Dear Editor –in –Chief,

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

HYPERTENSION: ALONG ARIADNE’s 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,

Barker’s hypothesis and Brenner’s hypothesis.

Barker’s 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.

Brenner’s 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 Ariadne’s 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 ARIADNE’s 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 organ-

genesis, being usually expressed in adulthood.

A thread, similar to that of legendary Ariadne’s, 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, Barker’s, “developmental origins of adult disease”, and Brenner’s,

regarding the relationship hypertension - reduced nephron number, address this period and

discuss the relationship between this stage of development and its pathology in adulthood

Barker’s 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 foetus’s 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 Ariadne’s 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 “Ariadne’s 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 glucose-

undergoes 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.

Barker’s 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 “Barker’s 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).

Barker’s 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).

BRENNER’S HYPOTHESIS AND LBW

According to Barker’s 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. Gădălean 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).

Barker’s hypothesis and Brenner’s 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 over-

reactivity 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 Barker’s, regarding the

relationship of LBW with high blood pressure in adulthood, and Brenner’s, 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 mother’s 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 foetus’s metabolism and developmental programme is closely

connected to nutrition.

The foetus’s 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)

Moritz’s 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-ß- 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-ß-HSD 2 is

correlated with LBW. (61)

However, not all authors have found a relationship between the activity of 11-ß- HSD 2

type 2 and birth weight (62).

If 11-ß- 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)

Gădălean 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 Barker’s 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 Barker’s 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 defined”latent 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 Ariadne’s 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).

References

1. Barker DJ: Childhood causes of adult disease: Arch Dis Child. 1988; 63, 7, 867-869.

2. Barker , DJ., Osmond, C: Low birth weight and hypertension : BMJ 1998, 297,(6641) 5641- 134-135.

3. Brenner, BM : The etiology of adult hypertension and progressive renal injury: a hypothesis: Bul Mem

Acad Med Belg 1994, 13,2, 141-147.

4. Lucas,A,Gore,SM,Cole TJ, Bamford MF, Dossetor JF, Barr I, Dicarlo L, Cork S, Lucas PJ:A

multicentric trial of finding low birth weight infants effects of diet on early growth: Arch. Dis. Child

1984,89,722-730.

5. Barker, D.J.: Foetal origin of coronary heart disease : BMJ,1995, 311, 6998, 171-174

6. Zandi-Nejad, K, Luyikx, V. Brenner, BK: Adult hypertension and kidney disease. Hypertension 2005,

47, (part2) 502-508.

7. Luyckx, Bertram JF, Fall,C, Hoy,WE, Ozanne,SE, Vikse, BE, Brenner, BM: Effect of fetal and child

health on kidney development and long-term risk of hypertension and kidney disease: Lancet

2013,;382(9888):273-83.

8. Davies, JA, Fisher, CE: Genes and protein in renal development: Exp. Nephrol 2002,10,2,102-113.

9.Solomon,R,Teller,AL,AttieBitadi,T,Amiel,jVekems,M,Lyonet,S,DurcanP,Niaudet,P,Gubler,MC,Broyer

,M:P:Pax 2 mutations in oligomeganephronia. Kidney Int.2001,59,457-468.

10. Cullen-Mc Ewen, L.A, Kett, MM, Dowling, J,Anderson, WP, Bertram, J.C: Nephron number, renal

function and arterial pressure aged GDNF heterozygous mice: Hypertension, 3003,41,335-340.

11.Luyckx,VA, Brenner,BM:The clinical importance of nephron mass: J.Am.Soc. Nephrol

2010.,21,6,898-910.

12. Langlley-Evans,SC,McMullen.S:Developmental origin of adult disease.Med Princ.Pract.2010,19,2,87-

98.

13. Chen.M., Zhang, L.: Epigenetic mechanisms in developmental programming of adult disease: Drug

Discov Today 2011, 16, (23-24) 1007-1018.

14. Jones, J., Jurgens, J.A., Evans, S.A., Ennis, R.C., Villar, Van A.M., Jose, P.A.: Mechanisms of fetal

programming in hypertension: Int J. Pediatr 2012, doi, 10.1155/2012/584871

15. Zawada, A., Rogacev, K.S., Heine, G.H.: Clinical relevance of epigenetic dysregulation? in chronic

kidney disease associated cardiovascular disease: Nephrol Dial Transplant 2013, 28, 7, 1663-1671.

15. Dressler, G.R., Epigenetics, development and the kidney: J Am Soc Nephrol 2008, 19, 2060-2067.

16. Negrato, C.A., Giomes, M.A.:Low birth weight: causes and consequences: Diabetol. Metab Syndr,

2013, 5, 49, Published online 2013 September 2. doi: 10.1186/1758-5996-5-49.

