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Series

Global Kidney Disease 4


Eect of fetal and child health on kidney development and
long-term risk of hypertension and kidney disease
Valerie A Luyckx, John F Bertram, Barry M Brenner, Caroline Fall, Wendy E Hoy, Susan E Ozanne, Bjorn E Vikse

Developmental programming of non-communicable diseases is now an established paradigm. With respect to


hypertension and chronic kidney disease, adverse events experienced in utero can aect development of the fetal
kidney and reduce nal nephron number. Low birthweight and prematurity are the most consistent clinical surrogates
for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in
later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity,
and rapid childhood weight gain should alert clinicians to an individuals lifelong risk of hypertension and kidney
disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity
are aected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and
early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of
hypertension and kidney disease in the future.

Introduction
Hypertension is now the leading risk factor for the global
disease burden and it is a major cause and result of
chronic kidney disease.1 Global deaths from kidney
disease have risen by 83% since 1990.2 Recognition of the
burden of chronic kidney disease, its risk factors, and
implementation of prevention strategies is, therefore,
key to saving many lives.

Search strategy and selection criteria


We searched PubMed for articles published between January,
1988, and February, 2013, with the terms nephron number,
nephron endowment, nephron mass, nephrogenesis,
birth weight, low birth weight, high birth weight,
prematurity, preterm birth, developmental
programming, developmental origins of adult health and
disease, catch-up growth, growth restriction, SGA, and
IUGR, with other keywords including kidney, kidney
mass, kidney size, kidney volume, diabetes, gestational
diabetes, cardiovascular disease, obesity, human,
hypertension, hypertensive disorders in pregnancy,
preeclampsia, vitamin A deciency, maternal diet, and
maternal nutrition. We also looked at the reference lists of
existing manuscripts, textbooks, and websites. Furthermore,
we identied data, references, and links by searching the
WHO, UNICEF, and Google Scholar websites between
January, 2012, and February, 2013, with the keywords low
birth weight, preeclampsia, gestational diabetes,
maternal and newborn health, nutrition, and childhood
obesity. We restricted our search to English language
publications only. We largely included publications from the
past 5 years but also considered older seminal papers. Some
references to experimental data were included when these
were judged necessary to explain ideas strongly supporting
the pathophysiology but not yet proven in man.

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Increasingly, the important contribution of fetal


and early childhood development to growth in noncommunicable disease is being recognised.3,4 Epidemiological observation suggests a graded risk for
hypertension, type 2 diabetes, cardiovascular disease,
and chronic kidney disease across the range of fetal and
early childhood development.3,4 Acknowledgment of this
paradigm is important because interventions to optimise
fetal and child health as strategies to prevent adult noncommunicable diseases have great potential economic,
societal, and individual benet.4 Many developing countries carry the dual burdens of undernutrition and
overnutrition, contributing to the vicious cycles of poor
maternal health, suboptimum fetal development, and
unhealthy childhood growth that all augment the risk of
adult disease.5,6

Lancet 2013; 382: 27383


Published Online
May 31, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)60311-6
This is the fourth in a Series of
six papers about global
kidney disease
Division of Nephrology,
University of Alberta,
Edmonton, AB, Canada
(V A Luyckx MBBCh);
Department of Anatomy and
Developmental Biology,
Monash University, Melbourne,
VIC, Australia
(Prof J F Bertram PhD); Brigham
and Womens Hospital, Harvard
Medical School, Boston, MA,
USA (Prof B M Brenner MD);
MRC Lifecourse Epidemiology
Unit, Southampton General
Hospital, Southampton, UK
(Prof C Fall FRCPCH); Center for
Chronic Disease, School of
Medicine, University of
Queensland School of
Medicine, Brisbane, QLD,
Australia
(Prof W E Hoy FRACP AO);
University of Cambridge
Metabolic Research
Laboratories, Institute of

Key messages
Low birthweight and prematurity are risk factors for hypertension, proteinuria, and
chronic kidney disease in later life
Worldwide, low birthweight and prematurity occur in 15% and 96% of livebirths,
respectively, suggesting a high proportion of the worlds children are at risk of
hypertension and kidney disease
Low birthweight and prematurity are associated with a congenital reduction in nephron
number; in turn, small numbers of nephrons are associated with raised blood pressure
and increased susceptibility to kidney disease
High birthweight, particularly as a result of exposure to maternal diabetes in utero, is
associated with increased risk of proteinuria and kidney disease in later life
Risk of low birthweight and prematurity is aected by maternal nutrition and health
before and during pregnancy and by the mothers own birthweight, indicating the
intergenerational eects of programming
Upward crossing of percentiles for weight or body-mass index in childhood or
adolescence is associated with increased risk of high blood pressure, progression of renal
disease, type 2 diabetes, obesity, and cardiovascular disease in later life; these eects can
be independent of birthweight

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Metabolic Science, Cambridge,


