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doi: 10.1093/ndt/gfs167
Editorial Comment
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
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Table 1. Genetic control of nephrogenesiswhich genes govern renal development (modied according to Dotsch [7])
Genes
Renal disease
WT1
Glomerular defects
Nephrotic syndrome
Oligomeganephronia
Renal aplasia (agenesis)
Renal hypoplasia
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.
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NPHS1
LMX1B
LAMB2
NPHS2
PAX2
EYA1
PAX2
SALL1
GLI3
GDNF
FRAS1, FREM1
SOX9
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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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Received for publication: 07.3.2012; Accepted in revised form: 1.4.2012
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