17.Bogdarina,I,Hasse,A.Langley-Evans,S,Clark,AYL:Glucocortical effects on the programming of AT1b

angiotensin receptor gene methylation and expression in the rat: Plos One 2010,5,2 e9237.

18. Ritz, E, Amann, K, Koleganova, N, Benz, K: Prenatal programming- effects on blood pressure and

renal function: Nat Rev Nephrol 2011, 7,(3),137-144.

19. Hoy, WE Rees, M, Kile E , Mathews JD, Wang Z.: A new dimension to the Barker hypothesis: low

birth weight and susceptibility to renal disease: Kidney Int.1999 ,56,3,1072-1077.

20. Luyckx, V.A., Shukh, K., Brenner, B.M.: Low nephron number and its clinical consequences:

Rambam Maimonides Medical Journal :2011, 24, doi, 105041/RMMJ 10061.

21. Loe SM, Sanchez-Ramos L, Kaunitz, AM. :Assessing the neonatal safety of indomethacin tocolysis: a

systematic review with meta-analysis:Obstet Gynecol 2005,106,1,173-179.

22. Barker DJ:The origins of the developmental origins theory: J Intern Med 2007,2615,412-417.

23. De Boo, HA, Harding, JE, The developmental origins of adult disease (Barker hypothesis) Aust Nz J.

Obstet Gynaecol 2006, 46, 1, 4-14.

24. Barker, D.J: Adult consequences of fetal growth restriction: Clin.Obstet Ginecol 2006, 49, 270-283.

25. Delisle, H.: Foetal programming of nutrition-related chronic disease: Sante 2002, 12, 1, 56-63.

26 Harrison,N, Langly-Evans, SC: Intergenerational programming of impaired nephrogenesis and

hypertension in rats following maternal protein restriction during pregnancy: Br J Nutr, 2009, 101, 7, 1020-

1030.

27. Brenner, B.M., Garcia D.L., Anderson, S:Glomeruli and blood pressure. Less of one, more the other?

:Am J Hypertens 1988, 1 (4 pt 1) 335-347.

28.Gadalean F, Kaycsa A, Gluhovschi G, Velciov S, Gluhovschi C, Bob F, Bozdog G, Petrica L :Is the

urinary biomarkers assessment a non-invasive approach to tubular lesions of the solitary kidney?: Ren Fail.

2013,35,10, 1358-1364.

29. Luyckx,V.A,Shukh,K,Brenner,B.M.:Low nephron number and its clinical consequences. Rambam

Maimonides Med J. 2011. 2(4): e0061. Published online 2011 October 31. doi: 10.5041/RMMJ.10061

30. Brenner ,BM., Chertow, G.M.: Congenital oligonephropathy and the etiology of adult hypertension

and progressive renal injury. Am. J Kidney Dis 1994, 123, 171- 175.

31.Luyckx,V,A, Brenner :Low birth weight, nephron number, and disease:Kidney Int,2005,68,Suppl

97,S68-S77..

32. Luyckx, V.A, Brenner, B.M: The clinical importance of nephron mass. J Am Soc Nephrol. 2010;

21(6):898-910.

33.Reyes, L., Manalich, R.: Long-term consequences of low birth weight Kidney Int 2005, 68. suppl 97,

S107-S111.

34. Manalich, R., Reyes, L., Herrera, M., Melendi,C., Fundora, I: Relationship between weight at birth

and number and size of renal glomeruli in humans a histomorphometric study; Kidney Int 2000, 58.2, 770-773.

35. Chong, E., Yosypiv, IV: Developmental programming of hypertension and kidney disease. Int J

Nephrol 2012, doi, 10.1155/2012/760580.

36. Myrie, S.B., Mcknight.:.L.,Van Vliet, B.W., Bertolo R.F:Low birth weight is associated with reduced

nephron number and increased blood pressure in adulthood in a novel spontaneous intrauterine growth-

redistricted model in Yucatan miniature swine: Neonatology 2011, 100,4, 380-386.

37. Mu, M., Wang, S.F., Sheng, I., Zhao, Y., Li, M.Z., Hu, C.L., Tao, F.B.:Birth weight and subsequent

blood pressure and meta-analysis. Arch Cardivasc Dis 2012, 105, 2, 99-113.

38. Andersson, S.W., Lapidus, L., Naklasson, H., Hallberg, L., Benytsson, C., Huethen, L:, Blood

pressure and hypertension in middle-age women in relation to weight and length at birth: a follow-up study : J

Hypertens. 2000, 18, 12, 1753-1761.

39. Brenner, B.M., Garcia D.L., Anderson, S: Glomeruli and blood pressure. Less of one, more the other?

Am J Hypertens 1988, 1 (4 pt 1) 335-347.

40.Yiu V, Buka S, Zurakowski D, McCormick M, Brenner B, Jabs, K: Relationship between birthweight

and blood pressure in childhood .Am J Kidney Dis. 1999 ;33,2,:253-260.

