Human & Veterinary Medicine OPEN ACCESS

International Journal of the Bioflux Society Review

Anatomy and ontogeny of kidney development

1,2
Carmen Micu, 2Bogdan Micu, 1Ana-Nadia Schmidt, 3Nicolae Miu
1
Department of Anatomy and Embryology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, România; 2 Vth
Surgical Clinic, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, România; 3 Department of Pediatrics, IInd
Pediatric Clinic, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, România.

Abstract. Understanding the significant events in the development of the urinary system has great importance in both early diagnosis of congenital
anomalies before the onset of irreversible complications and in the correlational relationship between various diseases found in one single patient.

Key Words: intermediate mesenchyme, metanephros, ontogeny

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.

Corresponding Author: C. Micu, [email protected]

Introduction type 2) is estimated between 5.0 and 6.1% compared to a 1.3 to

2.8% prevalence in the general population (Moore et al 2000;
Concerns about prenatal diagnosis of congenital renal disease
Sheffield et al 2002; Jeansen et al 2004; Davis et al 2010).
(Morcel et al 2011; Gérard-Blanluet et al 2011; Amsalem et al
2011) and changes in the deterministic background, account-
ing new risk factors (Sun et al 2010; Harewood et al 2010; Development of the urinary system
Martinovic-Bouriel et al 2010; Dührsen et al 2011, Demirel et The urinary system develops from intermediate mesenchyme and
al 2011), justify the normal development of the kidneys. it is intimately associated with the reproductive system in early
Fetal ultrasound examination should be performed based on a stages but it precedes it (Lermann et al 2007; Standring 2008).
rigorous “checklist” program (Syngelaki et al 2011) for a care- Intermediate mesenchyme (IM) is disposed longitudinally in
ful fetal anatomy scan (Stoll et al 2010; Abdelazim et al 2010; the trunk, subjacent to the somites, adjacent to the splanchno-
Taori et al 2010). pleuric mesoderm (medially) and to the somatopleuric meso-
In the UK, NICE (National Institute for Clinical Excellence) derm (laterally).
recommends to perform two ultrasound examinations on preg- In lower vertebrates, intermediate mesenchyme typically devel-
nant women (National Collaborating Centre for Women’s and ops serial, segmented epithelial diverticuli called nephrotomes
Children’s Health 2008). (Larsen et al 1997).
According to this program, the second examination performed Each nephrotome encloses a cavity (the nephrocele), which com-
at 20 weeks of pregnancy is aimed at identifying fetal struc- municates with the coelom through a peritoneal funnel called
tural abnormalities. the nephrostome. The dorsal wall of the nephrostome evagi-
Detection rate (Harewood et al 2010) of some anomalies (in- nates as a nephric tubule. The dorsal tips of the cranial nephric
cluding renal anomalies) was compared with data reported by tubules bend caudally and fuse to form a longitudinal primary
“European Network for Surveillance of Congenital Anomalies”, excretory duct, which grows caudally and curves ventrally to
including figures provided by medical records from 20 coun- open into the cloaca. The more caudally placed, and therefore
tries, figures covering 28% of all births in the European Union. chronologically later, tubules open secondarily into this duct or
(Garn et al 2000; Harewood et al 2010). into tubular outgrowths from it (Keeling 2001).
Renal agenesis or dysgenesis are potentially fatal birth defects Glomeruli, specific arrangements of capillaries and overlying
affecting 2 to 5 children per 10,000 live births annually in the coelomic epithelium, arise from the ventral wall of the nephro-
United States (Davis et al 2010). cele (internal glomeruli) or the roof of the coelom adjacent to
According to the National Center on Birth Defects and the peritoneal funnel (coelomic or external glomeruli), or from
Developmental Disabilities (2006), 3 to 5 children are born to both (Schmidt 2002).
diabetic mothers in the United States every year. It has been customary to describe the urinary system as three
Maternal diabetes, known as a risk factor for other birth defects, organs, the pronephros, mesonephros and metanephros, suc-
is also increasingly recognized for renal agenesis/dysgenesis. ceeding each other in time and space, so that the last to devel-
The prevalence of all types of congenital malformations in chil- op is retained as the permanent kidney (Keeling 2001; Schmidt
dren born to mothers with pregestational diabetes (type 1 and 2002; Deprest et al 2010).

