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We send you with regard to consideration for publication the article entitled

HYPERTENSION: ALONG ARIADNEs THREAD FROM FOETUS TO ADULT

AGE.
LOW BIRTH WEIGHT (LBW) AND LOW NEPHRON NUMBER
The article addresses an issue that raises remarkable interest, the issue of the relationship
between the period of intrauterine development of the foetus, respectively the organogenesis
period, and adult hypertension.
This chapter belongs to the long line of studies regarding hypertension, from genetic
aspects and intrauterine development of the conception product, to hypertension in adulthood.
The article refers to 2 hypotheses or concepts about the origin of high blood pressure,
Barkers hypothesis and Brenners hypothesis.
Barkers hypothesis emphasises the role of external epigenetic factors and especially of
environmental factors in developmental programming of adult disease with reference to
hypertension and to chronic renal diseases, to cardiovascular diseases and to diabetes mellitus.
Brenners hypothesis refers to the number of nephrons and hypertension, respectively to the
relationship between low birth weight, the number of nephrons and hypertension in
adulthood.
The two concepts complete each other: low birth weight and low nephron number in
relation to environmental factors that act on the foetus during the intrauterine period, without
neglecting epigenetic and genetic factors, represent important contributors with expression in
adulthood. They are situated within the multifactor aetiology of hypertension.
The article establishes a consistent relationship between obstetricians and nephrologists
and not only: cardiologists, diabetologits. In fact, they study the intrauterine period for finding
an answer to pathological aspects in adult life.
By means of the way in which they monitor and guide the development of the foetus in
its intrauterine environment obstetricians will have the opportunity of programming future
adult pathologies.
If we take into consideration that a quarter of the adult population has high blood
pressure, this effort is justified.
We consider that this article analyses the line of high blood pressure evolution within its
intricate labyrinth, by studying the intrauterine period and its adult perspectives. It reunites
into an integrated whole the specialists involved in treating hypertension. The obstetrician,
who guides the first steps of this process, should not be absent from this whole.
Regarding the title of the article, we used the term State of the art because we want to
clarify the fact that the article intends to produce a unitary synthesis of the knowledge in
specialised literature presented by different authors from different angles. To this aim we
quoted review articles, our study intending to present the opinion of several authors who
approached this modern issue.
The conclusions of our article present the perspective of this paper in which, between the
two known poles of arterial hypertension- periuterine and adult age- there exists a stage that
we defined as latent.
We want to draw the attention to this insufficiently known stage. It is important to
approach this stage especially taking into account its relationship with environmental and
epigenetic factor, without neglecting the intervention of known risk factors.
That is why we introduced in this paper the metaphor of Ariadnes thread, for drawing the
attention to this stage. This fact would also arouse special interest for this period and it would

allow complex future research studies on hypertension. At the end we drew the attention on a
modern concept, multiorgan protection, that has to address not only the whole organism but
also the entire period of development.
Prof .Gheorghe Gluhovschi MD, Ph.D
Romanian Academy of Medical Sciences
Former Dean of the University of Medicine and Pharmacy Timisoara, Romania

[HYPERTENSION: ALONG ARIADNEs THREAD FROM

FOETUS TO ADULT AGE.
LOW BIRTH WEIGHT (LBW) AND LOW NEPHRON
NUMBER. STATE OF THE ART AND PERSPECTIVES
GHEORGHE GLUHOVSCHI, MD, Ph. D
Romanian Academy of Medical Sciences, Emergency County Clinical Hospital Timisoara,
Romania, Division of Nephrology
CRISTINA GLUHOVSCHI, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Nephrology
DORU ANASTASIU, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Obstetrics and Gynecology
ROMULUS TIMAR, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Metabolic Diseases
SILVIA VELCIOV, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Nephrology
LIGIA PETRICA, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Nephrology
FLORICA GADALEAN, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Nephrology
ADRIAN GLUHOVSCHI, MD, Ph. D
University of Medicine and Pharmacy V. Babes Timisoara, Romania, Division of
Obstetrics and Gynecology

Corresponding author information:

Prof. Gheorghe Gluhovschi MD, Ph. D
Romanian Academy of Medical Sciences
Former Dean of the University of Medicine and Pharmacy Timisoara, Romania
Calea Alexandru Ioan Cuza No.8 Ap.16
300088 Timisoara
Romania:
e-mail: ggluhovschi@yahoo.com
Phone: +40-256-435950
Fax: +40-256-486967

