The Effect of Preterm Birth on Renal Development

and Renal Health Outcome

Amanda Dyson, MBBCh, FRACP, MMed (Clin Epi),*† Alison L. Kent, BMBS, FRACP, MD‡
*Centenary Hospital for Women and Children and Department of Neonatology, Canberra Hospital, Woden, Australia
†
Australian National University, Canberra, Australia
‡
University of Rochester and Division of Neonatology, Golisano Children’s Hospital at URMC, Rochester, NY

Education Gaps
1. Clinicians should be aware that preterm birth is associated with a reduced
functional nephron mass, predisposing an individual to chronic kidney
disease and quicker progression to end-stage chronic kidney disease.
2. Patients and health-care professionals must take an active role in
protecting the kidneys of preterm survivors from further injury
throughout life.

AUTHOR DISCLOSURE Drs Dyson and Kent
have disclosed no financial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
Abstract
Preterm birth is associated with adverse renal health outcomes including
hypertension, chronic kidney disease, and an increased rate of progression
to end-stage renal failure. This review explores the antenatal, perinatal, and
postnatal factors that affect the functional nephron mass of an individual
and contribute to long-term kidney outcome. Health-care professionals
have opportunities to increase their awareness of the risks to kidney health
in this population. Optimizing maternal health around the time of conception
and during pregnancy, providing kidney-focused supportive care in the NICU
during postnatal nephrogenesis, and avoiding accelerating nephron loss
throughout life may all contribute to improved long-term outcomes. There is
a need for ongoing research into the long-term kidney outcomes of preterm
survivors in mid-to-late adulthood as well as a need for further research into
interventions that may improve ex utero nephrogenesis.

ABBREVIATIONS Objectives After completing this article, readers should be able to:
AKI acute kidney injury
CKD chronic kidney disease 1. Improve awareness of NICU professionals on how to protect kidneys of
CysC cystatin C
preterm infants from further injury, particularly during the period of ex
DBP diastolic blood pressure
eGFR estimated glomerular filtration rate utero nephrogenesis.
FGR fetal growth restriction
2. Encourage surveillance of preterm survivors in childhood and adulthood
GA gestational age
GFR glomerular filtration rate to reduce obesity and observe for evidence of hypertension or insulin
LBW low birthweight resistance to minimize further “hits” to an already reduced nephron mass.
SBP systolic blood pressure