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 Micu et al 2013

Pronephros body. It develops subregions, and a gonad develops on its me-

dial surface (Larsen 1997).
The intermediate mesenchyme becomes visible in stage 10 em-
There are striking similarities in structure between the mesone-
bryos and can be distinguished as a nephrogenic cord when 10
phros and the permanent kidney or metanephros, but the me-
somites are present. The pronephros appears in human embryos
sonephric nephrons lack a segment that corresponds to the de-
as clusters of cells in the most cranial parts of the nephrogenic
scending limb of the loop of Henle. The mesonephros is believed
cord. More caudally, similar groups of cells appear and become
to produce urine by stage 17 (Keeling 2001; Schmidt 2002).
vesicular. Their central ends are connected with the coelomic
A detailed comparison of the development and function of the
epithelium by cellular strands, which probably represent rudi-
mesonephros and metanephros in staged human embryos is
mentary peritoneal funnels. Glomeruli do not develop in as-
not available.
sociation with these cranially situated nephric tubules, which
ultimately disappear. It is doubtful whether external glomeruli
develop in human embryos (Keeling 2001; Schmidt, 2002). Mesonephric duct
Once mesonephric nephrons connect to the primary excretory
Primary excretory duct duct it becomes the mesonephric duct. This runs caudally in the
lateral part of the nephric ridge, and at the caudal end of the
In stage 11 (embryos with 14 somites), the primary excretory
ridge it projects into the cavity of the coelom in the substance
duct can be seen as a solid cell cord in the dorsal part of the
of a mesonephric fold. As the mesonephric ducts approach the
nephrogenic cord. Its cranial end is about the level of the ninth
urogenital sinus the two mesonephric folds fuse between the
pair of somites and its caudal tip merges with the undifferenti-
bladder (ventrally) and the rectum (dorsally).
ated mesenchyme of the cord (Larsen 1997; Standring 2008).
In the male, the mesonephric duct forms (Mizuno 2010; Hofkamp
It differentiates before any nephric tubules, and when the latter
et al 2010): epididymal duct, deferent duct and ejaculatory duct.
appear it is at first unconnected with them. In older embryos,
There is a well known close connection in development between
the duct has lengthened and its caudal end becomes detached
the urinary and the genital system.
from the nephrogenic cord to lie immediately beneath the ec-
The mesonephros derived from intermediate mesoderm gives
toderm. From this level it grows caudally, independent of the
birth to the mesonephric duct (MD) or Wolffian duct, as a result
nephrogenic mesenchyme, and then curves ventrally to reach
of the epithelial-mesenchymal interactions. Mesonephric duct
the cloaca. It becomes canalized progressively from its caudal
develops cranially (from the pronephros) to the cloaca (caudally)
end to form a true duct, which opens into the embryonic cloaca
along the urogenital ridge and it is the common origin for male
in stage 12 (Standring 2005).
reproductive system and urine collection tubes.

Mesonephros Ureteric bud

From stage 12, mesonephric tubules which develop from the
The ureteric bud, also known as the metanephrogenic diverticu-
intermediate mesenchyme between somite levels 8-20, begin
lum, emerged as a diverticulum of the distal portion of the MD.
to connect to the primary excretory duct, which now becomes
It is oriented - increasing caudally - towards the metanephric
the mesonephric duct. More caudally, a continuous ridge of
blastema and interacts with it, and then branches off creating
intermediate mesenchyme extends to the level of somite 24.
the urinary collecting tubes system. Ureteric bud branching
The mesonephric tubules (nephrons) are not metameric - there
also induces nephrogenesis inside the metanephric blastema
may be two or more mesonephric tubules corresponding to
(Larsen 1997).
each somite.
Later, the mesonephric duct develops under the influence of
Within the mesonephros, each mesonephric tubule first appears
growth factors and testosterone in males (regresses in females),
as a condensation of cells, which epithelialize and form a vesicle.
resulting in male genital tract.
One end of the vesicle grows and opens into the mesonephric
Thus, a possible disruptive mesonephric duct (MD) development
duct, while the other dilates and invaginates. The outer layer
would cause renal abnormalities (agenesis, hypoplasia and dys-
forms the glomerular capsule, while the inner cells differenti-
genesis) of the urinary and/or genital tract in male (Mizuno 2010).
ate into mesonephric podocytes, which clothe the invaginating
In both urinary and genital systems in males, the pathogenetic
capillaries to form a glomerulus (Larsen 1997).
mechanism (suggested by animal experiments) would involve
The capillaries are supplied with blood through lateral branches
homeobox genes, adhesion molecules, growth factors and their
of the aorta. It has been estimated that 70-80 mesonephric tu-
receptors (Hofkamp et al 2010).
bules and a corresponding number of glomeruli develop.
Glomeruli are not all present at the same time, it is rare to find
more than 30-40 in an individual embryo, because the glomer- Metanephros
uli and the cranial tubules develop and atrophy before the de- The pronephros and mesonephros are linear structures. They
velopment of those situated more caudally (Standring 2005). both contain stacks of tubules distributed along the craniocau-
By the end of the sixth week, each mesonephros is an elongated, dal axis of the embryo. This display results in the production
spindle-shaped organ that projects into the coelomic cavity, on of hypotonic urine.
both sides of the dorsal mesentery, from the level of the septum In contrast, the metanephric tubules are arranged concentrical-
transversum to the third lumbar segment. This whole projec- ly, and the loops of Henle are directed towards the renal pelvis.
tion is called the mesonephric ridge, mesonephros, or Wolffian This arrangement allows different concentration gradients to
develop within the kidney and results in the production of