ABSTRACT
In spite of all progress, hypertension is an important unknown factor: 85-95 % cases are
defined as essential.
Hypertension originates in conception products, which contribute the parents genes,
and continues in intrauterine life, when epigenetic or environmental factors act on organgenesis, being usually expressed in adulthood.
A thread, similar to that of legendary Ariadnes, guides us through the labyrinth of
organism development to hypertension with its complications.
This review deals with the foetal development period, when preponderantly
environmental factors impair programmed normal evolution, the result being low birth
weight, reduced nephron number and hypertension in adulthood.
Two hypotheses, Barkers, developmental origins of adult disease, and Brenners,
regarding the relationship hypertension - reduced nephron number, address this period and
discuss the relationship between this stage of development and its pathology in adulthood
Barkers concept defines foetal modifications under the influence of factors affecting
foetal development nutrition, hormones, medication - that develop in adulthood as foetal
imprinting/development programming. They are associated with development plasticity of
the foetus, ensuring foetal survival at the expense of low birth weight, of reduced nephron
number and of consequences in adulthood: hypertension, chronic kidney and cardiovascular
diseases, diabetes mellitus, etc.
The two conceptions complete each other. They impose prophylactic measures
addressing the foetus in the organ-genesis period.
The article draws the attention to the period between the periuterine stage and
adulthood, which may be defined as the latent stage of hypertensive disease.
The involvement of the foetal period in hypertension represents an important interest.
In the perspectives section, the article draws the attention to the especially important
stage between the periuterine and the adulthood period, which we defined as the latent
stage. In this stage the patient usually does not present increased values of hypertension but
environmental, epigenetic and risk factors, could as well influence in time an earlier
appearance of hypertension and its subsequent severity. The concepts of cardioprotection and
nephroprotection, that can be included in the concept of multiorgan protection, are to be
extended to the above-mentioned period.

INTRODUCTION
High blood pressure occupies a special place in pathology because of its frequency (a quarter
of the world population is hypertensive), its secondary complications, especially
cardiovascular ones, and the extremely high consumption of resources for its treatment. In
about 85-90% cases its causes are not known.
This disease originates in the conception product, which contributes the parents genes,
continues in intrauterine life and is most frequently manifested in adult life.
The intervention of family factors in hypertension is well-known and it is the object of
complex genetics studies, but there are but few data about the development of this disease
during intrauterine life. The foetus, although apparently protected, is exposed to numerous
environmental factors that act upon it via the mother, crossing the placental barrier, and can

influence its development. The alterations produced in this period will be latent for a long
time and they will manifest as diseases in adulthood. It is believed that environmental factors
act during intrauterine organogenesis, influencing it. But these organs, well-programmed for
extra-uterine life, undergo a process of imprinting in their development under the influence of
these factors.
High blood pressure as a disease seems to be related to this process. In order to have a
general view on it we have to take into account two theories, one of Barker et al and one of
Brenner et al, theories that tend to constitute concepts that interact with each other. (1)(2)(3).
Barker et al, taking over the observations of Lucas et al, (4) found that foetal
development under the influence of environmental factors (mainly poor nutrition) has initial
consequences on low birth weight (LBW), which, in their turn, are reflected in their
development of some organs and later, in their pathology in adulthood. Thus, Barker et al
found in persons who had low LBW high incidence of coronary artery disease when they
reached adult age (5).
Barker and Osmond found an association of LBW with hypertension in adults (2)
Brenner et al reported a relationship between LBW and the foetuss low number of
nephrons at birth that manifested itself in adulthood by hypertension and chronic renal disease
(3)
Subsequent studies found, in addition to the relationship of LBW with hypertension,
cardiovascular and chronic renal disease, a connection with insulin resistance, diabetes
mellitus and obesity (5)
The main objective of the present paper is to analyse the state of the arts of the role of
the perinatal period in AH, respectively the relationship between the low number of nephrons
and LBW reflected in adulthood as hypertensive pathology, and to briefly review its
involvement in the pathology of chronic renal, cardiovascular and nutrition diseases.
It is high time we analysed AH, initially regarded as an adult disease, in its complexity,
along the whole lifetime of a person.
Research studies point to the relationship of AH with the perinatal period, with the
multitude of genetic, epigenetic and environmental factors, which in fact is the objective of
the present paper. There exist numerous observations on adult AH, but an important element
is missing from the present chain of knowledge about AH, the link between periuterine and
adult life.
If in the light of present data we can bring into discussion a perinatal and an adult period
in AH, it is difficult to anticipate what happens to the mechanisms triggered in the perinatal
period and to the expression of AH in adulthood.
The situation having so many unknown elements, we compared it metaphorically to a
similar one in Greek mythology, in which Perseus, a legendary Greek hero, knew the entrance
to the labyrinth where the minotaur he had to confront lived, but was not familiar with the
interior of the labyrinth. It was Ariadnes threat that guided him through that labyrinth.
Analysing in this article the present knowledge about the relationship of AH with the
perinatal period, we have to consider in future this intermediate period, which we defined as
latent, and to look for Ariadnes thread that could guide us, bridging the gap between the
perinatal and the adult period.
Since this topic has been approached in its complexity, but from different perspectives,
we appreciated that a synthesis of present-day data based on recent studies in specialised
literature is to be taken into consideration.
The perspectives section draws the attention to the especially important stage between
the periuterine and the adulthood period, which we defined as the latent stage. In this stage
the patient usually does not present increased values of hypertension but environmental,
epigenetic and risk factors could influence in time an earlier appearance of hypertension and