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 3. Stimulate research in areas where there are gaps in the evidence, in
particular long-term follow-up of cohorts of preterm survivors into late
adulthood.
INTRODUCTION
Fifteen million births occur before 37 weeks’ gestational age
(GA) worldwide each year. (1) Over the past decade, preterm
birth rates in the United States have varied between 9.8%
and 11.4% and currently are at 9.9%. (2)(3) Around 2.8% of
births are early preterm births occurring before 34 weeks’
gestation. (2) Although this group experiences a greater
proportion of long-term morbidity, all preterm infants have
higher rates of morbidity than their term-born contempo-
raries. (3) The preterm population is diverse in both GA and
the underlying cause for prematurity. Conditions associated
with an adverse intrauterine environment include preeclamp-
sia, multiple births, and chorioamnionitis, and account for
38% of preterm deliveries. (3)
The renal consequences of preterm birth are becoming
increasingly recognized and include a higher risk of chronic
kidney disease (CKD), (4) a quicker progression of renal
pathology, (5) and a predisposition toward hypertension. (6)
CKD is associated with significant morbidity and mortality
and is estimated to affect 14% of the US population. (7) The
global burden of disease study highlighted that CKD is a
growing public health problem that is increasingly contrib-
uting to global mortality. (8) As the preterm population
surviving into childhood and adulthood grows, there is an
increasing need to better understand the renal long-term
effects of preterm birth and to identify ways to reduce
morbidity associated with preterm survival.
NORMAL RENAL DEVELOPMENT
Renal development begins with the differentiation of the
pronephros in the third week of gestation followed by the
mesonephros at 4 weeks of gestation. (9) The pronephros is
nonfunctional in humans and involutes whereas the meso-
nephros transiently functions as an excretory structure until
the definitive kidney develops from the metanephros. (10)
The metanephros gives rise to the ureteric bud which
undergoes branching; through reciprocal signaling, the
branching of the ureteric bud progresses, and the mesen-
chyme differentiates to form the renal vesicles. The renal
vesicles ultimately form the glomeruli, tubules, and loop of
Henle of the mature nephron, with the first glomeruli
present from 9 to 10 weeks’ gestation and fetal urine
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production beginning at 10 weeks. (9) The fetus becomes
the main producer of amniotic fluid from around 16 weeks’
gestation. (9) Maximal human kidney growth has been
shown to occur toward the end of the second and beginning
of the third trimester between 26 and 34 weeks’ GA, (11)
with nephrogenesis complete by term GA. (12)
Perinatal autopsy studies have demonstrated that there is
individual variation in the GA at which nephrogenesis is
complete; 1 group examined normally grown fetuses, dem-
onstrating ongoing nephrogenesis at 31 weeks’ GA and
complete nephrogenesis in all infants by 38 weeks’ GA,
with some variability in those between 35 and 37 weeks. (12)
Another group demonstrated that nephrogenesis was com-
plete by 32 weeks’ GA in some fetuses. (13) Term infants are
born with the total number of nephrons that they will have in
their lifetime; optimizing nephrogenesis is advantageous
for the long-term renal health of an individual.
NEPHROGENESIS IN THE PRETERM INFANT
Many preterm infants are born at a time when they are still
undergoing nephrogenesis, with some born before reaching
their maximal period of nephron development. Nephron
development continues after very preterm birth with active
glomerulogenesis, characterized by the presence of baso-
philic S-shaped bodies, and continuing until 40 days’ post-
natal age. (14) Extremely preterm infants more than 40 days
old who experienced acute renal failure (defined as a sus-
tained elevation in creatinine >2.0 mg/dL) have fewer
nephrons than preterm infants without a history of renal
failure. During normal kidney development, nephrons grow
from the corticomedullary junction toward a nephrogenic
zone situated below the renal capsule, forming nephron
“generations.” (13) The newest nephrons are therefore sit-
uated in the outer renal cortex. An autopsy study has
recently shown that many preterm infants have abnormal
glomeruli in their outer renal cortex, implying that neph-
rons that develop ex utero may not develop normally. (13)
Autopsy studies have also shown that preterm birth is
associated with accelerated renal maturation and the pres-
ence of a larger proportion of morphologically abnormal
glomeruli compared with gestation-matched stillborn con-
trols. (13) It is clear that the number of nephrons that form in
the first 4 to 6 weeks after delivery is important in establish-
ing the lifelong nephron mass of a preterm infant and that
this should be supported as much as possible by avoiding
postnatal kidney injury.
Preterm birth and reports of its effect on the glomerular
filtration rate (GFR) have been contradictory. Preterm
infants born before 32 weeks’ GA were found to have a
reduced estimated GFR (eGFR), measured using cystatin C
(CysC) at term postmenstrual age. (15) In contrast, an
extremely preterm cohort of less than 28 weeks’ gestation
at birth was shown to have an eGFR comparable to that of
