Series

Global Kidney Disease 4

Effect 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 Lancet 2013; 382: 273–83
hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal Published Online
kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates May 31, 2013
http://dx.doi.org/10.1016/
for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in
S0140-6736(13)60311-6
later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity,
This is the fourth in a Series of
and rapid childhood weight gain should alert clinicians to an individual’s lifelong risk of hypertension and kidney six papers about global
disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity kidney disease
are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and Division of Nephrology,
early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of University of Alberta,
hypertension and kidney disease in the future. Edmonton, AB, Canada
(V A Luyckx MBBCh);
Department of Anatomy and
Introduction Increasingly, the important contribution of fetal Developmental Biology,
Hypertension is now the leading risk factor for the global and early childhood development to growth in non- Monash University, Melbourne,
disease burden and it is a major cause and result of communicable disease is being recognised.3,4 Epi- VIC, Australia
(Prof J F Bertram PhD); Brigham
chronic kidney disease.1 Global deaths from kidney demiological observation suggests a graded risk for and Women’s Hospital, Harvard
disease have risen by 83% since 1990.2 Recognition of the hypertension, type 2 diabetes, cardiovascular disease, Medical School, Boston, MA,
burden of chronic kidney disease, its risk factors, and and chronic kidney disease across the range of fetal and USA (Prof B M Brenner MD);
MRC Lifecourse Epidemiology
implementation of prevention strategies is, therefore, early childhood development.3,4 Acknowledgment of this
Unit, Southampton General
key to saving many lives. paradigm is important because interventions to optimise Hospital, Southampton, UK
fetal and child health as strategies to prevent adult non- (Prof C Fall FRCPCH); Center for
communicable diseases have great potential economic, Chronic Disease, School of
Search strategy and selection criteria Medicine, University of
societal, and individual benefit.4 Many developing coun-
Queensland School of
We searched PubMed for articles published between January, tries carry the dual burdens of undernutrition and Medicine, Brisbane, QLD,
1988, and February, 2013, with the terms “nephron number”, overnutrition, contributing to the vicious cycles of poor Australia

“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 deficiency”, “maternal diet”, and
“maternal nutrition”. We also looked at the reference lists of
existing manuscripts, textbooks, and websites. Furthermore,
we identified 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.
maternal health, suboptimum fetal development, and (Prof W E Hoy FRACP AO);
University of Cambridge
unhealthy childhood growth that all augment the risk of
Metabolic Research
adult disease.5,6 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 9·6% of livebirths,
respectively, suggesting a high proportion of the world’s 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 affected by maternal nutrition and health
before and during pregnancy and by the mother’s own birthweight, indicating the
intergenerational effects 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 effects can
be independent of birthweight

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 Series

Metabolic Science, Cambridge,

UK (S E Ozanne PhD); and Pregnancy
Institute of Medicine,
University of Bergen, and Maternal diabetes Maternal Societal factors Maternal health Genetic polymorphisms
Department of Medicine, or gestational development Poverty, conflict or war, Low protein diet, pre-eclampsia, PAX2, RET, OSR1, ACE,
Haukeland University Hospital, diabetes Low birthweight, teenage pregnancy, hypertension, vitamin A deficiency, iron BMPR1A
Bergen, Norway short stature antenatal care, birth spacing, deficiency, substance abuse, malaria, chronic
(Prof B E Vikse MD) environmental conditions kidney disease, multiple gestation
Childhood/fetal development

Correspondence to: High birthweight

Dr Valerie A Luyckx, Division of
Low nephron number
Nephrology, University of Alberta, Intrauterine growth restriction or Clinical surrogates:
Edmonton, AB, Canada T6G 2S2 low birthweight or prematurity Low birthweight, prematurity, short stature, gestational diabetes
vluyckx@ualberta.ca exposure, ethnic origin, large glomeruli, small kidneys