its subsequent severity. The concepts of cardioprotection and nephroprotection, that can be
included in the concept of multiorgan protection, are to be extended to the above-mentioned
period.

Factors influencing the development of the foetus and the relationship with
LBW and low nephron number
The kidney development is under the influence of three main types of factors: genetic,
epigenetic and environmental. It is under genetic control undergoing constant remodeling (6).
The intervention of epigenetic and environmental factors is usually limited. Under
different conditions their intervention can impair the normal development of the foetus
producing LBW, as the kidneys have a reduced number of nephrons
Low nephron number is associated with LBW, intrauterine growth restriction (IUGR)
and prematurity (7). In fact, IUGR and prematurity are the main causes associated with LBW.

GENETIC FACTORS
Genetic factors play an important part in the process of nephrogenesis. According to
Davies and Fisher (8) they intervene in different stages:
-in transcription processes at mesoderm level: Pax2, Lim-1, Eya-1, Foxc-1(8). Solomon
et al report Pax mutations in cases of oligomeganephronia. (9)
-in producing the Wolf duct: GDNF in a mouse model, the loss of one allele of GDNF,
results in 30% diminution of the normal sized glomeruli (10).
-in modulating ureteric bud branching: BMP family
-at the level of developing nephrons: the transcription factors WT-1, PAX 2, Hoxa 11, d
11
-Wnt 4(8)
There exists a polymorphism in which the Pax 2 and RET genes are involved. (11)
Programming is suggested to be a product expression of key genes (12)
.

Epigenetic factors
Epigenetic regulation of gene expression pattern plays a part in developmental
programming of adult disease (13)
Epigenetic modifications can intervene, according to Jones et al, in foetal programming
producing high blood pressure. (14)
According to Dressler, epigenetic modifications will lead to stable and potentially
heritable changes in gene expression (15).Epigenetic factors could mediate the relationship
between genes and environment (16).
Metyrapone11 beta-hydroxylase inhibitor, administered in pregnant rats, normalised the
methylation of promoter region of AT1b angiotensin receptor gene and prevents development
of hypertension in offspring. (17)..
Ritz et al., analysing the effects of prenatal programming on blood pressure and renal
function, appreciate that plasticity during development of the foetus is related to the fact that
the transcription of the genetic code is modified by epigenetic factors (18).