term infants using urinary CysC despite having smaller
kidneys, leading the authors to conclude that this may be
evidence of glomerular hyperfiltration and compensation
for reduced nephron mass. (15)
NEPHRON MASS
Nephrons are the functional units of the kidney; the neph-
ron mass of an individual refers to the total number of
functioning nephrons a person has at any given time. (16)
Data regarding normal human nephron number and den-
sity have predominantly been determined histologically
from autopsy studies or from renal transplant donors. There
is large variation in nephron number and density between
individuals with 4- to 8-fold variations in nephron number
observed at autopsy. (10) The reason for this degree of var-
iability between individuals is not fully understood but is
likely related to an interplay among genetics, the environment
of an individual during nephrogenesis, and renal insults that
occur over the course of a lifetime. (12)(17) Nephron mass
naturally declines with age; a study examining the kidneys of
healthy renal transplant donors demonstrated a 48% differ-
ence in the nonsclerotic glomerular number between donors
aged 19 to 28 years and those aged 70 to 75 years. (18) Older
donors have more sclerotic glomeruli. (18)
A reduced nephron mass has been associated with CKD
(19)(20) and hypertension (21) in adulthood. Because it is
not possible to directly measure nephron mass in living
subjects, kidney size, and in particular, kidney length and
volume, are often used as surrogate markers of nephron
mass. (22) Unfortunately, ultrasonography has been shown
to underestimate true renal volume by a median of 24%
(range 5%–48%) in an animal model. (23) It has been
proposed that measuring the renal parenchyma using ultra-
sonography may be a more reproducible and potentially
more accurate tool for estimating normal and abnormal
renal development. (24) Normal kidney size and volume do
not differentiate between normal growth and compensa-
tory hypertrophy of an oligonephronic kidney. (25) Renal
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parenchymal thickness has been shown to be closely asso-
ciated with renal volume, (26) and renal cortical thickness
has been shown to be correlated with renal function in
adults. (27) Currently, renal volume as seen on ultrasonog-
raphy cannot be considered a surrogate for nephron
number.
Examining the effects of nephron mass on renal function
is challenging; noninvasive estimates of GFR vary in accu-
racy. The gold standard plasma and urinary clearance stud-
ies are accurate but invasive, whereas other noninvasive
estimates of GFR have been shown to be accurate at pre-
dicting a population mean but not individual GFR, (28)
limiting their clinical usefulness at the bedside. Noninvasive
calculated eGFR values are often used in clinical studies,
because they are more acceptable to study participants. A
number of alternative biomarkers to creatinine have been
used to measure GFR, in particular CysC (29); however,
again, the accuracy of this biomarker to estimate GFR is
variable. The development of new real-time measured GFR
using transdermal sensors that detect fluorescent filtration
markers may change the way in which both clinicians and
researchers are able to measure and study the effect of
nephron mass on renal function, as well as the impact on
both acute kidney disease and CKD. (30)
DEVELOPMENTAL PROGRAMMING AND
NEPHROGENESIS
David Barker first observed that in utero events are associated
with adult disease and described the “Barker hypothesis,”
which underpins current theories around the developmental
origins of health and disease. (31) Brenner et al hypothesized
that this principle could be applied to kidney development,
postulating that reduced nephron numbers could predispose
a person to hypertension. (32) Glomerular hypertrophy is
thought to occur in response to reduced nephron mass and
glomerular hypertension (maintaining glomerular surface
area), leading to hyperfiltration, salt sensitivity, sodium and
water retention, hypertension, and glomerulosclerosis.
Support for the Brenner Hypothesis
It has been demonstrated that glomerular surface area is
similar between individuals with different kidney sizes,
supporting the theory that glomerular hypertrophy occurs
in oligonephronic kidneys. (33) Glomerular hypertrophy has
been shown to be more prevalent in populations with a higher
risk of CKD, including Australian aboriginal and black pop-
ulations. (5) Glomerular hypertrophy has also been associ-
ated with poor post-transplantation outcomes. (5) Autopsy
studies have shown a large variability in nephrogenesis in
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 fetal life, thus supporting the hypothesis that the intrauterine
environment influences kidney development. (12)
Low Birthweight
Birthweight has been demonstrated to be an important
predictor of nephron and glomerular mass. (12)(21)(34)(35)
Low birthweight (LBW <2.5 kg) has been associated with
the development of end-stage renal failure, (36)(37) CKD,
(19)(38)(39) and a more rapid deterioration in renal function
in patients with underlying kidney disease. (5) Some infants
are LBW as a result of prematurity, others are term but have
experienced fetal growth restriction (FGR), and some are both
growth restricted and preterm. Preterm birth is estimated to
account for up to 80% of the LBW population. (40) FGR has