Catch-up growth

Overweight or obese Hypertension Hyperfiltration Proteinuria

and salt sensitivity ↓ Renal functional reserve
↓ Glomerular filtration rate
Metabolic Ischaemic
Adult

syndrome heart disease

Diabetes Glomerulosclerosis, chronic kidney disease, end-stage renal disease

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

Here, we describe how fetal and child health affect
kidney development and risk of disease. We focus
mainly on human studies but use experimental data
when necessary to provide further insight.
Effect of fetal development on the kidney
About 25 years ago, Brenner and colleagues7 pro-
posed 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 filtration
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 popu-
lations with an increased frequency of low birthweight,
35
30
25
Prevalence (%)
Low birthweight (% livebirths)
Preterm birth (% livebirths)
Vitamin A deficiency* (% pregnant women)
Childhood obesity† (%)
whereby low birthweight was expected to be associated
with a lower number of nephrons (figure 1).8 Consistent
with this hypothesis, data from various experimental
models confirm the association of low birthweight with
later-life hypertension, mediated, in part, by acquisition
of fewer nephrons in utero (the pathophysiological
mechanisms affecting nephrogenesis are reviewed
elsewhere).9 Similarly, in human beings, low birth-
weight 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 (figure 2).11–15
In view of the complexity and far-reaching effect 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 effect.4
Low birthweight is defined universally as a birth-
weight less than 2·5 kg, and high birthweight is
classed as a birthweight heavier than 4·0 or 4·5 kg.16

20 Other terms used to indicate neonatal size include

15 intrauterine growth restriction (IUGR), small for
gestational age, and large for gestational age. For
10
simplicity, we define low birthweight as all babies with
5 a birthweight less than 2·5 kg, including those who
0 are small for gestational age, and high birthweight as
World Africa Asia Europe Latin America North Oceania children with a birthweight greater than 4·0–4·5 kg,
and Caribbean America
Region
including those who are large for gestational age. A
premature infant—ie, who is born before 37 weeks of
Figure 2: Worldwide prevalence of factors affecting programming of renal disease, by UN region gestation—is generally low birthweight, which might
Error bars represent the range of prevalence, by region. *Excludes countries with 2005 gross domestic product of
be an appropriate weight for gestational age if growth
US$15 000 or higher, where vitamin A deficiency is presumed absent. †Obesity figures for North America and
Europe are extrapolated from data for “developed countries”. Childhood obesity is defined as two or more SD from occurred normally until birth, but could be small for
weight-for-height median. Data are pooled from references 11–15. 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 African-
American 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
significantly in infants with low birthweight.20,21 The total
number of nephrons in an adult human kidney reflects
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 4·5-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 affect 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
modifiable 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 affect
the risk of low birthweight and prematurity and should
be judged risk factors for low nephron number in
offspring.25 Mothers who themselves were low birth-
weight, compared with mothers who were not, were
more likely to have babies of low birthweight (odds
ratio 1·8, 95% CI 1·3–2·5), a finding that is independent
of socioeconomic factors, suggesting a genetic or epi-
genetic intergenerational effect.26
Hypertensive disorders during pregnancy
Disorders linked to high blood pressure in pregnancy
were noted in 8·4 million women worldwide in 2004, and
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Series
Effect on kidney
Prenatal
Maternal vitamin A deficiency Small infant kidney size
Low birthweight Decreased nephron number
Growth restriction Reduced glomerular filtration rate at 7·5 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 23% reduction in newborn kidney volume
AAA haplotype
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 filtration rate at 7·5 years;
increased odds of renal dysfunction at 6·4 years
Catch-up growth, childhood and adolescent overweight Increased glomerular volume; faster
or obesity 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 See Online for appendix
outlined in a Comment linked to this Series,28 risk of pre-
eclampsia in a mother is increased if she herself was low
birthweight (odds ratio 1·69, 95% CI 1·4–2·02),29 pre-
mature (1·95, 1·54–2·47),30 or either of the mother’s
parents were born after pre-eclamptic pregnancies (2·2,
2·0–2·4),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.
Gestational diabetes
The worldwide prevalence of gestational diabetes is
poorly recorded but is reported as 0·1–25·3%.33 Maternal
obesity, now present in 15–20% of pregnancies, is a
strong risk factor for gestational diabetes, as is maternal
prematurity.30,34 In experimental models, maternal hyper-
glycaemia is associated with reduced nephron number,
raised blood pressure, microalbuminuria, and dimin-
ished glomerular filtration rate in offspring.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 affects 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 effect 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 deficient 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 deficiencies
are common in developing countries, and maternal
malnutrition, underweight, iron deficiency, and anaemia
are all recognised risk factors for low birthweight.41
Vitamin A deficiency is also highly prevalent among
pregnant women worldwide (figure 2).12 In animals,
maternal diets deficient in vitamin A, resulting in
amounts similar to those seen in deficient people, induce
a dose-dependent reduction in nephron number, whereas
vitamin A supplementation augments nephron number.42
Importantly, vitamin A deficiency alone does not cause
low birthweight, suggesting the effect of deficiency could
be overlooked if normal birthweight was presumed to
exclude an adverse developmental environment. The
active metabolite of vitamin A—retinoic acid—regulates
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 deficiency in Indian mothers was
associated with significantly lower newborn adjusted
renal volume in their offspring compared with babies
born to Canadian mothers who were vitamin A replete,
probably reflecting lower nephron numbers (table 1).43
Prematurity
About 9·6% of liveborn babies are premature (figure 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,
276
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 affected
(table 1). Indeed, extrauterine growth restriction was
associated with a significantly lower glomerular filtration
rate in very low birthweight children at a mean age of
7·6 years; conversely, the frequency of renal impairment
was 33% lower at 6·4 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-inflammatory agents, gluco-
corticoids, and aminoglycosides. Extrapolating from
experimental models, these and other drugs can affect
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 affect kidney development, but the effects
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 poly-
morphisms in several genes known to participate in
kidney development correlate with altered gene tran-
scription 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 investi-
gated.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 poly-
morphisms and environmental circumstances during
kidney development have not been studied. Gene micro-
array analysis of neonatal kidneys has shown global
downregulation of gene expression in experimental
models of maternal low protein diet or placental insuffi-
ciency.53 Therefore, altered levels of gene expression
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resulting from a polymorphism could become even