Environmental factors

It is generally known that the development of the foetus, and of the kidney, is under the
control of some genes.
At the same time, intrauterine development, its phenotype, is related to environmental
factors.
Experimental and epidemiologic studies highlighted the importance of environmental
factors in the process of nephrogenesis. Environmental factors influence the phenotype which
will adapt itself to the new conditions in the environmental medium. As a consequence, the
environmental factors that influence the intrauterine development of the foetus will have
effect after birth, programming different affections (high blood pressure, obesity, insulin
resistance) that will appear in adults.
The environment will influence foetus development, exerting its action via the mother
and the placenta, through which numerous external factors will transfer from the mother to the
foetus.
In fact, there is permanent interaction between genes and environmental factors. The
action of the environmental factors is important if exerted on the nephrogenesis process that
takes places between the 6th and the 36th week of pregnancy. The development of the foetus
undergoes a continuous remodelling process. The intervention of epigenetic factors and of
environmental ones can influence this remodelling process, the foetus proving plasticity under
their action. They imprint the modifications they produce, alterations that will find expression
in adulthood.
As a consequence of the action of environmental factors there occurs intrauterine growth
retardation (IUGR), with reduction of the number of nephrons. At birth, the foetus will have
LBW. Premature birth can also occur, also having LBW as a consequence.
Hoy mentions among the causes of IUGR malnutrition, protein deficits, micronutrient
deficits, hypoxia, toxins, medication administered during the intrauterine, maternal or
perinatal period, metabolic disturbances, physical and psycho sensorial stress (19). IUGR can
be associated with exposure to hormones or destruction in placental structure and function
(14). Other associated factors that can cause LBW are preeclampsia, hypertension, vitamin E
deficiency, iron deficiency, beta lactams, gentamicin, alcohol, uterine ischemia,
dexamethasone (20).
It is of utmost importance to be familiarised with the action of environmental factors in
order to be able to adopt the prophylactic actions required by the situation.

Adaptative phenomena of the organism in special situations

During its general development, as well as in special circumstances, the organism has
special adaptation capacities, being able to re-organize its physiological activities.
One of the most prominent examples in biology is represented by the way in which the
organism re-organises itself from a circulatory point of view in order to face haemorrhagic
shock.
Generalised circulatory redistribution occurs in this case, blood being redirected to vital
organs: brain, lungs, heart- to the detriment of other circulatory areas: kidney, skin etc.
What could be the explanation for this redistribution?
An accumulation of nitrate products, as well as of other compounds resulting from
metabolic activity- some with toxic potential, consecutive to protein metabolism-, is not
vitally dangerous for a few days.
It is generally known that the brain without oxygen - that is without appropriate blood
circulation to ensure the necessary oxygen and other metabolic products, mainly glucoseundergoes irreversible lesions in about 5 minutes. The lungs that provide the indispensable
oxygen also require an appropriate circulatory flow.

A surprising (at least at first sight) phenomenon, similar to the one described above, but
with a longer time-span, occurs in the organism when appropriate placental circulation is not
provided or when it does not contribute the metabolic elements indispensable for the
development of the foetus.
In the absence of the necessary constitutive metabolic elements, the body will direct the
existing ones through the circulatory system of the foetus, preponderantly towards vital
organs. This context brings about a sacrifice of the kidneys, whose functionality in
intrauterine life, although but partly known, allows the development of the foetus even under
the circumstances of a limited input of nutritive substances. Under these new conditions, the
foetus does not have an appropriate general development. This defines IUGR (intrauterine
growth restriction) and the child is born with LBW (low birth weight) or prematurely (20).
Under these circumstances, the kidneys do not develop appropriately, the nephrogenesis
process is impaired and the result is a low number of nephrons.
Jones et al mention that IUGR is associated with disturbances in the expression of the
genes responsible for nephrogenesis. Thus, nutritive substances are rerouted for developing
vital organs, the process resulting in LBW and deficit in nephron endowment (14). The two
elements, LBW and the low number of nephrons at birth are cumulated (14).
Since the process of nephrogenesis starts in week 8, ends in week 36 of foetal
development and new nephrons can not be created later, the organism that was born with a
low endowment of nephrons and usually with LBW, will reach adulthood with a low number
of nephrons.
Persons with LBW, who usually also have a low number of nephrons, develop more
frequently than those with normal weight at birth a pathology represented mainly by strong
predisposition to hypertension, but also by type 2 diabetes mellitus, insulin resistance, obesity,
cardiovascular and renal disease.

Barkers hypothesis. Developmental origin theory

Foetal stage has a critical importance in the formative period in normal development (21).
After conducting epidemiologic studies in East England and Wales, Barker pointed to a
correlation between child mortality and variations in mortality from ischemic heart disease in
adulthood (22).
Subsequent studies found a relationship between LBW of children and ischemic heart
disease (5).
These observations have been defined and accepted as Barkers hypothesis or
Developmental origins of adult disease hypothesis (23).
Barker also assesses LBW in relationship with other associated diseases such as high
blood pressure, stroke and diabetes mellitus (24).
Barkers concept, defined as foetal imprinting or developmental programming is based,
according to Jones, on the fact that adverse environmental insult in early life, especially
during the critical period of development in utero and early post natal period, can produce
silent and long-term morphological and physiological alterations and translate in disease
(14).
Foetal programming refers to the critical period in the development of the foetus when,
consecutive to adverse intrauterine conditions, there occur permanent changes in the
metabolism or the structure of the foetus (25). Foetal programming implies that during critical
periods of prenatal growth, permanent changes in metabolism or structures result from
adverse intrauterine conditions (25).
Harrison and Langly-Evans brought into discussion the issue whether alterations of
nephrogenesis in intrauterine life leading to hypertension in adulthood are also present in