various causes, including placental insufficiency and mater-
nal smoking, which are often associated with an adverse
intrauterine environment for a developing fetus. (41) The
hypotheses underlying why LBW is associated with CKD vary
depending on the etiology. In normally grown preterm
infants, it is likely a result of an interruption in normal organ
and vascular growth followed by ex utero nephrogenesis
altered by the postnatal environment. In term infants born
after a pregnancy complicated by placental insufficiency, the
fetal kidneys may not have received adequate nutrition or
oxygenation for nephron development. (42)(43) Many pre-
term infants are subjected to both the effects of being born
during nephrogenesis and by an adverse intrauterine envi-
ronment for organ development.
Maternal Diet and Nutrition
Maternal diet and nutrition during pregnancy have been
shown to influence fetal nephrogenesis. (44) Micronutrient
deficiencies, including vitamin A, iron, and folate, may
affect human renal growth while macronutrient deficiency,
in particular protein deficiency, has been shown to affect
fetal renal growth in animal studies. (44)
Antenatal Drugs
Smoking is a risk factor for preterm birth. Cigarette expo-
sure in pregnancy has a demonstrated dose effect, with the
more cigarettes smoked per day increasing the risk of
preterm birth. (45) Nicotine causes vasoconstriction and
reduces placental blood flow. Maternal smoking during
pregnancy has been associated with a smaller kidney vol-
ume and lower eGFR in school-age children (46) and a
smaller kidney size in both fetuses and newborns. (47) A
large retrospective cohort study in Japan found that mater-
nal smoking was an independent risk factor for proteinuria
at age 3 years in offspring. (48) In animal studies, etha-
nol use has been shown to reduce nephron number in
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offspring. (49) An Australian cohort study has demon-
strated an association between maternal alcohol use in
pregnancy and mild CKD in offspring during their 30s. (50)
Many preterm infants are exposed to in utero medications
aimed at improving their survival and outcomes, a number of
which may have an impact on nephrogenesis. Atosiban,
which is an oxytocin receptor antagonist sometimes used
as a tocolytic to delay preterm labor, may reduce renal cell
growth, renal vasodilation, and the carbonic anhydrase activ-
ity. (51) Corticosteroids have been shown to reduce nephro-
genesis in animal models and upregulate the expression of
angiotensin II and its receptors. (51) Antibiotics (in particular
aminoglycosides) and nonsteroidal anti-inflammatory drugs
also cross the placenta and may affect fetal renal function. (52)
Indomethacin is known to reduce amniotic fluid volume as a
result of fetal renal dysfunction. Indomethacin in a neonatal
rat model has been shown to cause glomerular injury and
reduce glomerular number in adulthood, suggesting that
indomethacin should be avoided if other less nephrotoxic
medications are available. (53)
THE POSTNATAL ENVIRONMENT AND
NEPHROGENESIS
Significant physiologic changes occur after preterm birth,
which lead to structural and functional changes in the devel-
oping kidney. The renal perfusion pressure of a fetal kidney is
estimated to be around 3% of the cardiac output, which
increases to 15% after delivery. (54) A sudden change in
glomerular vascular resistance has been proposed as a possible
mechanism for glomerular injury after preterm birth. (55)
Hyperoxia
Nephrogenesis and ureteric branching ordinarily occur in a
hypoxic environment, with animal studies showing that
mice undergoing nephrogenesis in a physiologically hyp-
oxic environment had more ureteric branches and larger
kidneys than those in a physiologically hyperoxic environ-
ment. (43) Conflicting results demonstrating worsened
ureteric branching and smaller kidneys in a hypoxic envi-
ronment have been seen in a similar mouse model, raising
questions about whether kidneys respond to hyperoxia
differently during different stages of nephrogenesis. (43)
Another mouse model examining the effects of hyperoxia
after preterm birth demonstrated a reduced glomerular
count in pups with retinopathy of prematurity exposed to
a hyperoxic environment, (56) again suggesting that hyper-
oxia impairs nephrogenesis. The arterial oxygen tension
increases suddenly after preterm birth, altering the envi-
ronment in which organogenesis occurs. Hyperoxia and
hypoxia have both been shown to be deleterious to the
outcomes of preterm infants and both should be avoided
in the NICU whenever possible. (57)
Nephrotoxin Exposure
Nephrotoxic medications are widely used in NICUs world-
wide, (58)(59)(60) with the smallest and least mature infants
often experiencing the largest exposures. In a retrospective
review of infants born weighing less than 1,500 g, it was
demonstrated that the majority of nephrotoxin exposure
occurred in the first 40 days of age, which coincides with the
period of ex utero nephrogenesis. (60) It has been shown
that up to 87% of very-low-birthweight infants in NICUs
are exposed to more than 1 nephrotoxic medication, most
commonly gentamicin, indomethacin, or vancomycin, up to
a total of 2 weeks in their hospital stay. (59)
Aminoglycoside antibiotics are widely used in the NICU,
often as empiric therapy for suspected early- or late-onset