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 Micu et al 2013

hypertonic urine. Metanephric nephrons do not join with the and minor calyces, as well as the distal branches of the ureteric
existing mesonephric duct but with an evagination of that duct, ducts that will form the collecting ducts of the kidney. As the
which branches dichotomously to produce a characteristic pat- collecting ducts elongate the metanephric mesenchyme con-
tern of collecting ducts. denses around them.
The metanephric kidney develops from three sources: Each epithelial group elongates, and forms first a comma-shaped,
1. an evagination of the mesonephric duct – the ureteric bud, then an S-shaped, body, which continues to elongate and sub-
2. a local condensation of mesenchyma – the metanephric blastema, sequently fuses with a branch of the ureteric duct at its distal
3. the angiogenic mesenchyme migrates into the metanephric end, while expanding as a dilated sac at its proximal end. The
blastema only later to produce the glomeruli and vasa recta. latter involutes, and cells differentiate locally such that the outer
An intact nerve supply may also be needed for metanephric cells become the parietal glomerular cells, while the inner ones
kidney induction. become visceral epithelial cells (podocytes). The podocytes de-
An epithelial/mesenchymal interaction between the duct sys- velop in close proximity to invade capillaries derived from an-
tem and the surrounding mesenchyme occurs in both meso- giogenic mesenchyme outside the nephrogenic mesenchyme.
nephric and metanephric systems. In the mesonephric kidney, This third source of mesenchyme produces the endothelial and
development proceeds in a craniocaudal progression, and cra- mesangial cells within the glomerulus. The metanephric-derived
nial nephrons degenerate before caudal ones are produced. In podocytes and the angiogenic mesenchyme produce fibronec-
the metanephric kidney a part of the mesenchyme remains as tin and other components of the glomerular basal lamina. The
stem cells that continue to divide and enter the nephrogenic isoforms of type-IV collagen within this layer follow a specific
pathway later, when the individual collecting ducts lengthen programme of maturation if the filtration of macromolecules
(Brancati et al 2010). from the plasma becomes restricted (Standring 2005).
Experimental studies on mutant mice demonstrated that a de- Platelet derived growth factor (PDGF) β-chain and the PDGF
fective mechanism in the apoptosis in the undifferentiated mes- receptor β-subunit (PDGFR β) have been detected in develop-
enchyme induces an abnormal interaction between the ureteric ing human glomeruli between 54 and 109 days of pregnancy
bud and the metanephric blastema (Suresh et al 2011). These (Standring 2005).
changes would cause preexisting intrinsic abnormalities of the PDGF β-chain is located in the differentiating epithelium of glo-
kidneys that would validate early, and the role of certain genes merular vesicles during its comma and S-shaped stages, while
and biochemical modulators is undoubtedly. PDGFR β is expressed in undifferentiated metanephric blaste-
Angiotensin II receptor type 1 (AT1 receptor) plays an important ma, vascular structures and interstitial cells.
role in the final stage of nephrogenesis, participating in nephron Both PDGF β-chain and PDGFR β are expressed in mesangial