UK (S E Ozanne PhD); and
Institute of Medicine,
University of Bergen, and
Department of Medicine,
Haukeland University Hospital,
Bergen, Norway
(Prof B E Vikse MD)

Pregnancy

Childhood/fetal development

Maternal diabetes
or gestational
diabetes

Adult

Correspondence to:
Dr Valerie A Luyckx, Division of
Nephrology, University of Alberta,
Edmonton, AB, Canada T6G 2S2
vluyckx@ualberta.ca

Maternal
development
Low birthweight,
short stature

Societal factors
Poverty, conflict or war,
teenage pregnancy,
antenatal care, birth spacing,
environmental conditions

Maternal health
Low protein diet, pre-eclampsia,
hypertension, vitamin A deficiency, iron
deficiency, substance abuse, malaria, chronic
kidney disease, multiple gestation

Genetic polymorphisms
PAX2, RET, OSR1, ACE,
BMPR1A

High birthweight
Intrauterine growth restriction or
low birthweight or prematurity

Low nephron number


Clinical surrogates:
Low birthweight, prematurity, short stature, gestational diabetes
exposure, ethnic origin, large glomeruli, small kidneys

Catch-up growth
Overweight or obese

Metabolic
syndrome

Hypertension
and salt sensitivity

Hyperltration
Renal functional reserve
Glomerular filtration rate

Proteinuria

Ischaemic
heart disease

Diabetes

Glomerulosclerosis, chronic kidney disease, end-stage renal disease

Figure 1: Factors aecting developmental programming of hypertension and kidney disease

Here, we describe how fetal and child health aect


kidney development and risk of disease. We focus
mainly on human studies but use experimental data
when necessary to provide further insight.

Eect of fetal development on the kidney


About 25 years ago, Brenner and colleagues7 proposed that a congenital (developmentally programmed)
decrease in nephron number could account for why
some individuals are more susceptible to hypertension
and renal injury than others. A kidney with fewer
nephrons was postulated to have a diminished ltration
surface area, resulting in limitation of sodium excretion
leading to raised blood pressure and reduction of
renal adaptive capacity in the setting of injury. This
hypothesis provided a plausible link between a high
prevalence of hypertension and renal disease in populations with an increased frequency of low birthweight,
35

Low birthweight (% livebirths)


Preterm birth (% livebirths)
Vitamin A deficiency* (% pregnant women)
Childhood obesity (%)

30
Prevalence (%)

25
20
15
10
5
0

World

Africa

Asia

Europe

Latin America
and Caribbean

North
America

Oceania

Region

Figure 2: Worldwide prevalence of factors aecting programming of renal disease, by UN region


Error bars represent the range of prevalence, by region. *Excludes countries with 2005 gross domestic product of
US$15 000 or higher, where vitamin A deciency is presumed absent. Obesity gures for North America and
Europe are extrapolated from data for developed countries. Childhood obesity is dened as two or more SD from
weight-for-height median. Data are pooled from references 1115.

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whereby low birthweight was expected to be associated


with a lower number of nephrons (gure 1).8 Consistent
with this hypothesis, data from various experimental
models conrm the association of low birthweight with
later-life hypertension, mediated, in part, by acquisition
of fewer nephrons in utero (the pathophysiological
mechanisms aecting nephrogenesis are reviewed
elsewhere).9 Similarly, in human beings, low birthweight is a risk factor for hypertension and chronic
kidney disease.10
Low birthweight is a marker of poor fetal growth.
Risk factors for low birthweight vary in developed and
developing countries but the global incidence is 15%
a year, suggesting that many children are at risk of
hypertension and kidney disease in later life (gure 2).1115
In view of the complexity and far-reaching eect of
developmental programming, understanding the most
proximal origins of hypertension and renal disease risk
is crucial for expansion of public health strategies to
reduce their global eect.4
Low birthweight is dened universally as a birthweight less than 25 kg, and high birthweight is
classed as a birthweight heavier than 40 or 45 kg.16
Other terms used to indicate neonatal size include
intrauterine growth restriction (IUGR), small for
gestational age, and large for gestational age. For
simplicity, we dene low birthweight as all babies with
a birthweight less than 25 kg, including those who
are small for gestational age, and high birthweight as
children with a birthweight greater than 4045 kg,
including those who are large for gestational age. A
premature infantie, who is born before 37 weeks of
gestationis generally low birthweight, which might
be an appropriate weight for gestational age if growth
occurred normally until birth, but could be small for
gestational age if growth were restricted.16
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Nephron number in children and adults