subsequent generations. They studied such modifications in rats following maternal protein
restriction during pregnancy. Harrisson and Langly-Evans introduced the term of
intergenerational programming of impaired nephrogenesis and hypertension.(26).

BRENNERS HYPOTHESIS AND LBW

According to Barkers hypothesis, LBW is accompanied by asymmetric growth
restriction. Thus, the re-distribution of blood flow to the benefit of vital organs (heart, brain,
lungs, adrenal glands) sacrifices other organs, the kidney included. As a consequence, LBW
will associate with its poor development, with its reduced size and nephron number.
Brenner et al. suggested the hypothesis of a relationship between the number of
nephrons and hypertension. According to this hypothesis, the reduced number of nephrons
would be related to the presence of high blood pressure (27).
Nephrogenesis ends in the 36th week of foetal evolution and, after this period, the
organism of a person born with LBW will remain with the same reduced number of nephrons.
In fact, Barker and Osmond pointed out that those persons born with LBW present
hypertension in adulthood. They found in persons between 46-64 years a relationship between
birth weight and the values of blood pressure in adulthood (2).
Brenner appreciated that the low number of nephrons of a person would cause
adaptative changes
Adaptative phenomena consist in the intervention of hyperfiltration (the hydrostatic
pressure at glomerular capillary level increases on each nephron) and nephron hypertrophy.
These phenomena could lead subsequently to sodium retention, and glomerular injury like
focal glomerulosclerosis.
At the same time, the filtration surface at glomerular level diminishes. It was found that
a person with a reduced number of nephrons would develop later, especially in adulthood,
hypertension.
The tubules also undergo adaptative phenomena like volume growth, followed later by
lesional phenomena. Gdlean et al. showed that solitary kidneys with a reduced number of
nephrons present increased values of tubular biomarkers (NAG, alpha 1-microglobulin and
albumin) as an expression of tubular injury. (28)
According to Luyckx et al, adaptation phenomena would be overwhelmed when renal
insults or rapid growth are added. They will cause proteinuria, nephron loss and progressive
renal functional decline (29)
As a consequence, the diminution of the number of nephrons, associated with LBW,
results in increased risk of high blood pressure. Renal injury also increasingly risks to
progress towards chronic renal failure (30). Programmed factors which are associated with an
increased risk of hypertension include salt hypersensitivity, altered expression of renal sodium
transporters, altered vascular reactivity, and sympathetic nervous system over-reactivity (31).
It is to be mentioned that low nephron number and its relation with hypertension was noticed
in populations of Caucasian origin and in Australian Aborigines. This relationship was not
demonstrated in Afro-Americans. (32).
Barkers hypothesis and Brenners hypothesis represent two concepts that complete each
other (33).

Hypertension, low birth weight and low nephron number

One of the main remarks Barker and Osmond made was that about the relationship
between LBW and hypertension in adulthood. These remarks form part of the basis of the
concept defined as foetal imprinting or developmental programming. (2)
Starting from histomorphopathological studies, Manalich et al established that there
exists a relationship between birth weight and the number and size of renal glomeruli in
humans.(34) They also found that a low number of nephrons may be a risk factor for
hypertension and progression of renal disease.
According to Chong and Yosipiv, high susceptibility for hypertension could exist in
persons born with LBW or prematurely, because of the low number of nephrons.(35)
Experimental studies on miniature swine demonstrated that low birth weight is
associated with reduced nephron number and increased blood pressure in adulthood. (36)
In humans, a meta-analysis performed by Mu et al on 78 studies and 20 articles
(reporting 27 original studies) found an inverse linear association between birth weight and
later risk of hypertension, respectively between birth weight and systolic blood pressure (37)
Andersson et al consider that the relationship between LBW and adult hypertension
becomes stronger with age. (38)
Rapid weight gaining in patients with prematurity after birth is added augments the risk
of developing hypertension in adulthood .(20).
Brenner postulated that the reduced number of nephrons could be the main abnormality
on which high blood pressure is based in the general population. In consequence, it could
diminish the capacity of excreting sodium, leading to salt-sensitive hypertension (39).
An important role is attributed to endothelial dysfunction in relationship with impaired
nephrogenesis and apparent reduction in the production of nitric oxide. According to Luycks
et al associated salt hypersensitivity, altered vascular reactivity, sympathetic nervous overreactivity are considered together nephron number ,as programmed factors associated with
increased risk of hypertension.(29)
Changes in vessel formation could also intervene, expression of metabolic genes, with
increased inflammatory cytokines. (14)
As it was mentioned before, the two concepts, respectively Barkers, regarding the
relationship of LBW with high blood pressure in adulthood, and Brenners, concerning the
relationship between the number of nephrons and hypertension, complete each other.
Yiu et al appreciate that birth weight in relation to hypertension could be an element in
the multi-factorial cause of essential hypertension. (40)