maturation and ureter formation process. Angiotensin II stimu- cells, which may promote further mesangial cell proliferation
lates the branching of the ureteric bud and this sequentially in- (Standring 2005, 2008).
duces metanephric blastema (metanephric mesenchyme) in both Metanephric mesenchyme will develop successfully in vitro,
glomeruli and proximal and distal renal tubules. which makes experimental perturbation of kidney development
In Germany, the use of ARBs (hypotensive) led to the emer- comparatively easy to evaluate. Early experimental studies dem-
gence of a drug-induced fetopathy: altered - dysgenic proxi- onstrated that other mesenchymal populations and spinal cord
mal and distal renal tubules with oliguria and renal hypoplasia were able to induce ureteric bud division and metanephric de-
(Hünseler et al 2011). velopment. Nerves “enter” the developing kidney very early,
The temporal development of the metanephric kidney is pat- travelling along the ureter (Keeling 2001).
terned radially (Hünseler et al 2011), so that the outer cortex is If developing kidney rudiments are incubated with antisense
the last part to be formed. The following interactions occur in oligonucleotides, which neutralize nerve growth factor recep-
the development of the metanephric kidney. The ureteric bud tor (NGF-R) mRNA, nephrogenesis is completely blocked. It
undergoes a series of bifurcations within the surrounding me- is thus suggested that metanephric mesenchyme induction is a
tanephric mesenchyme and forms smaller ureteric ducts. At the response to innervation, the inductive being accomplished by
same time, the metanephric mesenchyme condenses around the the nerves.
dividing ducts to form S-shaped clusters, which transform into The powerful inductive effect of the spinal cord on metanephric
epithelial structures and fuse with the smaller ureteric ducts at mesenchyme may be a further expression of this phenomenon.
their distal ends. Blood vessels invade the proximal ends of the All stages of nephron differentiation are present concurrently
epithelial structure to form vascularized glomeruli. in the developing metanephric kidney.
The ureteric bud bifurcates when it comes into contact with Antigens for the brush border of the renal tubule appear when
the metanephric blastema in response to extracellular matrix the S-shaped body has formed. They appear first in the inner
molecules synthesized by the mesenchyme. Both chondroitin cortical area. The metanephric kidney is lobulated throughout
sulphate proteoglycan synthesis and chondroitin sulphate gly- its fetal life, but this condition usually disappears during the
cosaminoglycan processing are necessary for the dichotomous first year after birth. Varying degrees of lobulation may persist
branching of the ureteric bud. through-out life.
In metanephric culture, incubation of fetal kidneys in β-d-xyloside, The growth of left and right kidneys is well matched during
an inhibitor of chrondroitin sulphate synthesis, dramatically in- development.
hibits ureteric bud branching (Standring 2005). Fetal kidney volume increases most during the second trimester
Subsequent divisions of the ureteric bud and associated mes- of pregnancy (in both sexes). For reasons that are not under-
enchyme define the gross structure of the kidney and the major stood, male fetuses show greater values for renal volume than

