decrease AKI incidence
or RET116 genes, which are associated
disease,128 there are no clinical data on could lead to better long-term out-
with reduced kidney volume at birth,
renal outcomes in humans. comes. Appropriately designed long-
epigenetic factors such as DNA methyl-
ation appear to play an equally impor- term studies are needed.
tant role in nephrogenesis.117,118 The Experimental Models
identification of these potentially modi- Given the lengthy time horizon between Counting Nephrons
fiable epigenetic factors raises the premature birth and the development The Brenner hypothesis has been crit-
possibility that eventually strategies of CKD, valid experimental models are icized by authors who point out that all
might be developed to extend a pre- essential for understanding nephro- supporting evidence is circumstantial
mature infant’s period of normal neph- genesis and its disruptors. The pro- given the inability to measure nephron
rogenesis to 36 weeks’ postmenstrual hibitive expense of primate research number in a living person.138 In exper-
age, allowing their kidneys to attain and the normally occurring postnatal imental animals, cationic ferritin has

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 STATE-OF-THE-ART REVIEW ARTICLE

been used safely to label the glo-

merular basement membrane (Fig 4),
allowing an accurate count of glomer-
uli using MRI.139,140 If validated, such
techniques could provide accurate and
noninvasive measurement of glomer-
ular counts for clinical or research
purposes in the future.
FIGURE 4
SUMMARY MRI of glomeruli labeled with cationic ferritin in a mouse kidney (A). Glomeruli are undetectable without
cationic ferritin (B). Images courtesy of Scott Beeman and Kevin Bennett.
Thanks to the contributions of our
predecessors, contemporary pedia-
tricians can celebrate the extraordi- respiratory or infectious diseases, and LBW infants and emphasizes the
nary success story of neonatal intensive kidney disease is seldom a proximate need for increased awareness among
care. Today, most of even the tiniest cause of life-threatening illness for all pediatricians of the significance of
infants will survive, and many of them infants while they are in the NICU. Al- low nephron number. Despite a sound
will leave the NICU without any apparent though pediatricians are attuned to the theoretical rationale and emerging
morbidity. Although many of the original short-term risks associated with pre- basic science and epidemiologic data,
challenges in neonatal intensive care maturity and LBW such as chronic lung there is little high-quality evidence
remain, the bigger challenge for the disease or neurocognitive delays, the from appropriately designed studies
current generation of pediatricians is to longer-term risk of developing CKD of- with meaningful long-term outcomes
continue to improve long-term out- ten escapes notice. Yet that risk may be to guide pediatricians in the man-
comes for these infants. significant. With the first generation of agement of these patients. We urge
Most infants in the NICU begin life with infants from the “surfactant era” only professional organizations, funding
an incomplete complement of imma- now reaching young adulthood, it is agencies, and the entire community of
ture nephrons. They are then exposed to possible that there is already a silent pediatricians to consider this issue, so
a variety of external stressors that can epidemic of CKD in this population. that the next half-century of neonatal
hinder ongoing kidney development or The evidence reviewed here highlights intensive care can match the suc-
cause nephron loss. However, unlike the risk of renal disease in premature cesses of the past.

REFERENCES
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 Short-Term Gestation, Long-Term Risk: Prematurity and Chronic Kidney
Disease
J. Bryan Carmody and Jennifer R. Charlton
Pediatrics 2013;131;1168; originally published online May 13, 2013;
DOI: 10.1542/peds.2013-0009
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
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Short-Term Gestation, Long-Term Risk: Prematurity and Chronic Kidney
Disease
J. Bryan Carmody and Jennifer R. Charlton
Pediatrics 2013;131;1168; originally published online May 13, 2013;
DOI: 10.1542/peds.2013-0009

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/131/6/1168.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org by guest on March 13, 2015