The total number of nephrons in the normal adult
human kidney varies widely.17 The average number of
nephrons per kidney for many years was assumed to be
between 900 000 and 1 000 000, yet the observed range
between individuals varies more than tenfold.17,18 In the
largest study to date,18 total nephron number ranged
from 210 332 to 2 702 079 in 176 adults of AfricanAmerican ethnic origin and from 227 327 to 1 660 232 in
132 white individuals.
Birthweight correlates linearly with nephron number
in adults and children, and nephron number increases
by 257 426 per kg increase in birthweight,19 suggesting
(by extrapolation) that nephron numbers are lower
in people with a low birthweight. Although nephron
numbers have been measured rarely in adults of
known low birthweight, nephron numbers are reduced
signicantly in infants with low birthweight.20,21 The total
number of nephrons in an adult human kidney reects
the number of nephrons formed during development
(nephron endowment) minus the number of nephrons
subsequently lost; therefore, cumulative injury over time
could contribute to a kidney reaching a very low nephron
number, leading to disease.17 Human nephrogenesis
ends at around 36 weeks of gestation, after which
no new nephrons can form.20 In an Australian study,
nephron number in 15 infants who died before the age
of 3 months ranged 45-fold, from 246 181 to 1 106 062,
suggesting that much of the variation in nephron
number in adults is established before birth.22

Developmental determinants of low


nephron number
The most robust clinical surrogates for low nephron
number are low birthweight and prematurity. However,
not all factors that aect nephron number result in low
birthweight, therefore, awareness of risk factors for low
nephron number per se is also important (table 1). The
most important risk factors, some of which could be
modiable with public health interventions, include
maternal health and nutrition, prenatal and postnatal
environments, prematurity, and genetic predisposition.24

Maternal factors
Figure 1 shows maternal health factors that could aect
the risk of low birthweight and prematurity and should
be judged risk factors for low nephron number in
ospring.25 Mothers who themselves were low birthweight, compared with mothers who were not, were
more likely to have babies of low birthweight (odds
ratio 18, 95% CI 1325), a nding that is independent
of socioeconomic factors, suggesting a genetic or epigenetic intergenerational eect.26

Hypertensive disorders during pregnancy


Disorders linked to high blood pressure in pregnancy
were noted in 84 million women worldwide in 2004, and
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Eect on kidney
Prenatal
Maternal vitamin A deciency

Small infant kidney size

Low birthweight

Decreased nephron number

Growth restriction

Reduced glomerular ltration rate at 75 years

Prematurity

Decreased nephron number; reduced kidney


size in growth-restricted children

Genetics
RET (1476A) polymorphism

10% reduction in newborn kidney volume

PAX2 AAA haplotype

10% reduction in newborn kidney volume

Combined RET (1476A) polymorphism and PAX2


AAA haplotype

23% reduction in newborn kidney volume

I/D ACE polymorphism

8% reduction in newborn kidney volume

BMPR1A rs7922846 polymorphism

13% reduction in newborn kidney volume

OSR1 rs12329305(T) polymorphism

12% reduction in newborn kidney volume

Combined OSR1 and RET polymorphisms

22% reduction in newborn kidney volume

Combined OSR1 and PAX2 polymorphisms

27% reduction in newborn kidney volume

ALDH1A2 rs7169289(G) polymorphism

22% increase in newborn kidney size

Postnatal
Renal failure

Decreased nephron number

Growth restriction

Reduced glomerular ltration rate at 75 years;


increased odds of renal dysfunction at 64 years

Catch-up growth, childhood and adolescent overweight


or obesity

Increased glomerular volume; faster


progression of renal disease

Adapted from reference 23, with permission of Lippincott Williams and Wilkins. RET=tyrosine kinase receptor.
PAX2=paired box gene 2. ACE=angiotensin-converting enzyme. OSR=Odd-Skipped related. BMPR=bone morphogenic
protein receptor. ALDH=aldehyde dehydrogenase. See appendix for relevant references.

Table 1: Developmental factors associated with nephron number, kidney size, and function

these are major risk factors for low birthweight.27 As


outlined in a Comment linked to this Series,28 risk of preeclampsia in a mother is increased if she herself was low
birthweight (odds ratio 169, 95% CI 14202),29 premature (195, 154247),30 or either of the mothers
parents were born after pre-eclamptic pregnancies (22,
2024),31 showing the complexity of intergenerational
programming. Prepregnancy maternal chronic kidney
disease and hypertension are also relevant risk factors for
pre-eclampsia, low birthweight, and preterm delivery.32 In
a Cuban cohort,21 maternal hypertension was associated
with low birthweight, which in turn was associated with
low nephron number.

See Online for appendix

Gestational diabetes
The worldwide prevalence of gestational diabetes is
poorly recorded but is reported as 01253%.33 Maternal
obesity, now present in 1520% of pregnancies, is a
strong risk factor for gestational diabetes, as is maternal
prematurity.30,34 In experimental models, maternal hyperglycaemia is associated with reduced nephron number,
raised blood pressure, microalbuminuria, and diminished glomerular ltration rate in ospring.35 In adult
children whose mother had diabetes, compared with
those who had a diabetic father, renal functional reserve
was decreased, suggesting a reduction in nephron
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number was acquired during exposure to gestational


diabetes.36 Maternal diabetes is also associated with a
threefold increased risk of renal agenesis and dysgenesis;
therefore, hyperglycaemia strongly aects fetal renal
development.37 Furthermore, gestational diabetes is
sometimes associated with high birthweight in infants,
which is a known risk factor for subsequent hypertension,
type 2 diabetes, renal disease, and cardiovascular disease,
although the eect on nephron number is unknown.38

