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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.
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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Series
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
Catch-up growth
Overweight or obese
Metabolic
syndrome
Hypertension
and salt sensitivity
Hyperltration
Renal functional reserve
Glomerular filtration rate
Proteinuria
Ischaemic
heart disease
Diabetes
30
Prevalence (%)
25
20
15
10
5
0
World
Africa
Asia
Europe
Latin America
and Caribbean
North
America
Oceania
Region
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Series
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
Eect on kidney
Prenatal
Maternal vitamin A deciency
Low birthweight
Growth restriction
Prematurity
Genetics
RET (1476A) polymorphism
Postnatal
Renal failure
Growth restriction
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
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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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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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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Prematurity
Sex
Age
3676 fewer glomeruli per kidney per year of age older than 18 years (nephron loss)
Adult height
Kidney mass
Glomerular volume
Ethnic origin
Possible correlates
Gestational diabetes
exposure
Adapted from reference 23, with permission of Lippincott Williams and Wilkins. See appendix for relevant references.
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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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Conclusion
The association between fetal and childhood development
and increased risk of adult disease is now quite
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