infection. Aminoglycosides can accumulate in the kidney,
leading to high concentrations in the renal cortex and
ultimately leading to tubular injury. (61) Aminoglycoside-
associated acute kidney injury (AKI) is generally felt to be
less prevalent in newborns than in older children or adults;
however, it can still lead to significant tubular damage and
injury. (62) Nonsteroidal anti-inflammatory medications are
often used in preterm infants to treat a patent ductus
arteriosus, and indomethacin may be used as prophylaxis
for intraventricular hemorrhage. Both act as prostaglandin
inhibitors, which lead to vasoconstriction and reduced blood
flow in renal and mesenteric vessels in addition to the
intended vasoconstriction of the patent ductus arteriosus.
(63) Animal studies have demonstrated that both ibuprofen
and indomethacin reduce cyclooxygenase 2 and vasodilator
prostanoids, with indomethacin having a more profound
effect than ibuprofen. (64) This reduces renal blood flow
and often leads to oliguria. Ibuprofen use in preterm infants
has been shown to reduce GFR in the first month of age, (65)
whereas indomethacin use has been shown to increase
urinary podocyte and albumin concentration in the urine
of preterm infants of less than 33 weeks’ GA compared with
preterm and term controls, suggesting that it causes glo-
merular injury. (66) Although ibuprofen was found to cause
glomerular injury in a neonatal rats, it did not result in
reduced glomerular number in adulthood. (67)
A recent retrospective review of newborns weighing less
than 1,500 g and of less than 30 weeks’ gestation found that
the prevalence of AKI increased with decreasing GA,
decreasing birthweight, and increasing nephrotoxic medi-
cation exposure. (60) Given that nephrotoxin administra-
tion is a potentially controllable risk factor for AKI, this has
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become the focus of a clinical practice improvement proj-
ect: the Nephrotoxin Injury Negated by Just-in-time Action
(NINJA). Implementing an initiative that triggers daily
creatinine measures in noncritically ill children who are
either receiving 3 simultaneous nephrotoxins or have re-
ceived an aminoglycoside for more than 3 days has been
shown to reduce AKI by 68%. (68) Trials of this approach
need to be conducted in neonatal populations.
Acute Kidney Injury
Preterm infants have a high incidence of AKI; extremely
preterm infants of less than 29 weeks’ GA have been shown
to have an incidence of 47.9% using the modified Kidney
Disease: Improving Global Outcomes (KDIGO) criteria.
(69) The preterm population of 29 to 36 weeks’ GA, in
whom adverse long-term outcomes have been traditionally
less concerning, has an incidence of AKI of 18.3%. (69)
Although AKI has been independently associated with
mortality in a preterm population (<1,200 g or <31 weeks’
gestation), (70) as previously mentioned, it is also associated
with reduced nephron mass. (14)
Although some epidemiologic evidence exists to support
an association between AKI and CKD in pediatric popula-
tions, (71)(72), more work needs to be done to show a causal
link between pediatric or neonatal AKI and adult CKD. The
IRENEO prospective cohort study has shown a reduced
kidney volume but no difference in eGFR at a median
age of 6.6 years in former preterm newborns (<33 weeks’
GA) who survived neonatal AKI compared with control
subjects. (73) Although the investigators demonstrated no
difference in eGFR between groups, the overall population
had a high incidence of albuminuria and diminished eGFR.
Similarly, the Follow-up of AKI in Neonates during Child-
hood Years (FANCY) study showed that extremely low-
birthweight newborns who experienced AKI in the NICU
had a more than 4-fold increased risk of renal dysfunction at
a median age of 5 years compared with control subjects (74)
and again demonstrated a high incidence of low eGFR
of less than 90 mL/min per 1.73 m2 (26%) in their entire
cohort. When possible, efforts should be made to prevent
AKI in preterm populations.
Postnatal Nutrition
The evidence to guide clinicians about what constitutes
optimal postnatal nutrition for ex utero nephrogenesis is
limited. Animal models have shown that increasing growth
through overfeeding postnatally may lead to an increase
in nephron mass without any improvement in the risk
for hypertension or renal dysfunction. (75) A rat model
demonstrated that early postnatal overnutrition led to an
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 increase in weight gain and 20% increase in nephron
number in overfed offspring compared with normally fed
offspring. (75) Despite their increased nephron number,
overfed male rats were more likely to have hypertension,
proteinuria, and glomerulosclerosis relative to controls.
Neonatal high-protein diets have been shown to be associ-
ated with glomerular hypertrophy and glomerulosclerosis
in an FGR rat model, (76) but to a lesser extent in an FGR
piglet model. (77)
A single-center prospective cohort study demonstrated
that postnatal growth failure is associated with a reduced
GFR relative to controls in a human preterm population.
(78) Ensuring optimal nutrition in this population is chal-
lenging because human evidence supports the idea that
catch-up growth leading to obesity in preterm infants may
worsen the progression of proteinuric kidney disease and
that obesity and prematurity are additive factors. (79) A