Maternal behaviour
Smoking by the mother has been associated with low
birthweight and low nephron number.21 Alcohol
consumption is linked to a dose-dependent increased
risk of prematurity and fetal growth restriction.39 In
experimental models, gestational alcohol exposure
impaired embryonic ureteric bud branching resulting
in low nephron number, and it could be a risk in
human beings.40

Prenatal factors
Maternal diets decient in protein, total calories, or iron
all reduce nephron numbers in experimental models and
are often associated with low birthweight.9 In human
beings, maternal protein and micronutrient deciencies
are common in developing countries, and maternal
malnutrition, underweight, iron deciency, and anaemia
are all recognised risk factors for low birthweight.41
Vitamin A deciency is also highly prevalent among
pregnant women worldwide (gure 2).12 In animals,
maternal diets decient in vitamin A, resulting in
amounts similar to those seen in decient people, induce
a dose-dependent reduction in nephron number, whereas
vitamin A supplementation augments nephron number.42
Importantly, vitamin A deciency alone does not cause
low birthweight, suggesting the eect of deciency could
be overlooked if normal birthweight was presumed to
exclude an adverse developmental environment. The
active metabolite of vitamin Aretinoic acidregulates
transcription of RET, a tyrosine kinase receptor important
for kidney development. Plausibly, therefore, vitamin A
intake could be a vital determinant of nephron number.
Indeed, vitamin A deciency in Indian mothers was
associated with signicantly lower newborn adjusted
renal volume in their ospring compared with babies
born to Canadian mothers who were vitamin A replete,
probably reecting lower nephron numbers (table 1).43

Prematurity
About 96% of liveborn babies are premature (gure 2),
and prematurity is associated with raised blood pressure,
renal disease, and cardiovascular disease in later life.13,16
Nephron number correlates with gestational age; in
premature infants, nephrogenesis might continue for a
period after birth, although glomeruli are large and
abnormal and renal maturation seems accelerated.20,44
Consistent with these morphological abnormalities,
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prematurity is a risk factor for acute kidney injury, which


is an independent predictor of mortality and subsequent
chronic kidney disease in very low birthweight infants.16

Postnatal factors
Human nephrogenesis is complete at term; however,
ongoing nephrogenesis has been recorded up to 40 days
after birth in infants born before 30 weeks of gestation.44
Thus, a window of vulnerability exists in preterm infants,
during which time kidney development can be aected
(table 1). Indeed, extrauterine growth restriction was
associated with a signicantly lower glomerular ltration
rate in very low birthweight children at a mean age of
76 years; conversely, the frequency of renal impairment
was 33% lower at 64 years among very low birthweight
children who had gained more weight in neonatal
intensive care, showing the importance of early nutrition
on kidney development.45,46 Nephron number was low in
premature infants who developed renal failure before
death, although whether renal failure was a cause or
outcome of low nephron number is unknown.44
Many premature infants receive perinatal drugs
such as non-steroidal anti-inammatory agents, glucocorticoids, and aminoglycosides. Extrapolating from
experimental models, these and other drugs can aect
nephron number and increase the risk of acute kidney
injury in infants.47 However, follow-up of people whose
mother was exposed to betamethasone for 48 h before
birth did not show any increase in blood pressure
at age 30 years compared with those whose mother
had received a placebo.48 Short-term steroids might,
therefore, not aect kidney development, but the eects
of such common drugs on human nephrogenesis merit
further study.

Genetics
Rare genetic and congenital abnormalities resulting in
renal hypoplasia contribute to about half of all cases of
childhood end-stage renal disease.49 Common polymorphisms in several genes known to participate in
kidney development correlate with altered gene transcription and newborn kidney size, which is proportional
to nephron number (table 1).22 These studies have been
undertaken mainly in white populations, therefore
implications for other populations need to be investigated.22,50,51 The molecular mechanisms regulating
nephrogenesis are reviewed elsewhere.52 Individual
permutations of these genetic variants could account for
the wide variability seen in human nephron numbers,
because some mutations reduce and some augment
kidney volume. Interactions between genetic polymorphisms and environmental circumstances during
kidney development have not been studied. Gene microarray analysis of neonatal kidneys has shown global
downregulation of gene expression in experimental
models of maternal low protein diet or placental insuciency.53 Therefore, altered levels of gene expression
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resulting from a polymorphism could become even


more amplied under conditions of superimposed
maternal nutrient deciency, further decreasing
nephron number.54