Association with nephron number
more amplified under conditions of superimposed
maternal nutrient deficiency, further decreasing Clinical surrogate

nephron number.54 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
Clinical surrogates for nephron number
Sex Nephron number 12% lower in women
At present, all reports of human nephron number have
Age 3676 fewer glomeruli per kidney per year of age older than 18 years (nephron loss)
come from kidneys obtained at autopsy. In view of the
Adult height 28 000 more glomeruli per cm increase in height
current reliance on autopsy specimens, surrogate
Kidney mass 23 459 more glomeruli per g of kidney tissue (in infants)
markers for nephron number are important (table 2).
Glomerular volume Inverse correlation between glomerular volume and nephron number
Similar to total nephron number, mean glomerular
volume varied up to tenfold in an Australian series of Ethnic origin Reduced number in Indigenous Australians compared with white and black
US population
420 kidneys from people in five ethnic groups.55 Total
Possible correlates
nephron number varies inversely with mean glomerular
Gestational diabetes Decrease in renal functional reserve in offspring of diabetic mothers versus
volume.17 An increase in glomerular volume probably exposure diabetic fathers
reflects compensatory hypertrophy and hyperfiltration
in individual nephrons. Indeed, total filtration surface Adapted from reference 23, with permission of Lippincott Williams and Wilkins. See appendix for relevant references.

