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Nephrol Dial Transplant (2012) 27: 30033007

doi: 10.1093/ndt/gfs167

Editorial Comment

Renal, cardiovascular and metabolic effects of fetal programming


N. Koleganova1, K. Benz2, G. Piecha1, E. Ritz3 and K. Amann4
Department of Pathology, University of Heidelberg, Germany, 2Department of Pediatric Nephrology, University of ErlangenNrnberg, Erlangen, Germany, 3Department of Nephrology, University of Heidelberg, Germany and 4Nephropathology,
Department of Pathology, University of Erlangen-Nrnberg, Erlangen, Germany
Correspondence and offprint requests to: K. Amann; E-mail: Kerstin.Amann@uk-erlangen.de

Abstract
Disturbed fetal development has long-lasting effects on
the offspring, specically a higher risk of renal, cardiovascular and metabolic disease in adult life as postulated by
Barkers hypothesis. Relevant to renal outcomes of the
offspring are maternal factors such as pre-eclampsia, malnutrition, smoking, drugs etc. The main renal abnormalities in the offspring include reduced nephron number and
higher risk of low glomerular ltration rate, albuminuria,
hypertension and worse outcome of primary kidney
disease. Relevant to renal outcomes is also the predisposition to obesity and type 2 diabetes.
Keywords: heart; intrauterine programming; kidney; metabolism;
vasculature

Introduction
Disturbed fetal development has long-lasting effects in the
offspring, increasing the risk of diseases in adult life.
Adverse conditions during pregnancy like pre-eclampsia,
malnutrition, smoking, alcoholism, certain drugs or the
presence of maternal disease, e.g. diabetes, may affect
birth weight and subsequently the health of the offspring
[1]. These consequences on the health of the offspring are
the result of fetal programming, i.e. an example of
environmental modulation of the transcription of the
genetic code by epigenetic modication of DNA. Of interest with respect to the kidney is the observation that faulty
renal development in utero causes a lower nal number of
nephrons, thus predisposing to hypertension and accelerated loss of renal function during later life and aggravating
the evolution of primary kidney disease. Recently, numerous clinical and experimental observations documented
that fetal undernutrition and/or low birth weight increases
the risk of hypertension, kidney disease, cardiovascular
disease and diabetes, to name only a few [2]. Against the
current background of a worldwide pandemic of obesity
and overweight, it is therefore important that children of
obese mothers are more frequently at risk to develop metabolic disorders, e.g. insulin resistance, dyslipidaemia as

well as hypertension and kidney disease [3, 4]. In the past,


it was thought that only maternal conditions impact on
fetal development, but recently, paternal factors have been
shown to impact on the phenotype of the offspring as
well: male rats on a high-fat diet cause impaired glucose
tolerance in female offspring, thought to be the result of
epigenetic modication of sperm DNA [5]. Thus, fetal
programming may be inuenced by environmental conditions to which either parent has been exposed.

Programming of renal diseases: the impact


of nephron number
Kidney development is a ne orchestrated process. The
nal number of nephrons (nephron endowment)
depends on both genetic and environmental factors [6, 7].
An inborn nephron decit, even a moderate one, is a risk
factor for the development of hypertension and chronic
disease including kidney disease in adulthood [8, 9]. The
number of nephrons is undoubtedly determined genetically (Table 1), but a growing body of evidence indicates
that in addition, glomerular number is inuenced as well
by non-genetic factors that affect the intrauterine environment, i.e. intrauterine malnutrition due to low protein
intake or poor health of the mother, placental malfunction,
glucocorticoid treatment, vitamin A deciency and salt
intake, to name only a few (Fig. 1) [1017]. Protein restriction of the mother, particularly during the last third of
gestation (the period of most intensive nephrogenesis),
results in a 2030% reduction in nephron number and the
subsequent development of hypertension in later life
[18, 19]. The environmental events inuencing nephron
formation occur at the same time that major changes in
DNA occur, particularly methylation and histone acetylation which modify gene expression in life. These
changes may interact with mutations of several genes
known to be involved in nephrogenesis [6] (Table 1).
Since the nephron number cannot be directly measured,
patients at risk can only be determined by the assessment
and knowledge of the various risk factors and surrogate
parameters of nephron development (Table 2). In rats and

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Nephrol Dial Transplant (2012): Editorial Comment

Table 1. Genetic control of nephrogenesiswhich genes govern renal development (modied according to Dotsch [7])
Genes