Clinical surrogates for nephron number


At present, all reports of human nephron number have
come from kidneys obtained at autopsy. In view of the
current reliance on autopsy specimens, surrogate
markers for nephron number are important (table 2).
Similar to total nephron number, mean glomerular
volume varied up to tenfold in an Australian series of
420 kidneys from people in ve ethnic groups.55 Total
nephron number varies inversely with mean glomerular
volume.17 An increase in glomerular volume probably
reects compensatory hypertrophy and hyperltration
in individual nephrons. Indeed, total ltration surface
area is fairly well preserved in kidneys with low nephron
number, possibly at the expense of increased glomerular
pressure, which can accelerate further nephron loss.18
Moreover, increased glomerular size is a predictor of
poorer renal outcomes in African-American populations,
Native Americans (Pima Indians), and Indigenous
Australians, and without other causes should be judged
a surrogate for low nephron number.9 In view of the
heterogeneity and hypertrophy occurring in glomeruli,
kidney size does not correlate consistently with nephron
number in adults, but the relation seems linear in
infants younger than 3 months.22,56

Birthweight, prematurity, and blood pressure


Studies of monozygotic twins, in which the twin who
weighed the least subsequently had higher blood pressure, suggest that environmental programming could be
more crucial than genetic factors.57 Low birthweight and
prematurity have been associated consistently with
increased risk of higher blood pressure in later life
(panel).58,59 In a meta-analysis of 27 studies,59 a 228 mm Hg
(95% CI 124333) increase in systolic blood pressure
was recorded in individuals whose birthweight was less
than 25 kg, compared with those heavier than 25 kg.
Unfortunately, in most studies to date, a distinction has
not been made between low birthweight as a result of
growth restriction at any gestational age and prematurity
with appropriate size for gestational age. Therefore, the
potential for unmeasured confounding or eect modication by gestational age, growth restriction, or both must
be borne in mind.16
Findings of a systematic review of ten studies showed
that, in preterm babies born at a mean gestational age of
302 weeks and with a mean birthweight of 128 kg, blood
pressures in later life were 25 mm Hg higher (95% CI
1733) than in infants born at term.58 Prematurity has
been associated predominantly with high, but still normal,
blood pressures, because cohorts studied are still fairly
young. Overt hypertension has been recorded in two
studies of premature babies: in the rst, the children
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Association with nephron number


Clinical surrogate
Low birthweight

Increase of 257 426 glomeruli per kidney, per kg increase in birthweight

Prematurity

Decrease in glomerular number, proportional to gestational age, in premature


compared with term infants

Sex

Nephron number 12% lower in women

Age

3676 fewer glomeruli per kidney per year of age older than 18 years (nephron loss)

Adult height

28 000 more glomeruli per cm increase in height

Kidney mass

23 459 more glomeruli per g of kidney tissue (in infants)

Glomerular volume

Inverse correlation between glomerular volume and nephron number

Ethnic origin

Reduced number in Indigenous Australians compared with white and black


US population

Possible correlates
Gestational diabetes
exposure

Decrease in renal functional reserve in ospring of diabetic mothers versus


diabetic fathers

Adapted from reference 23, with permission of Lippincott Williams and Wilkins. See appendix for relevant references.

Table 2: Clinical surrogates for nephron number

Panel: Clinical associations with programming of kidney function


Low birthweight or prematurity
Increased blood pressure
Salt sensitivity
Proteinuria
Reduced glomerular ltration rate
Reduced renal functional reserve
Accelerated progression of primary renal disease
Chronic kidney disease
End-stage kidney disease
Death
Low nephron number
Increased blood pressure
Increased glomerular volume
Possible predisposition to renal failure in neonates
Reduced renal size
Increased blood pressure
Salt sensitivity
Reduced glomerular ltration rate
High birthweight or maternal diabetes
Proteinuria
Reduced renal functional reserve
End-stage kidney disease
Rapid increase in weight or body-mass index in childhood and adolescence,
particularly after low birthweight
Faster progression of renal disease
Larger glomeruli
Higher blood pressure
Diabetes and impaired glucose tolerance
Cardiovascular disease and death
Obesity
Metabolic syndrome
Adapted from reference 23, with permission of Lippincott Williams and Wilkins.

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were aged 2 years and the prevalence of hypertension


(dened as systolic or diastolic blood pressure greater
than the 95th percentile) was 30% overall; and in the
second, pregnant women were aged 25 years and chronic
hypertension was present in 14% of those born preterm
compared with 08% born at term (odds ratio 17, 95% CI
132220).30,60 Researchers have tried to dissect the relative
roles of prematurity and growth restriction; some suggest
prematurity alone is the predominant risk factor, whereas
others judge small for gestational age to be most important
when ascertaining risk of raised blood pressure and kidney
disease.61 These dierences show the complex interplay of
intrauterine and extrauterine events and timing of insults,
which vary considerably in premature infants.16
Because odds ratios for risk of high blood pressure
were similar between the meta-analysis of low birthweight59 and the systematic review of prematurity,58 and
since prematurity does not account for all babies with
low birthweight, both low birthweight and prematurity
must be deemed important risk factors for high blood
pressure. The association starts in early childhood
and becomes augmented in adulthood, at which stage
blood pressures typically reach hypertensive ranges,
suggesting the programming eects are compounded by
growth, age, and lifestyle.