cohort study examining 153 former preterm infants at a
median age of 11.5 years demonstrated that rapid weight
gain in early childhood (>1 year of age) was associated with
a higher body fat percentage and worsened metabolic
markers of insulin resistance and hypertension relative to
controls whereas rapid weight gain in infancy (<1 year of
age) was not. (80)
LONG-TERM RENAL EFFECTS OF PRETERM BIRTH
Growing evidence demonstrates that prematurity has an
impact on long-term renal health (Table). As large cohorts of
preterm survivors continue to reach adulthood, more infor-
mation is being gained about their long-term medical
outcomes. Although a number of preterm cohorts have
been followed up into early adulthood, we are yet to fully
understand the effects of preterm birth on morbidity in
mid-to-late adulthood.
Nephrocalcinosis
Preterm infants are at an increased risk for calcium depo-
sition in the kidney, known as “nephrocalcinosis.” This has a
variable incidence in the literature and is thought to be
associated with decreasing birthweight (81)(82); increased
calcium, phosphorus, and ascorbic acid intake; and increased
exposure to furosemide, dexamethasone, thiazides, and the-
ophylline. (81) A matched cohort study in Greece examined
105 infants born before 36 weeks’ GA and found evidence of
mild tubular dysfunction and a reduced kidney length in
those with nephrocalcinosis relative to controls at 1 year of
age. (83) Kist-van Holthe et al also demonstrated that former
preterm children born at less than 32 weeks’ GA with neph-
rocalcinosis were more likely to have mild renal insufficiency
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and tubular dysfunction compared with control subjects at a
mean age of 7.5 years. (84) These findings suggest that pre-
term infants with nephrocalcinosis may be at an increased risk
of developing long-term renal dysfunction into adulthood;
however, this has not yet been demonstrated in the literature.
Kidney Size, Growth, and Function
As previously discussed, kidney size and volume are
used as noninvasive markers of nephron mass. Preterm
infants have smaller kidneys at term postmenstrual age
than their term-born contemporaries; however, preterm
infants have been shown to have larger kidney-to-bodyweight
ratios, (13)(14)(15) potentially because of glomerular hyper-
trophy. A population of preterm infants has recently been
shown to exhibit catch-up renal growth over the first
6 months of age. (85) Preterm infants born at 30 to
32 weeks’ GA were shown to have smaller kidneys at term
postmenstrual age than term-born controls; however, they
subsequently exhibited an increased renal growth rate,
leading to similar kidney length at 6 months’ corrected
age. (85) Their renal cortical regions grew more during this
period of catch-up growth while their medullary regions
remained smaller. The cause for this catch-up growth is
uncertain; however, this suggests that while catch-up growth
may occur, this is not necessarily associated with normal
renal development.
A number of groups have examined former preterm
infants’ kidney sizes in adulthood. The renal volumes of
20-year-old former premature female survivors (small for
GA and appropriate for GA) have been shown to be smaller
(both length and volume) compared with term controls. This
association was seen irrespective of whether the study
participants were small or appropriate for GA at birth.
(86) More recently, the Health of Adults Born Preterm
(HAPI) cohort study performed in Canada showed that
adults born at less than 29 weeks’ GA had smaller kidneys
as young adults (average age 23 years) compared with
matched term-born controls. (6) Their renal volume cor-
rected to body surface area was 10% lower than controls.
There was no difference in eGFR between groups; however,
young adults born preterm had higher albumin-to-creatinine
ratios (albeit still within the normal range) relative to term-
born controls, suggesting that they may have reduced glo-
merular endothelial integrity. (6)
Prematurity has been demonstrated to have an impact on
kidney function. At 11 years of age, former preterm infants
have been shown to have a reduced eGFR measured by
urinary CysC and symmetric dimethylarginine compared
with term controls. (87) A Polish cohort study has shown
that in children born extremely preterm, eGFR measured
using CysC was significantly higher in former preterm
infants at both 7 and 11 years of age compared with matched
term controls. Their eGFR worsened slightly over time,
implying that long-term follow-up would be prudent. (88)
Not all longitudinal studies have shown a reduction in eGFR
during mid-childhood. Vieux et al’s cohort in France (27–31
weeks’ gestation evaluated at 5 years of age) all had normal
eGFRs in follow-up. (89) As many former preterm cohorts
continue to age, it is important to monitor their renal
function longitudinally to gain a better understanding of
how these early changes in kidney function and structure
manifest themselves in mid-to-late adulthood.
Chronic Kidney Disease
A recent large Swedish cohort study demonstrated that
extremely preterm infants (<28 weeks’ GA) have a 3-fold
risk of developing CKD (odds ratio 3.01 [1.67–5.45]) and that
late preterm infants have a risk that is almost twice that of
term infants (odds ratio 1.84 [1.62–2.08]). (4) This asso-
ciation was strongest in childhood and persisted until