Prematurity
It is defined as birth before 37 complete weeks of pregnancy. Its incidence is of about
12% of the annual life birth in the USA. (41)
Prematurity that interrupts normal morphogenesis has consequences on the structure and
functioning of organs. (42)
We retain the following consequences of prematurity:
-in case of prematurity, the child being born before nephrogenesis is completed (in week
36), nephrogenesis will continue after birth
-prematurity is associated with LBW and a low number of nephrons. Studies conducted
by Stellah et al on rats in an experimental model found that prematurity leads to a reduced
nephron number and to hypertension.(41)
- most premature children do not have an appropriate evolution in the first week after
birth, a fact that will delay the development of the foetus. This effect is defined by Curtis and
Rigo as extrauterine growth restriction. (43)

Keijzer-Veen et al also report high values of blood pressure after19 year in patients with
IUGR and preterm-birth (44). To be noted that prematurity presents long-term risks for
chronic kidney disease. (45)
Optimisation of the mothers health and of early childhood nutrition are considered able
to limit the risk for adult hypertension, influencing foetal programming. (31)

NUTRITION-LBW and the reduced nephron number

The development of the foetus is under the influence of environmental factors. One of
these is nutrition, as the foetuss metabolism and developmental programme is closely
connected to nutrition.
The foetuss genes and nutrition are in permanent interaction that determines its growth
rhythm. (46)
If nutrition disturbances occur during the critical foetal period, the metabolic
programming and that of foetal growth are altered. There occurs re-programming related to
the existing nutrition factors, defined as reprogramming.
According to Jackson, during the period of early life and development, the foetus would
manifest plasticity of metabolic functions, which would allow it to adapt to the new
conditions. (46)
The maternal diet would influence the programming of embryonic kidney gene
expression. (47)
Moreover, it was found in rats that low protein diet influences the adaptation processes
during apoptosis processes. (48)
According to Bagby et al. there occurs a process of asymmetric growth restriction.
According to it, redistribution of blood circulation under stress and hypoxia would provide, as
we have already mentioned at the beginning of this paper, preponderant circulation and
nutrition at main organ (brain, heart, adrenals) level. On the other hand, other organs (for
instance the kidney and the skeletal muscles) have deficient circulatory flow and nutrition
because of redistribution. These organs, as well as the foetus in general, will have a slower
development, hence low birth weight and number of nephrons. (49).
According to Bagby programming limits the range of postnatal adaptability, a fact that
leads to disease vulnerability: nephron protection begins at birth.(50).
New foetal programming consecutive to poor nutrition will persist, having consequences
in adult life.
Experimental studies highlighted the role of foetal deficient nutrition. In rats, low
protein diets reduce the nephron number by approximately 30%.(51) Maternal low protein
diet not only impairs nephrogenesis but it also causes LBW and promotes hypertension in
adult rats .(52)
One of the most eloquent events that revealed the influence of nutrition on the foetus is
represented by World War II Dutch famine, when the population of Holland was subject to
serious protein restriction for a limited period of time. Women exposed to famine during early
gestation, as compared to women who were not exposed to such a diet, presented in adulthood
high cardiovascular mortality and mortality of cancer, especially breast cancer .(53)
Prenatal exposure to Dutch famine in mid gestation is also associated with obstructive
airways diseases and microalbuminuria. (54)