Nephron number and blood pressure


In rodents, nephrogenesis continues for up to 710 days
after birth, providing a windowsimilar to that seen in
premature infantsduring which postnatal events can
aect nephron number. In rats of low birthweight, rescue
of nephron number by optimisation of postnatal
nutrition abrogated development of subsequent hypertension; conversely, undernutrition after birth of rat pups
of normal birthweight led to lower nephron numbers
and higher blood pressure.62,63 These data accord with a
role of nephron number in hypertension.
In a German cohort of adults who died in accidents,
nephron numbers were signicantly lower among
those with hypertension compared with normotensive
controls.64 Low nephron numbers have also been
associated with raised blood pressure in Indigenous
Australians and white populations from the USA and
Australia, although birthweights were unknown.65
The relation between nephron number and blood
pressure in people of African origin seems less clear,
but glomerular volume is a signicant independent
predictor of high blood pressure in this population.65
Additional factors probably contribute to hypertension
in African populations, but the eect of birthweight
or the contribution of nephron number to severity of
hypertension, for example, cannot be excluded.
Observations of normalisation of glomerular ltration surface area despite low nephron numbers65
argue against the hypothesis that sodium excretion is
restricted. However, in patients and in experimental
models, low birthweight and low nephron number were
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associated with a salt-induced increase in blood pressure


(panel).66,67 Salt sensitivity in young adults and children
correlates inversely with birthweight, independent of
glomerular ltration rate, suggesting a primary defect in
renal sodium handling.68,69
Evidence that hypertension is not eliminated despite
normalisation of nephron number in some experimental
models suggests that additional factors participate in
developmental programming of hypertension.70 Experimental work has shown alterations in expression of renal
tubule sodium transporters and systemic changes in
vascular function, neuroendocrine adaptations to stress,
insulin sensitivity, and sympathetic nervous system
activity.70 Nephron number, therefore, is not the sole programmed risk factor for hypertension, but it is likely to
exacerbate any risk and contribute to kidney disease.

Renal function, birthweight, and nephron mass


Glomerular ltration rate
Without compensatory hyperltration, a kidney with a
reduced number of nephrons should have a diminished
glomerular ltration rate. Indeed, glomerular ltration
rate extrapolated from amikacin clearance on day 1 of life,
preceding any compensatory adaptation, was decreased
signicantly in premature and low-birthweight infants
compared with term controls.71 Glomerular ltration rate
measured by inulin clearance was signicantly lower at
age 76 years in children who had been born premature
and had severe growth restriction compared with nongrowth-restricted controls.45 In this study, the eects were
similar in children who were growth-restricted prenatally
or postnatally in intensive care, again showing the
importance of early nutrition. In a meta-analysis of eight
studies,10 the odds ratio for reduced glomerular ltration
rate with low birthweight was 179 (95% CI 131245).

Proteinuria
Microalbuminuria is one of the earliest signs of
glomerular hyperltration, and transition to macroalbuminuria accords with ongoing renal injury. Hoy and
colleagues72 reported an odds ratio of 28 (95% CI
126631) for macroalbuminuria in Indigenous
Australians who were low birthweight compared with
those of normal birthweight. In this population,
albuminuria was associated with a signicant increase
in cardiovascular and renal deaths, emphasising its
clinical relevance.73 Many study ndings have since
conrmed this association, reected in an odds ratio of
181 (95% CI 119277) for albuminuria in low-birthweight individuals in a meta analysis of nine studies.10 In
Native Americans (Pima Indians), however, the relation
is U-shaped, with an increased risk of proteinuria within
those whose birthweight was less than 25 kg and
greater than 45 kg.38 This population has a high
prevalence of gestational diabetes, exposure to which
was the strongest predictor of proteinuria in the highbirthweight people.38
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Chronic kidney disease and end-stage renal disease


Amplied progression of primary renal diseases has
been noted in people with low birthweight.9 In individuals
with diabetes, prevalence of nephropathy has been
associated with both low and high birthweight, and short
stature.38,74 All these observations suggest that abnormal
fetal growth increases long-term risk of renal disease
(panel). Consistent with this hypothesis, the odds ratio
for chronic kidney disease (including end-stage renal
disease) associated with low birthweight was 173
(95% CI 144208) from 18 studies.10 In populationbased studies, a U-shaped relation has been reported
between birthweight and risk of chronic kidney disease
or end-stage renal disease, suggesting high birthweight
is also important.8,75,76 In some studies, the programmed
risk of chronic kidney disease seems to be greater in
men.75 However, the dierential eect of sex on renal
programming is quite variable and needs further study.76,77
Similar to programming of blood pressure risk,
nephron number is unlikely to be the sole factor contributing to risk of renal disease, and a low nephron
number will probably not be sucient to cause
renal disease without additional variables. Moreover,
developmental programming of related disorderseg,
type 2 diabetes, cardiovascular disease, insulin resistance and obesitycould increase renal risk further.4,16
Programming of these disorders might take place
simultaneously in a developing fetus, depending on
timing and nature of the insults. All infants subjected to
adverse intrauterine conditions should be judged at risk
for all these disorders.