TABLE. Summary of the Effects of Preterm Birth on Renal Health

Outcome
RISK FACTOR RENAL HEALTH OUTCOME

Antenatal period Maternal malnutrition Poor renal growth (44)

Maternal smoking Increased risk of preterm birth (45)
Smaller kidney volume and eGFR at school age (46)(47)
Proteinuria at 3 years of age (48)
Maternal alcohol consumption Mild CKD in offspring in their 30s (39)
Perinatal period Low birthweight Increased risk of end-stage renal failure (36)(37)
Increased risk of chronic kidney disease (19)(38)(39)
More rapid decline in kidney function when there is
underlying kidney disease (21)
Ex utero nephrogenesis Abnormal glomerulogenesis (26)(40)
Acute kidney injury Reduced nephron mass (14)
Mortality (70)
Postnatal growth failure in very-low-birthweight infants Reduced GFR relative to term controls (78)
Childhood and Preterm birth Renal size and function Smaller kidney size relative to term born controls (6)(86)
adulthood Larger kidney to bodyweight ratio relative to term born
controls (13)(14)(15)
Renal function Increased risk of nephrocalcinosis (81)(82)
Higher albumin to creatinine ratios than term born controls
in young adulthood (6)
Reduced eGFR relative to term born controls at 7-11 years of
age (87)(88)
Increased risk of chronic kidney disease persisting into mid-
adulthood (4)
Hypertension Alterations in the function of the renin-angiotensin system
(6)(90)(91)
Higher blood pressure than term controls in childhood and
adulthood (92)(93)(94)(95)
A greater hypertensive effect in former preterm women
than men (95)(96)
Increased salt sensitivity (ie, blood pressure changes in
relation to a high salt diet) (97)
Nutrition Obesity is an additive risk factor to prematurity for
proteinuric kidney disease (79)
Greater risk of insulin resistance (99)

eGFR¼estimated glomerular filtration rate; CKD¼chronic kidney disease.