41. Stellah, C, Allen, K.P, Mattson, D.L, Larch-Gaggl. A., Reddy.S.: El-Meanawy.A: Prematurity in

mice lead to reduction in nephron number, hypertension and proteinuria: Transl Res 2012, 159, 2, 80-89 42. Abitol, CL., Rodriguez, MM.: The long-term renal and cardiovascular consequence of Prematurity.:

Nat Rev Nephrol 2012, 8, 5, 265-274.

43. Curtis, M., Rigo J. Extra-uterine growth restriction in very low birth weight infants: Acta Pediatr

2004, 93, 563-1568

44. Keijzer-Veen, MG, Finken MJ, Nauta J, Dekker FW, Hille ET, Frölich M, Wit JM, van der Heijden

AJ Dutch POPS-19 Collaborative Study: Is blood pressure increased 19 years after intrauterine growth

restriction and preterm birth?: A prospective follow-up study in The Netherlands. Pediatrics. 2005, 116.3:725-31

45.Cormody JB, Charlton JR: Short-term gestation, long-term risk, prematurity and chronic kidney

disease. Pediatrics.2013;13,6, 1168-1179.

46..Jackson, A.A.: Nutrient growth and the development of programmed metabolic function. Ad Exp Med

vol 2000, 478, 41-45.

47. Welham, S.J., Riley, P.R., Wade, A., Hubank, M., Woolf, A.S.: Maternal diet programs embryonic

kidney gene expression: Physical Gnomics 2005, 22, 48-5.

48. Welham, S.J., Wade, A., Woolf, A.S.: Protein restriction in pregnancy is associated with increased

apoptosis of mesenchymal cells at the start of rat metanephrogenesis.: Kidney Int 2002,61, 123-1242.

49. Bagby, S.P:Maternal nutrition, low nephron number. and hypertension in later life: pathways of

nutritional programming. J Nutr 2007, 137, 4, 1066-1072.

50. Bagby, SP: Development origins of renal disease: Should nephron protection begins of birth.?: Clin J

Am.Soc Nephrol 2009,4,10-13.

51. Langley-Evans, S.C., Langley-Evans, A.J., Marchand, M/C/,: Nutritional programming of blood

pressure and renal morphology: Arch Physiol Biochem 2003, 111,1,8-16.

52. Langley-Evans, S.C., Welham, S.J., Jackson, AA.: Fetal exposure to a maternal low protein impairs

nephrogenesis and promotes hypertension in the rat : Life Sciences 1999, 64, 11, 965-977.

53. Van Abeelen A.F.M., Veenendaal, M W.E., Painter, R.G., de Rooif S.R, Dijkgraaf MG, Bossuyt PM,

Elias SG, Grobbee DE, Uiterwaal CS, Roseboom T: Survival effects of prenatal famine exposure.: Am J Clin

Nutr 2012, 95, 179-183.

54. Painter, RC, Rosenboom, TJ, Bleker; OP: Prenatal exposure to the Dutch famine and disease in later

life: an overwiew. Reprod Toxicol, 2005, 20,3, 345-352.

55. Jansson,T,Powell,T.L.: Role of the placenta in foetal programming: underlying mechanisms and

potential interventional approaches : Clin Sci (Lond) 2007, 113,1, 1-13.

56. Jarvenpaa,J,Vuoristo,TJ,Savolainen,ER,Ukkola,O,Vaskuvuo,T,Ryynanen,M:Alterred expression of

angiogenesis in pre-eclampsia associated with intrauterine growth

restriction.:Gynecol.Endocrinol.2007.23,6,351-355

57. Alexander,: B.T: Placental insufficiency leads to development of hypertension in growth-restricted

offspring : Hypertension 2003, 41, 457-462.

58. Moritz. K.M., Mazzuca, M.Q., Siebel, A.L., Mibus, I., Arena, D., Tare, M., Owens, J., Wladek, M.E.:

Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but not hypertension with

ageing in female rats: J.Physiol 2009,1. 587 (Pt II), 2635-2646.

59.Gao, H., Yallampalli, U., Yallampalli, C.: Maternal protein restriction reduces expression of

angiotensin I converting enzyme 2 in rat placenta labyrinth zone in late pregnancy: Biol Reprod, 2012,84,2,31,

doi: 10.1095/biolreprod.111.094607.

60.Shams, M., Kilby, M.D., Somersat, DA, Howie AJ, Gupta A, Wood PJ, Afnan M, Stewart

PM:Ontogeny of placental 11-ß- hidroxysteroid HSD2, type 2 , reduced expression in intrauterine growth: Hum

Reprod 1998, 13, 799-804.