Eect of childhood weight gain on kidney


disease and function
Postnatal malnutrition and clinical circumstances can
aect nephrogenesis, childhood renal function, and longterm risk of renal disease (gure 1).16,44,46 In rats with low
birthweight, low nephron numbers were restored to
normal and development of hypertension was abrogated
by provision of adequate postnatal nutrition.62 When lowbirthweight rats were overfed after birth, nephron
numbers remained low and the rodents developed obesity,
hypertension, and renal injury over time.78 In rats with
normal birthweight that were overfed postnatally, despite
a higher-than-normal nephron number, blood pressure,
proteinuria, and glomerulosclerosis were all increased in
adulthood.79 Taken together, these data suggest that
normalisation of postnatal nutrition can be benecial, but
overfeeding is probably deleterious. In infants, postnatal
weight gain and nutrition have been implicated in
developmental programming of adult disease.80
Catch-up growth in children who were of low
birthweight has long been advocated, particularly
in developing countries, to boost resilience against
infections and reduce risk of undernutrition, stunting,
and cognitive impairment.5 However, in many populations worldwide, accelerated weight gain or an increase
www.thelancet.com Vol 382 July 20, 2013

in body-mass index (BMI), even in children with a


normal birthweight, has been associated consistently
with amplied risk of adult hypertension, type 2
diabetes, and cardiovascular disease.8082 This eect
grows as the child ages: upward crossing of weight
or BMI percentiles in mid-childhood or adolescence
is associated with strong adverse eects on later risk,
whereas upward crossing in infancy (younger than
1 year) has no or little eect on later blood pressure and
could protect against diabetes.8284 The gain in childhood
BMI associated with increased risk of adult disease is not
always excessive in terms of absolute number. In many
developing countries, children who grow rapidly can still
be small by international weight standards, but upwards
crossing of BMI percentiles seems to be the important
factor.8284 Therefore, one cross-sectional measurement
of a childs weight or BMI could be misleading in
such circumstances, emphasising the need for growth
tracking in early childhood.
Children born with a low birthweight who have an
adequate nutrient supply tend to gain weight rapidly.5
Among 22-year-old British adults, systolic blood pressure
increased by 13 mm Hg (95% CI 0323) for every
SD decrease in birthweight and rose by 16 mm Hg
(0627) for every SD gain in childhood weight between
age 1 year and 10 years.85 An association is well
recognised between rapid childhood weight gain and
raised blood pressure and increased arterial stiness,
which is sometimes already evident in childhood.83
In a study of 216 771 Scandinavian adults,81 those
with a birthweight of 25 kg and a BMI of 177 kg/m
(overweight) at age 7 years had a 44% increased risk of
cardiovascular disease in adulthood compared with those
with a median birthweight of 34 kg and a BMI of
153 kg/m (normal) at age 7 years. The highest risk
of raised blood pressure and cardiovascular disease,
therefore, was present in children born with low
birthweight who became heavy.81 Importantly, BMI was
associated strongly and positively with cardiovascular
disease risk in this study, independent of birthweight,
showing the importance of childhood obesity itself as a
risk factor for adult disease.
The prevalence of childhood obesity is increasing
worldwide (gure 2).14 Risk factors for obesity include
high birthweight, exposure to gestational diabetes, and
early postnatal weight gain.86 These factors are also
associated independently with altered nephrogenesis
and increased risk of hypertension, type 2 diabetes,
and renal dysfunction (gure 1). Furthermore, obesity
per se is a risk factor for progression of renal disease;
therefore, superimposition of the burden of obesity on a
small kidney with fewer nephrons is likely to compound
the risk and act as a second hit, accelerating renal
disease progression.87 How can we optimise postnatal
growth and positively change any subsequent disease
risk, particularly in low-birthweight infants? Avoidance
of obesity seems to be a safe guiding principle.
279