area is fairly well preserved in kidneys with low nephron Table 2: Clinical surrogates for nephron number
number, possibly at the expense of increased glomerular
pressure, which can accelerate further nephron loss.18
Moreover, increased glomerular size is a predictor of Panel: Clinical associations with programming of kidney function
poorer renal outcomes in African-American populations,
Native Americans (Pima Indians), and Indigenous Low birthweight or prematurity
Australians, and without other causes should be judged • Increased blood pressure
a surrogate for low nephron number.9 In view of the • Salt sensitivity
heterogeneity and hypertrophy occurring in glomeruli, • Proteinuria
kidney size does not correlate consistently with nephron • Reduced glomerular filtration rate
number in adults, but the relation seems linear in • Reduced renal functional reserve
infants younger than 3 months.22,56 • Accelerated progression of primary renal disease
• Chronic kidney disease
Birthweight, prematurity, and blood pressure • End-stage kidney disease
Studies of monozygotic twins, in which the twin who • Death
weighed the least subsequently had higher blood pres- Low nephron number
sure, suggest that environmental programming could be • Increased blood pressure
more crucial than genetic factors.57 Low birthweight and • Increased glomerular volume
prematurity have been associated consistently with • Possible predisposition to renal failure in neonates
increased risk of higher blood pressure in later life
(panel).58,59 In a meta-analysis of 27 studies,59 a 2·28 mm Hg Reduced renal size
(95% CI 1·24–3·33) increase in systolic blood pressure • Increased blood pressure
was recorded in individuals whose birthweight was less • Salt sensitivity
than 2·5 kg, compared with those heavier than 2·5 kg. • Reduced glomerular filtration rate
Unfortunately, in most studies to date, a distinction has High birthweight or maternal diabetes
not been made between low birthweight as a result of • Proteinuria
growth restriction at any gestational age and prematurity • Reduced renal functional reserve
with appropriate size for gestational age. Therefore, the • End-stage kidney disease
potential for unmeasured confounding or effect modifi-
cation by gestational age, growth restriction, or both must Rapid increase in weight or body-mass index in childhood and adolescence,
be borne in mind.16 particularly after low birthweight
Findings of a systematic review of ten studies showed • Faster progression of renal disease
that, in preterm babies born at a mean gestational age of • Larger glomeruli
30·2 weeks and with a mean birthweight of 1·28 kg, blood • Higher blood pressure
pressures in later life were 2·5 mm Hg higher (95% CI • Diabetes and impaired glucose tolerance
1·7–3·3) than in infants born at term.58 Prematurity has • Cardiovascular disease and death
been associated predominantly with high, but still normal, • Obesity
blood pressures, because cohorts studied are still fairly • Metabolic syndrome
young. Overt hypertension has been recorded in two Adapted from reference 23, with permission of Lippincott Williams and Wilkins.
studies of premature babies: in the first, the children