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 midadulthood in all groups. There was a strong inverse
association between GA and CKD, which included children
born at what is typically considered full term at 37 and 38
weeks’ GA. This study relied on medical coding data to make
a diagnosis of CKD, which means that the investigators
could have under- or overestimated the true incidence of
CKD in this population. Importantly, 24% of those who
experienced acute renal failure in the neonatal period (27%
of whom were preterm) were subsequently diagnosed with
CKD.
Hypertension
Preterm birth is associated with an increased risk of hyper-
tension. The underlying etiology of this association is not
fully understood and is likely to be multifactorial. Prema-
turity and exposure to antenatal steroids have been associ-
ated with alterations in the function of the renin-angiotensin
system. (90) A recent cohort study showed that angiotensin
I levels are elevated in preterm infants relative to term
infants and that changes in blood pressure in preterm
infants occurred in association with changes in renin and
angiotensin peptides, (6) which were not seen in term
controls. Alamandine, a vasodilatory counterregulatory pep-
tide moderated by the renin-angiotensin system, (91) has
also been shown to be elevated in hypertensive preterm
survivors but not in hypertensive term-born participants. It
has been theorized that this represents a counterregulatory
cardiovascular and renoprotective activation in preterm
survivors.
A meta-analysis of observational studies found that pre-
term birth is associated with a 2.2 mm Hg increase in
systolic blood pressure (SBP) compared with term controls.
(92) These studies were from different countries and
reported outcomes at varied ages until early adulthood.
Figure. Timeline of nephrogenesis outlining potential opportunities to support renal development in preterm infants. AKI¼acute kidney injury; CKD¼
chronic kidney disease.
e732 NeoReviews
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The incidence of hypertension was also increased in those
born preterm. The reason for this association is not fully
understood. Studies published since this systematic review
have continued to demonstrate increases in both SBP and
diastolic blood pressure (DBP) in those born preterm.
Edstedt Bonamy et al showed that both SBP and DBP were
higher (although not abnormal) in children born preterm
compared with control subjects at 6 years of age. (93) An
individual patient meta-analysis including 9 international
cohort studies recently demonstrated a 3.4 mm Hg increase
in SBP and a 2.1 mm Hg increase in DBP in adulthood
in those born with very low birthweight compared with
control subjects, (94) with a larger hypertensive effect
noted in former preterm women than men and in those
infants whose mothers had preeclampsia. A cross-sectional
study of 5,232 young adult women in Sweden (mean age, 18
years) showed that those born preterm had an elevated SBP
and mean blood pressure relative to those born at term.
(95) A meta-analysis performed by Parkinson et al also
showed an association between increased SBP and DBP
affecting women more than men. (96) Some observational
evidence shows that some preterm infants may exhibit salt
sensitivity (ie, changes in blood pressure with a higher salt
diet). (97)
Hypertension causes glomerulosclerosis and is a risk
factor for CKD and progression to end-stage CKD. (98) In a
population that begins life with fewer nephrons, ensuring
that hypertension is both detected and treated appropriately
is important. Evidence shows that preterm infants, partic-
ularly those born small for GA, are at an increased risk for
insulin resistance and metabolic syndrome. (99) Diabetes is
also strongly associated with end-stage CKD, (98) making
it important to identify those with insulin resistance early
to avoid nephron loss.
INTERVENTIONS AIMED AT IMPROVING
NEPHROGENESIS AND LONG-TERM RENAL HEALTH OF
PRETERM SURVIVORS
Interventions aimed at improving the long-term renal health
of preterm infants need to be multipronged (Figure). The
starting point of any preterm infant’s increased risk of
mortality and morbidity is the point at which they are born
early; any intervention aimed at reducing the risk of preterm
birth is therefore of huge potential benefit. A large proportion
of preterm birth remains unexplained; however, there are
interventions that have reduced the incidence of preterm
birth in specific high-risk groups, the details of which are
beyond the scope of this review. (100) Given that many
preterm infants experience the “double hit” of both preterm
birth and growth restriction, interventions that reduce risk
factors for FGR are also of benefit; this includes smoking
cessation, advice during (and ideally before) pregnancy with
regard to smoking, drug use, and good maternal nutrition
both around the time of conception and throughout preg-
nancy. The first 1,000 days is an international public health
initiative aimed at optimizing the nutrition of infants from
conception to their second birthday to reduce their risk of
programmed noncommunicable diseases. (101) Other obstet-
ric interventions such as screening for the risk of preterm
preeclampsia and providing aspirin to those who qualify
could potentially reduce iatrogenic preterm birth. (102)
Once preterm birth has occurred, attention should be
given to reducing renal injury during ex utero nephrogen-
esis. This includes reducing the risk of sepsis in the NICU,
which is associated with AKI, avoiding hyperoxia, and
reducing exposure to nephrotoxins. The evidence around
what constitutes optimal nutrition for nephrogenesis is
limited; however, human milk feeding (either expressed
maternal milk or banked breast milk) has been associated
with a reduction in hypertension in adolescents born pre-
term in nonrandomized studies. (103)
Ideas for novel drug and stem cell therapies aimed at
prolonging nephrogenesis in preterm infants are being
discussed and explored in the literature (104)(105)(106);
however, at this stage (to our knowledge) these have not
progressed to preclinical trials.
Given the increased risk that preterm survivors have for
hypertension and decreased insulin sensitivity, this popu-
lation should be followed throughout childhood and adult-
hood to ensure that they receive appropriate diagnosis and
treatment. Health-care professionals and people born pre-
term should receive education and advice regarding their
increased risk for CKD and the importance of lifestyle
interventions.
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FUTURE DIRECTIONS
Many gaps remain in our understanding of the effects of
preterm birth on long-term renal health. As preterm cohorts
are followed up into mid-to-late adulthood, we will gain further
knowledge of their risk profiles and renal complications, which
will continue to help guide future research, intervention, and
therapies. As new technology such as real-time measured
transcutaneous GFR becomes available, we may be able to
better identify and target our highest risk populations and
ensure that they receive appropriate follow-up.
CONCLUSIONS
Preterm birth leads to a reduced functional nephron mass and
to maladaptation of the kidney. This in turn predisposes
preterm survivors to reaching the threshold of glomeruloscle-
rosis at which renal function declines earlier in life. There is
still a lot to learn about the effects of prematurity on the kidney
and how to best support the kidneys of preterm survivors,
which should remain a focus for ongoing research. Currently
many opportunities exist for clinicians to avoid further con-
tributing to nephron loss in preterm infants. These include
avoiding neonatal AKI and nephrotoxin exposure during
nephrogenesis; educating preterm survivors and their fami-
lies about lifestyle risks that may contribute to nephron loss;
and educating primary health care professionals about the
importance of reducing obesity, screening for hypertension
and insulin resistance, and avoiding nephrotoxins in former
preterm children and adults.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the clinical manifestations, imaging, and laboratory
features of renal failure in the neonate.
• Hypertension.
• Know how prenatal diagnosis of renal abnormalities affects
postnatal management.
• Know the recommended supportive and corrective treatment of
anatomic abnormalities of the kidneys and urinary tract in infants.
• Recognize the clinical manifestations of anatomic abnormalities
of the kidneys and urinary tract in infants.
• Know the effects of drugs such as cyclo-oxygenase inhibitors,
angiotensin-converting enzyme inhibitors, prostaglandins, and
catecholamines on renal function (antenatal and postnatal).
• Know the changes in glomerular and tubular function that occur
during development, including the handling of glucose, sodium,
potassium, calcium, bicarbonate, and phosphate.
Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e733
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The Effect of Preterm Birth on Renal Development and Renal Health Outcome
Amanda Dyson and Alison L. Kent
NeoReviews 2019;20;e725
DOI: 10.1542/neo.20-12-e725

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The Effect of Preterm Birth on Renal Development and Renal Health Outcome
Amanda Dyson and Alison L. Kent
NeoReviews 2019;20;e725
DOI: 10.1542/neo.20-12-e725

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/20/12/e725

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