Placental insufficiency, low birth weight and arterial hypertension

The placenta plays an important part in the relationship between maternal environment
and the foetus. It ensures transfer of nutritive substances from the mother to the foetus. .
At the same time, noxious factors in the environment will be able to cross the placental
barrier, from the mother to the foetus. One example is represented by some medicines like
angiotensin converting enzyme inhibitors which can produce noxious effects on the foetus,
being thus counter-indicated during pregnancy.
The placenta ensures foetal programming (55)
Placental insufficiency can play an important part in the development of the foetus. It
can often occur in preeclampsia, accompanied by generalised endotheliosis and sometimes by
formation of placental micro-thrombi, determining insufficient development of the foetus,
respectively IUGR.
Jarvenpaa et al report in preeclampsia disturbances of the expression of angiogenesis
related placental genes, this condition being associated with IUGR (56)
IUGR can determine a decrease in the expression of genes involved in nephrogenesis.
Placental insufficiency by reduced uterine perfusion causes hypoxia and diminution of
the supply of nutritive substances. Experimental studies on rats showed that placental
insufficiency leads to low birth weight offspring and predisposes to hypertension
development. (57)
Moritzs experimental studies on female rats showed that placental insufficiency
produced by bilateral uterine vessel ligation is associated with a reduced number of nephrons.
It will be followed in adulthood by renal insufficiency, without associating concomitant
hypertension. (58).
IUGR consecutive to placental insufficiency results in both LBW and alteration of the
programming of the foetus development, with subsequent consequences in adulthood, for
example cardiovascular disease, and high blood pressure.
The quantity of circulating cortisol increases in pregnant women during pregnancy. At
placental level, 11-beta-hydroxisteroid dehydrogenase participates in its metabolization. In
case of placental insufficiency, at foetus level, there appear high amounts of cortisol that
influence foetus programming for adult hypertension and other metabolic diseases. (55).
According to Jansson and Powell changes in the maternal environment would affect the
methylation status of placental genes with perturbation of foetal growth and foetal
programming. That is why they logically ask the question whether the placenta is a nutrient
sensor. (55)
Recent studies showed in experimental animals (rats) a diminution of the expression of
angiotensin I- converting enzymes of the placenta during protein restriction in the mother, a
fact that could be responsible for IUGR and associated programming of adulthood
hypertension (59)

Glucocorticoids, LBW, reduced nephron number

As we mentioned above, during pregnancy, the placenta acts as a barrier limiting the
exposure of the foetus to increased values of cortisol present in the maternal blood. They
could have a deleterious effect at foetal level.
In order to protect the foetus, an enzyme - type 2 11-beta-hydroxisteroid dehydrogenase
(11-beta-HSD 2) - acts at placental level. It inactivates the cortisol, turning it into cortisone,
which has no noxious effects. The production of this enzyme is under the control of a specific
gene.

In fact 11-beta- HSD 2 is present in large quantities in the tissues of the foetus and of the
trophoblast, having a protective role (60)
During placental insufficiency, the activity of 11-- HSD 2 is diminished. When an
increased amount of cortisol reaches the foetus it influences its development, resulting in
LBW and a reduced number of nephrons. In fact, the activity of placental 11--HSD 2 is
correlated with LBW. (61)
However, not all authors have found a relationship between the activity of 11-- HSD 2
type 2 and birth weight (62).
If 11-- HSD type 2 neutralises naturally produced corticoids, it has no effect on
artificial corticoids, like dexamethasone, but it is in use in medical practice for preventing
preterm pregnancy as well as for stimulating the development of the respiratory apparatus.
Ortiz et al found in the adult offspring of rats that had received prenatal dexamethasone
during specific times of gestation, a reduced number of nephrons and hypertension. (63)
The diminution of the number of nephrons will result in hypertension in adult life.
In fact, Figuero et al consider that the programming of high blood pressure may be due
to aberrant branching of morphogenesis and decreasing of glomerulogenesis (Figueroa et
al)(64)