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 Series
were aged 2 years and the prevalence of hypertension
(defined 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 1·4% of those born preterm
compared with 0·8% born at term (odds ratio 1·7, 95% CI
1·32–2·20).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 differences 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 birth-
weight59 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 effects are compounded by
growth, age, and lifestyle.
Nephron number and blood pressure
In rodents, nephrogenesis continues for up to 7–10 days
after birth, providing a window—similar to that seen in
premature infants—during which postnatal events can
affect nephron number. In rats of low birthweight, rescue
of nephron number by optimisation of postnatal
nutrition abrogated development of subsequent hyper-
tension; 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 significantly 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 significant independent
predictor of high blood pressure in this population.65
Additional factors probably contribute to hypertension
in African populations, but the effect of birthweight
or the contribution of nephron number to severity of
hypertension, for example, cannot be excluded.
Observations of normalisation of glomerular filtra-
tion 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
278
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 filtration 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 Experi-
mental 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 pro-
grammed risk factor for hypertension, but it is likely to
exacerbate any risk and contribute to kidney disease.
Renal function, birthweight, and nephron mass
Glomerular filtration rate
Without compensatory hyperfiltration, a kidney with a
reduced number of nephrons should have a diminished
glomerular filtration rate. Indeed, glomerular filtration
rate extrapolated from amikacin clearance on day 1 of life,
preceding any compensatory adaptation, was decreased
significantly in premature and low-birthweight infants
compared with term controls.71 Glomerular filtration rate
measured by inulin clearance was significantly lower at
age 7·6 years in children who had been born premature
and had severe growth restriction compared with non-
growth-restricted controls.45 In this study, the effects 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 filtration
rate with low birthweight was 1·79 (95% CI 1·31–2·45).
Proteinuria
Microalbuminuria is one of the earliest signs of
glomerular hyperfiltration, and transition to macro-
albuminuria accords with ongoing renal injury. Hoy and
colleagues72 reported an odds ratio of 2·8 (95% CI
1·26–6·31) for macroalbuminuria in Indigenous
Australians who were low birthweight compared with
those of normal birthweight. In this population,
albuminuria was associated with a significant increase
in cardiovascular and renal deaths, emphasising its
clinical relevance.73 Many study findings have since
confirmed this association, reflected in an odds ratio of
1·81 (95% CI 1·19–2·77) for albuminuria in low-birth-
weight 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 2·5 kg and
greater than 4·5 kg.38 This population has a high
prevalence of gestational diabetes, exposure to which
was the strongest predictor of proteinuria in the high-
birthweight people.38
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Chronic kidney disease and end-stage renal disease
Amplified 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 1·73
(95% CI 1·44–2·08) from 18 studies.10 In population-
based 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 differential effect 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 con-
tributing to risk of renal disease, and a low nephron
number will probably not be sufficient to cause
renal disease without additional variables. Moreover,
developmental programming of related disorders—eg,
type 2 diabetes, cardiovascular disease, insulin resis-
tance and obesity—could 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.
Effect of childhood weight gain on kidney
disease and function
Postnatal malnutrition and clinical circumstances can
affect nephrogenesis, childhood renal function, and long-
term risk of renal disease (figure 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 low-
birthweight 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 beneficial, 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 popu-
lations worldwide, accelerated weight gain or an increase
www.thelancet.com Vol 382 July 20, 2013
Series
in body-mass index (BMI), even in children with a
normal birthweight, has been associated consistently
with amplified risk of adult hypertension, type 2
diabetes, and cardiovascular disease.80–82 This effect
grows as the child ages: upward crossing of weight
or BMI percentiles in mid-childhood or adolescence
is associated with strong adverse effects on later risk,
whereas upward crossing in infancy (younger than
1 year) has no or little effect on later blood pressure and
could protect against diabetes.82–84 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.82–84 Therefore, one cross-sectional measurement
of a child’s 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 1·3 mm Hg (95% CI 0·3–2·3) for every
SD decrease in birthweight and rose by 1·6 mm Hg
(0·6–2·7) 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 stiffness,
which is sometimes already evident in childhood.83
In a study of 216 771 Scandinavian adults,81 those
with a birthweight of 2·5 kg and a BMI of 17·7 kg/m²
(overweight) at age 7 years had a 44% increased risk of
cardiovascular disease in adulthood compared with those
with a median birthweight of 3·4 kg and a BMI of
15·3 kg/m² (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 (figure 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 (figure 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
The association of rapid childhood weight gain with high
blood pressure, diabetes, and obesity is likely to com-
pound 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 7·5 (SD 4·6) years.89 The effect of infant weight gain on
long-term renal function remains unknown.
Several mechanisms have been proposed to explain the
amplification 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 up-
regulation 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 amplified 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 asso-
For more on Childinfo see ciated with higher renal and cardiovascular mortality
http://www.childinfo.org in an Indigenous Australian cohort, which accords with
these experimental findings.95
Premature senescence in the kidney might be
attributable to ongoing hyperfiltration injury in kidneys
with a few nephrons, compounded by a rapid increase
in body size. In human beings, leucocyte telomere
length did not differ between British babies of low and
normal birthweight,96 but among 5-year-old children
from Bangladesh, telomeres were significantly 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 confirmed.
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 inter-
generational effect, because low birthweight increases
the risk of maternal pre-eclampsia, obesity, and
gestational diabetes, which all in turn further compound
future risks in their offspring.
Growing knowledge and understanding of the patho-
physiology of developmental programming has identified
at-risk populations that could be targets for screening
and interventions to interrupt this cycle. Identification
of nutritional deficiencies within populations (eg,
vitamin A deficiency) ought to prompt public health
interventions to correct these deficiencies 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
effective: 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 affect birthweight but did lower
neonatal mortality (relative risk 0·8, 95% CI 0·66–0·96),
whereas the relative risk of pre-eclampsia was 0·45
(0·31–0·65) with maternal calcium supplementation.99,100
As far as we know, no study has followed up the offspring
of such supplemented pregnancies to ascertain whether
risk of adult disease has been altered, but we should
assume a positive effect.
In later life, regular cardiovascular exercise abrogates
the metabolic outcomes of being small at birth among
men.101 Identification of at-risk pregnancies and offspring
of both high and low birthweight should prompt
www.thelancet.com Vol 382 July 20, 2013

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 benefits 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 effect of childhood weight gain on kidney function.
Conflicts of interest
We declare that we have no conflicts of interest.
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