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 Micu et al 2013

female fetuses from the third trimester onwards. Steroid hor- on a level with the second lumbar vertebra when the embryo
mones induce fetal kidney growth restriction and cystogenesis reaches a length of c.13 mm.
the developing kidney (Chan et al 2010). During its ascent, the metanephric kidney receives its blood sup-
Tumor mass such as sacrococcygeal teratomas may interfere in ply sequentially from arteries in its close vicinity, i.e. the median
both development and growth of the kidney and urinary tract, sacral and common iliac arteries (Standring 2005).
and therefore urological problems seem to be common in pa- The definitive renal artery is not recognizable until the begin-
tients with sacrococcygeal teratomas (Le et al 2011). ning of the third month. It arises from the most caudal of the
Fetal kidney develops during the first trimester of pregnancy three suprarenal arteries, all of which represent persistent me-
and becomes functional between 6-10 weeks of pregnancy, pro- sonephric or lateral splanchnic arteries (Schmidt 2002).
ducing urine at 11 weeks. Additional renal arteries are relatively common, and may en-
If maternal pregestational diabetes type 1 and type 2 are both ter the kidney through the hilum or the upper or lower pole of
present before pregnancy, the disease will have a negative im- the gland. They also represent persistent mesonephric arteries.
pact on kidney development during the critical period. Disruption of normal migration of the kidney before the eighth
Results based on animal studies leading to the association be- week determines its malposition during embryogenesis (or-
tween renal agenesis/dysgenesis and hyperglycaemic uterine ganogenesis). Frequently, the ectopic kidney is located in the
environment caused by uncontrolled diabetes. It has also been pelvic or lower back region. (Standring 2005, 2008; Schmidt,
shown that kidney structure is disorganized on a hyperglyce- 2002, 2005).
mic background (Al-Haggar et al 2010). Hyperglycemia leads Pelvic kidney is often considered to be a normal variant but
to ureteral bud dysmorphogenesis and therefore, to disruptions with a different prognosis (Batukan et al 2011).
in nephrogenesis (Davis et al 2010). Generally speaking, renal abnormalities would be more com-
On the other hand, in pregnant women between 24-28 weeks of mon in ectopic kidneys, which can be complicated by hydro-
pregnancy after the critical period of renal development, con- nephrosis, recurrent urinary infections and then kidney stones
trolled gestational diabetes is considered to affect fetal growth (Batukan et al 2011).
rather than organogenesis (Davis et al 2010). Pelvic kidney is defined as one located inside from the fetal pel-
vis bones and in close proximity to the bladder.
Endocrine development of the kidney In a study on 26,464 pregnant women, Batukan & Yuksel (2011)
diagnosed 36 cases of pelvic kidney confirmed postnatally. Of
The kidney functions not only as an excretory organ, but also these, 22.2% were isolated renal abnormalities, in 50% of them
as an endocrine organ, secreting hormones that are concerned associated abnormalities of the urogenital apparatus were de-
with renal haemodynamics. Before birth homeostasis is con- tected prenatally or postnatally, the others showing associated
trolled by the placenta. The fetal kidney produces amniotic malformations outside the urinary system.
fluid (Larsen 1997). Thoracic kidney is extremely rare, this high position could be
The kidneys of new-borns of less than 36 weeks are immature. caused by a different pathogenetic mechanism. In adults, tho-
They contain incompletely differentiated cortical nephrons, which racic kidneys are rare cases reported after severe trauma.
compromise their ability to maintain homeostasis. Problems of There are 4 groups of thoracic kidney according to Guessen,
immaturity are further emphasized by the effects of hypoxia 1984 and Liddell 1989 (Batukan et al 2011):
and asphyxia, which modify renal hormones (Keeling 2001). • thoracic kidney with closed diaphragm
Renal hormones include the renin-angiotensin system, renal • thoracic kidney with eventration of the diaphragm
prostaglandins, the kallikrein-kinin system, and renal dopamine. • thoracic kidney with congenital or acquired diaphragmatic hernia
Renin is found in the smooth muscle cells of arterioles, inter- • thoracic kidney with traumatic rupture of the diaphragm
lobular arteries and branches of the renal artery, and has also Thoracic kidney is accompanied by abnormal high origin of
been described in the distal convoluted tubule cells. the ipsilateral renal artery. Unlike other types of renal ectopia,
Kallikrein has been found in rat fetal kidney, and prostaglan- thoracic kidney is accompanied by a normal renal function and
dins in the renal medulla and renal tubules. apparently, the surgical indication would not necessarily be
Renal dopamine is produced mainly by the enzymatic conver- strong in the neonatal period (Deprest et al 2010; Athanasiadis
sion of l-dopa to dopamine in the early segments of the proxi- et al 2011).
mal convoluted tubule, being also sourced locally from dopa-
minergic nerves (Chan et al 2010).
Other renal hormones include antihypertensive lipid, which is Conclusion
produced in the interstitial cells of the renal medulla, and, pos- This paper is a review of the literature. Kidney development
sibly, histamine and serotonin. occurs in overlapping stages which have a well-established ge-
Growth factors produced by human embryonic kidney cells netic determinism. The action of a teratogenic factor or mutant
include erythropoietin and interleukin β (which stimulate genes’ expression can influence the embryogenesis of one or
megakaryocyte maturation) and transforming growth factor-β more organs, depending on the time they occurred.
(Keeling 2001).
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 Micu et al 2013

Micu, C., Micu, B., Schmidt, A.-N., Miu, N., 2013. Anatomy and ontogeny of kidney
Citation
development. HVM Bioflux 5(1):34-39.
Editor Ştefan C. Vesa
Received 14 February 2013
Accepted 9 March 2013
Published Online 10 March 2013
Funding None reported
Conflicts/
Competing None reported
Interests

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