Impairment of nephron development

Renal disease

Syndromes with renal involvement

WT1

Glomerular defects

Nephrotic syndrome

Frasier syndrome, Denys-Drash syndrome,


WAGR syndrome
Finnish type NS
Nail-patella-syndrome
Pierson syndrome
Steroid-resistant NS

Few, but large nephrons


Absence of one or rarely both kidneys
Lower nephron number

Oligomeganephronia
Renal aplasia (agenesis)
Renal hypoplasia

Lower number of abnormal nephrons

Renal dysplasia

Brancho-oto-renal syndrome
Renal coloboma
TownesBrocks syndrome
PallisterHall syndrome
Fraser syndrome
Campomelic dysplasia

NS, nephrotic syndrome; WAGR, Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation.

Fig. 1. Factors that directly or indirectly affect fetal development and may thus favour programming of diseases that occur in later life.

humans, low nephron numbers correlate with low birth


weight which can therefore be regarded as an indirect
marker of fewer nephrons. Low birth weight in term newborns was shown to be associated with increased susceptibility to many subsequent diseases in adulthood [20].
A recent observation in monogenetic twins showed that
in the twin with lower birth weight, the rate of loss of
GFR was accelerated illustrating the potential impact of
fetal malnutrition on the evolution of primary kidney
disease in adult life [21]. Higher glomerular diameters, as
often seen in individuals with low birth weight, correlated
closely with a higher incidence of proteinuria and lower
survival rate in IgA glomerulonephritis [22]. The adverse
impact of low birth weight on the evolution of primary
kidney disease has been clearly documented in a variety
of experimental studies [2325].
In summary, clinical ndings argue for a role of
nephron endowment for the evolution and progression of
acquired renal disease as postulated by Winberg [26].

Table 2. How can we identify patients with potentially impaired


intrauterine development who are at risk for prenatally programmed
diseases in later life?
Babies with intrauterine growth retardation/small for gestational age
(due to under-/malnutrition or under-/malperfusion)
Babies with low birth weight (as a surrogate parameter of impaired
intrauterine development)
Babies who are large for gestational age (due to maternal diabetes)
Babies who had a history of intrauterine exposure to drugs
(i.e. corticosteroids, gentamicin, ACE-inhibitors, cyclosporine A etc.)

Programming of cardiovascular disease:


development of hypertension in adult life
On the basis of animal experiments and clinical observations, Brenner et al. [8] had postulated more than 20
years ago that a low number of nephrons (nephron

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NPHS1
LMX1B
LAMB2
NPHS2
PAX2
EYA1
PAX2
SALL1
GLI3
GDNF
FRAS1, FREM1
SOX9

Nephrol Dial Transplant (2012): Editorial Comment

Programming of vascular dysfunction: role


of endothelial dysfunction
Experimentally, developmental programming of the aortic
structure has been documented in offspring of rats on a
high-fat diet [34], calorie-restricted mice [35] and also rats
on high salt [17]. Of note, a progressive long-lasting effect
on modelling of both central and muscular arteriesindependent of postnatal salt intake and systemic blood
pressureis associated with increased oxidative stress and
lower availability of nitric oxide (NO), indicating endothelial dysfunction. NO synthesis and/or bioavailability is
known to be altered in pathological pregnancies, i.e. due
to intrauterine growth restriction or pre-eclampsia, thus
leading to changes in placental blood ow which could
result in limiting fetal growth and development [36]. The
exact mechanisms involved in the development of endothelial dysfunction and hypertension caused by intrauterine under- or malnutrition remain to be elucidated,
however.

Programming of obesity and dysglycaemia: the


current health epidemic
In the past 30 years, the prevalence of obesity and overweight has doubled in Western societies. Data from the
Framingham Heart Study show that obesity contributes to
6070% of cases with essential hypertension, thus posing
a signicant risk of morbidity and mortality [37]. Moreover, it is known that offspring of obese women are 36%
more likely to develop type 2 diabetes than controls [38].
Evidence from experimental studies also supports the
hypothesis that maternal obesity, overweight or high-fat
diet is associated with obesity and hypertension in the offspring. Offspring of rats fed a high-fat diet for 10 days
prior to mating, during pregnancy and in the suckling
period become obese in adulthood. Interestingly, only the
female progeny develop hypertension [39]. Both male
and female offspring of diet-induced obese C57Bl/6J
mice demonstrate obesity-related hypertension by 3
months of age [40]. Male offspring of C57 mice on a
high-fat diet develop increased systolic blood pressure
and hypertriglyceridaemia, despite no elevation of body
fat, but the female littermates show programmed obesity
and hypertension [41]. Maternal obesity and diabetes are
known to alter the development of appetite circuits in the
neonatal rodent brain, which may in the long run predispose to an imbalance in appetite and sympathetic control
[42].
Even mild maternal overnutrition has been shown to
induce increased adiposity, glucose intolerance and
altered brain appetite regulators in the offspring [43].
Maternal obesity causes accelerated fetal pancreatic -cell
maturation which may contribute to premature -cell function loss and type 2 diabetes [44]. Hyperglycaemia in the
mother was associated with hyperglycaemia in the fetus
stimulating fetal pancreatic -cells to produce increasing
amounts of insulin [45]. One of mechanisms underlying
the growth-promoting action of insulin during fetal development resulting in newborn macrosomia is presumably
the ability of fetal hyperinsulinaemia to increase the availability of farnesylated p21-Ras [46].