THE CONGENITAL SOLITARY KIDNEY

It is characterized by a reduced number of nephrons (70% of the nephrons of a person with
two kidneys, according to Douglas-Denton et al.{65 ). Congenital solitary kidney develops
hypertension in time. (66)
Genetic factors are mainly responsible for producing congenital solitary kidneys (CSK).
Environmental factors seem to intervene in addition to genetic factors..(67)
CSK represents an instance for the fact that the number of nephrons can be programmed
during gestation. At the same time, according to Seeman et al, unilateral renal agenesis, by its
reduced nephron number, could represent a risk factor for high blood pressure .(68).
According to Mackenzie et al, the programming of fewer nephrons at birth could explain
development of hypertension in people with low birth weight.(69)
Gdlean et al find that high blood pressure is present both in patients with CSK and in
those with surgically acquired SK, its incidence being even higher in the latter.
(70).Hypertension in patients with SK seems to be related to the low number of nephrons,
irrespective of its origin. Similar results are reported by Dursun et al. (71)
Other authors, like Wikstad, et al find that patients born with unilateral agenesis or
patients with childhood nephrectomy do not present a marked increase of blood pressure. (72)

OTHER DISEASES ASSOCIATED WITH LBW

LBW, as well as the reduced number of nephrons usually associated with it, is the result
of numerous factors that act upon the developing foetus. As a consequence of its insufficient
development there occurs LBW, and because the foetus is affected by these factors during its
organogenesis period, the development of its various organs is impaired. This is mainly due to
the fact that oxygenation and nutrition is mainly provided for vital organs, to the detriment of
other organs, which will suffer. The period in which external factors act is maximal during
organogenesis.
Thus, it is a logical consequence that it is not only the kidney that is impaired during this
process with consequences in adult life.

If Brenner et al took over Barkers theory and suggested the hypothesis of the
relationship between the reduced number of nephrons and hypertension subsequently in
relation to LBW, later studies brought complex remarks regarding the relationship between
LBW and other diseases that develop in adulthood.
According to Reyes and Manalich the diseases associated with LBW are mainly high
blood pressure, ischemic cardio-myopathy, stroke, glucose intolerance, type 2 diabetes
mellitus, chronic obstructive respiratory syndrome, dyslipidemia, obesity and glucocorticoids
.(73)
Later, one noticed associations of LBW with other diseases which do not make the
object of the present paper.
Regarding low nephron number, according to Luycks et al, it is associated with both risk
of hypertension and of kidney disease (7).
White et al, after a meta-analysis of 31 studies, appreciated that LBW presents a 70%
risk of developing a renal disease.(74).In a recently published British birth cohort study
Silverwood et al report the role of lower birth weight in renal disease and becoming
overweight in adulthood.(75)
Hoy et al even mention that the relation between LBW and susceptibility to renal
disease confers a new dimension to Barkers hypothesis. (76)

CONCLUSION
High blood pressure is to be regarded as a unitary whole during the life of the
hypertensive patient, starting with the intrauterine period to adulthood, without minimizing
the role of genetic factors. Since various epigenetic, especially environmental, factors can act
during organogenesis, the development programme of the foetus can undergo transformations
that will be reflected in low birth weight, as well as in a reduced number of nephrons, which
is associated in adulthood with hypertension.
However, neither the new concept in hypertension aetiology, developmental
programming regarding adverse reactions to environmental factors, nor that of Brenner,
regarding the reduced number of nephrons and hypertension, completely clarifies the
aetiology of hypertension, its aetiology being multi-factorial. LBW and low nephron number
represent risk factors for developing adult hypertension.

Perspectives
Essential hypertension is no longer to be regarded as a phenomenon with unknown
causes appearing in adulthood, but as a bipolar phenomenon: the periuterine period and adult
age, with established hypertension.
An invisible thread connects the two poles in which a hitherto very little known period
of hypertension during life, which may be definedlatent phase, heads to a clinically
manifest stage .Fig 1.
During this intermediary period we advance through a labyrinth knowing very few data.
That is why we compared hypertension with Ariadnes thread, which guided the ancient hero
toward the final test in that intricate labyrinth.
We also consider that the concept of multi-organ protection - presented by us in
previous articles (Gluhovschi et al) (77,78), that refers to the fact that organ protection forms
a complex protecting the whole organism is to be regarded not only in cross-section, but also
in its whole evolutional dimension, from the periuterine stage to that of the manifest disease.

This long-term interdisciplinary aspect, adds to the concept of interdisciplinarity,

opening new perspectives that permit complete prophylaxis, which is the concern of
nephrologists, but also of obstetricians, cardiologists and diabetologists, etc.
In fact, Rookmaker and Jules, referring to the relationship between hypertension and
nephron endowment, and the nephron number count, have recently very suggestively defined
this relationship using the term from womb to tomb that illustrates the scope of the issue in
the perspective of present-day medicine(79).

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