Series

Early growth and kidney function

For more on Childinfo see


http://www.childinfo.org

The association of rapid childhood weight gain with high


blood pressure, diabetes, and obesity is likely to compound any primary programmed renal risk. Indeed, in a
retrospective analysis of 80 children with proteinuric
kidney disease, renal disease progressed fastest in those
who had been premature and became obese.88 Glomerular
size was increased in all obese children, whether premature
or term, whereas kidney size remained small in all those
who had been premature, independent of obesity.
Similarly, among infants with very low birthweight who
developed neonatal acute kidney injury, excessive weight
gain was a predictor of poorer renal function at a mean age
of 75 (SD 46) years.89 The eect of infant weight gain on
long-term renal function remains unknown.
Several mechanisms have been proposed to explain the
amplication of renal and cardiovascular disease risk by
rapid weight gain after growth restriction. One possibility
is development of premature senescence.90 Cellular
senescence is a state of growth arrest induced by upregulation of the cell-cycle inhibitors P53, P21, and
P16INK4a.91 Upregulation of the genes for these proteins
can be induced by progressive telomere shortening,
which takes place with cell replication and is a robust
marker of ageing, and by reactive oxygen species induced
by cellular stress.91
Chronic cardiovascular and renal diseases are
associated with increased expression of senescence
markers.92 In experimental models, low birthweight
followed by rapid postnatal weight gain was associated
with shorter telomeres and amplied expression of
senescence markers in the kidneys, heart, and aorta,
in addition to premature death, which all accord with
accelerated ageing.90,93,94 Low birthweight was also associated with higher renal and cardiovascular mortality
in an Indigenous Australian cohort, which accords with
these experimental ndings.95
Premature senescence in the kidney might be
attributable to ongoing hyperltration injury in kidneys
with a few nephrons, compounded by a rapid increase
in body size. In human beings, leucocyte telomere
length did not dier between British babies of low and
normal birthweight,96 but among 5-year-old children
from Bangladesh, telomeres were signicantly shorter
in those who were of low birthweight.97
Senescence is linked to oxidative stress. In children
born small for gestational age, compared with controls of
appropriate size for gestational age, markers of oxidative
stress were highest in those who experienced catch-up
growth.98 The link between nephron numbers, catch-up
growth, premature senescence, and development of
hypertension and renal disease seems plausible, but it
has not yet been conrmed.

Conclusion
The association between fetal and childhood development
and increased risk of adult disease is now quite
280

convincing.3 Low birthweight and prematurity are


associated with raised blood pressure and decreased
renal function, manifesting in early childhood, which
could progress to overt disease in adulthood. Nutrition is
a cornerstone of this association. Maternal nutrition and
health before and during pregnancy are crucial for fetal
growth and for development of a kidney with enough
nephrons to maintain homoeostasis in response to
dietary and metabolic stresses and to sustain function in
the face of superimposed nephron loss. Early postnatal
nutrition, particularly after premature birth, is also
important for renal development. Furthermore, upward
crossing of weight or BMI percentiles after the infant
period programmes risk of hypertension and renal
disease. Developmental programming has an intergenerational eect, because low birthweight increases
the risk of maternal pre-eclampsia, obesity, and
gestational diabetes, which all in turn further compound
future risks in their ospring.
Growing knowledge and understanding of the pathophysiology of developmental programming has identied
at-risk populations that could be targets for screening
and interventions to interrupt this cycle. Identication
of nutritional deciencies within populations (eg,
vitamin A deciency) ought to prompt public health
interventions to correct these deciencies well before
pregnancy. Adequate antenatal care should identify
women who develop pre-eclampsia and gestational
diabetes, optimise their care during pregnancy, and
lead to lifestyle education and lifelong screening of
these women for later disease. Currently, few women
worldwide are screened for gestational diabetes.33
With the rising prevalence of obesity, such screening
should be more widespread. Similarly, according to
the UNICEF project Childinfo, only about 60% of all
children are weighed at birth, and this number should
increase. Several interventions to reduce maternal and
childhood malnutrition, where prevalent, have been
eective: supplementation of protein energy intake
during pregnancy has reduced the risk of babies born
at term with low birthweight by 32%; supplementation
of multiple micronutrients in pregnancy decreased the
proportion of children with low birthweight by 16%;
and implementation of malaria prophylaxis diminished
the risk of low-birthweight babies by 37%.99 Vitamin A
supplementation did not aect birthweight but did lower
neonatal mortality (relative risk 08, 95% CI 066096),
whereas the relative risk of pre-eclampsia was 045
(031065) with maternal calcium supplementation.99,100
As far as we know, no study has followed up the ospring
of such supplemented pregnancies to ascertain whether
risk of adult disease has been altered, but we should
assume a positive eect.
In later life, regular cardiovascular exercise abrogates
the metabolic outcomes of being small at birth among
men.101 Identication of at-risk pregnancies and ospring
of both high and low birthweight should prompt
www.thelancet.com Vol 382 July 20, 2013

Series

maternal education to optimise childhood nutrition


and activity to prevent obesity. Prematurity and low
birthweight are among the top ten contributors to the
global burden of disease, calculations that might not
always have included the long-term costs of programmed
adult non-communicable diseases.1,27 Acknowledgment of
the role of developmental programming in hypertension
and renal disease risk, and implementation of locally
adapted pre-emptive strategies in individual countries,
will have important long-term benets in terms of future
health, productivity, and cost savings worldwide.
Contributors
VAL developed the idea and outline for the paper. All authors
contributed to writing. JFB contributed to the section on nephron
number in children and adults. VAL and BMB contributed to the section
on developmental determinants of nephron number. WEH, VAL, and
BEV contributed to sections on clinical outcomes associated with
birthweight and nephron number. CF and SEO contributed to the
section on the eect of childhood weight gain on kidney function.
Conicts of interest
We declare that we have no conicts of interest.
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