61. Stewart PM, Whorwood CB: Mason JI:Type 2 11 beta-hydroxysteroid-dehydrogenase in foetal adult

life: J Steroid Biochem Mol Biol.1995 ,55(5-6):465-71.

62.Rogerson, F. M., Kaves, M.K., White, P.G.: Variation in placental type 2 11-ß-hydroxisteroid

dehydrogenase activity is not related to birth and placental weight: Mol Cell Endocrinol 1997, 128, 103-109.

63. Ortiz, L.A., Quam, A., Weinberg, A., Baum, N: Effects of prenatal dexamethasone on rat renal

development. Kidney Int. 2001, 59, 1663-1669.

64. Figueroa, J.P., Rose, J.C., Massman, B.A., Zang, J., Acuna, G: Alterations in foetal kidney

development and clinical doses of antenatal glucocorticoids: Ped Rev 2005, 58, 3, 510-515

65. Douglas-Denton R, Moritz KM, Bertram JF, Wintour EM :Compensatory renal growth after unilateral

nephrectomy in the ovine fetus: J Am Soc Nephrol.2002 Feb;13,2,406-410.

66. Gluhovschi G, Gadalean F, Gluhovschi C, Petrica L, Velciov S, Gluhovschi A, Timar R:The solitary

kidney-a nephrologic perspective: Rom J Intern Med. 2013 Apr-Jun;51(2):80-88.

67. Akl, K: The anomalies associated with congenital solitary functioning kidney in children : Saudi J

Kidney Dis and Transplant 2011, 1,67-71.

68. Seeman, T., Patzer, L., John, U. Dusek J, Vondrák K, Janda J, Misselwitz J:.Blood pressure, renal

function and proteinuria in children with unilateral renal agenesis: Kidney Blood Press Res 2006, 29, 4, 210-21.

69.Mackenzie, H. S., Lawler, E.U., Brenner. B.M. Congenital oligonephropathy: the fetal flow in essential

hypertension? :Kidney Int. Suppl 1995, 55, 5 ,30-34

70.Gădălean, F.N., Gluhovschi, G., Trandafirescu, V, Petrică L., Velciov, S., Bozdog, G., Gluhovschi, C.,

Bob, F., Vernic, C: Estimated glomerular filtration rate in patients with surgically acquired single kidney

implications for kidney transplant from live donors : Exp Clin Transplant 2010, 228-236.

71. Dursun, H., Bayazit, A.K., Cengiz, N., Seydaoglu, G., Buyukcelik, M., Soran, M., Noyan, A., Anarat,

A., Ambulatory blood pressure monitoring and renal function in children with a solitary kidney :Pediatr Nephrol

2007, 22, 559-564.

72. Wikstad, I., Celski, G., Larsson, L., Herin, P., Aperia, A: Kidney function in adults born with

unilateral agenesis or nephrectomised in childhood .Pediatr Nephrol 1988, 2, 2,177-18.

73. Reyes, L., Manalich, R.: Long-term consequences of low birth weight : Kidney Int 2005, 68. suppl 97,

S107-S111.

74. White, S.I., Perkovic, O., Cass, A., Chang, C.L., Poulter, W. R., Spector, T., Haysom L,Craig, J.C.,

Salmi, I.A., Chadban, S.J., Huxley, R.P.:Is low birth weight an antecedent of CKD in later life? A systematic

review of observation studies: Am J Kidney Dis 2009, 54,2. 248-261

75. Silverwood ,RS,Pierce, M, Hardy, R, Sattar N, Whincup P,Ferro, C ,Savage C,Kuh, D,Nitsch Low

birth weight ,later renal function ,and the roles of adulthood blood pressure,diabetes,and obesity in British birth

cohort.Kidney Int. 2013,84,1262-1270.

76. Hoy W.E., Rees,M,Kile, E., Mathews, J.D.,Wang, Z.:A new dimension to the Barker hypothesis; low

birth weight and susceptibility to renal disease Kidney Int 1999, 56,3,1072-1077.

77. Gluhovschi G, Bozdog G, Petrica L, Schiller A, Trandafirescu V, Velciov S, Gluhovschi C, Bob F.

Multi-organ protection and the kidney. From nephroprotection, cardioprotection, neuroprotection to

multiorganprotection, Nefrologia. 2004; 24(6):519-30, 532, 534-545.

78.Gluhovschi G, Gluhovschi C, Bob F, Velciov S, Trandafirescu V, Petrica L, Bozdog G.:Multiorgan-

protective actions of blockers of the renin-angiotensin system, statins and erythropoietin: common pleiotropic

effects in reno-, cardio- and neuroprotection. Acta Clin Belg. 2008 ; 63(3):152-169

79 Rookmaker, M.B., Jules, J.A.: The nephron number counts-from womb to tomb: Nephrol Dial.

Transplant. 2013, 28, 6,1325-1328.