Postnatal modication of fetal


programming: the effect of catch-up growth
A potential strategy to modify the effects of fetal programming is the avoidance of hyperalimentation after
birth in small-for-gestational age or low-birth-weight
babies, in order to prevent the so-called catch-up
growth. Here, in addition to experimental evidence, the
late outcome of the offspring of two famines during
World War 2, the Dutch famine [47] and the siege of
Leningrad [48] provides important information. In the
Dutch Hunger Winter of 194445, if pregnant women
were exposed to the famine during early gestation, hypertension was seen in the offspring at adult age, while
reduced maternal caloric intake in late gestation was
associated with increased adult adiposity and glucose intolerance [47] in their offspring. In contrast, offspring

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underdosing) predisposes to the development of hypertension later in life. Increased blood pressure is often
present in the setting of renal disease and is a major factor
in the rate of progression of renal disease, but a relationship between low nephron numbers and higher blood
pressure values presumably develops much earlier in the
pathophysiological cascade. Support for the Brenner
concept was provided most clearly by Keller et al. [9]; in
a small casecontrol autopsy study, they reported that
patients with hypertension had 50% fewer glomeruli
with a mean volume 50% larger compared with people
without hypertension. These relationships have been conrmed in a larger autopsy study in Caucasian Americans
but could not be documented in African Americans [27].
Experimental data also support this paradigm, i.e. in rats
and sheep, unilateral nephrectomy in the perinatal period
resulted in later hypertension which preceded any decline
in renal function [28]. Of note, children with a solitary
kidney (due to unilateral agenesis) also experienced
increased blood pressure [29], whereas the same loss of
nephrons (unilateral nephrectomy, living kidney donation)
at adult age does not lead to higher blood pressure [30].
This observation indicates that it is not the number of nephrons per se which leads to hypertension, but most
likely the time and environment during which the
nephron decit occurs, i.e. a vulnerable period during
development.
Apart from nephron underdosing, non-renal mechanisms have been postulated to play as well a role in cardiovascular programming [31], i.e. the concept that an
altered environment (i.e. high salt diet) in pregnancy
causes a lasting imprint, e.g. hyper-responsiveness of the
kidney to stress even in the absence of any nephron
decit and late-life hypertension [32], mainly but not
exclusively due to increased activation of the sympatho
adrenal system [33].

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Summary and conclusion


In recent years, ample experimental and clinical evidence
has been provided for an important role of the intrauterine
and perinatal milieu for the development of adult renal,
cardiovascular and metabolic diseases. We know that for
the development of the ne structure of many organs, a
delicate balance is needed between too little and too
much energy provided, for example, by a high-protein
intake during pregnancy. We have also learned that birth
weight is a good surrogate parameter for intrauterine development. We have further increased our knowledge
about toxins and drugs that interfere with kidney development and particularly nephron formation during the fetal
period. This newly gained knowledge has led to the birth
of a new subspeciality in medicine, and particularly paediatrics, i.e. the fetal origin of diseases or diseases associated with disturbances of the intrauterine period. Here,
newborns at risk could be identied early on by their
history or by birth weight so that treatment could be
changed accordingly and offspring could be more closely
followed until adulthood. In addition, this new look at the
developmental origin of diseases also sheds light on diseases that we currently encounter as increasing health problems, i.e. hypertension, obesity and associated problems.
By gaining more insight into the conditions under which
the diseases develop and the pathomechanisms involved,
we may be able to identify new treatment strategies in the
near future.
Conict of interest statement. None declared.

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Nephrol Dial Transplant (2012): Editorial Comment

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