Basic development of nephron and Kidney

1. DEVELOPMENT
OF
KIDNEY
- Dr. Garima Aggarwal
- DM Nephrology
- Amrita Institute of Medical Sciences
- Kochi, India Created – September, 2013

2. OBJECTIVES
Stages of Kidney Development
Development of Nephron
Development of the Collecting System
Development of Vasculature
Molecular Biology
Timeline of Events
Applied Aspects

3. Basic Concepts
INTERMEDIATE
MESODERM
The 3 embryonic
germ layers

4. Mammalian Kidney Development
 After the folding of the embryonic disc, the intermediate mesoderm
forms a bulging on the posterior abdominal wall, called the
NEPHROGENIC CORD/ UROGENITAL RIDGE
 It extends from the cervical region to the sacral region of the
embryo.
UROGENITAL
RIDGE

5. Stages of Kidney Development
• The Human Kidney
develops in 3 successive
stages (rostral to caudal)
PRONEPHROS
MESONEPHROS
METANEPHROS
 They are aligned adjacent
to the
Wolfian / Nephric Duct

6. PPrroonneepphhrrooss
· TThhee PPRROONNEEPPHHRROOSS
ddeevveellooppss ffrroomm tthhee ccrraanniiaall
mmoosstt ppaarrtt ooff uurrooggeenniittaall
rriiddggee..
· IItt iiss ttrraannssiittoorryy aanndd
rreeggrreesssseess ccoommpplleetteellyy bbyy 55
wweeeekkss ooff ggeessttaattiioonn
· FFoorrmmss tthhee kkiiddnneeyy iinn
llaarrvvaall ssttaaggeess ooff
aammpphhiibbiiaannss aanndd ffiisshh
· IItt iiss nnoonn ffuunnccttiioonnaall iinn
HHuummaannss..

7. MMeessoonneepphhrrooss
 MESONEPHROS develops
caudal to the Pronephros.
 It consists of a series of
tubules that drain into the
nephric duct, which can be
called the Mesonephric duct.
 Excretory organ for embryo
until metanephros takes
over.
 By the 4th month of
gestation-completely
disappears.
 Before its degeneration some
of its cells migrate and
ultimately form the
Adrenal glands
Gonads

8. MMeettaanneepphhrrooss
· MMEETTAANNEEPPHHRROOSS,, tthhiirrdd
aanndd ffiinnaall ssttaaggee ooff KKiiddnneeyy
ddeevveellooppmmeenntt
· IItt rreessuullttss ffrroomm RReecciipprrooccaall
iinndduuccttiivvee ssiiggnnaallss bbeettwweeeenn
tthhee MMeettaanneepphhrriicc
MMeesseenncchhyymmee ((MMMM)) aanndd
tthhee UUrreetteerriicc BBuudd ((UUBB)) aatt
tthhee ccaauuddaall eenndd ooff tthhee
UUrrooggeenniittaall bbrriiddggee..
· UUrreetteerriicc bbuudd iiss aann
oouuttggrroowwtthh aatt tthhee ddiissttaall eenndd
ooff tthhee WWoollffiiaann dduucctt,, ffiirrsstt
vviissiibbllee aatt aapppprrooxx.. 55 wweeeekkss
ooff ggeessttaattiioonn..

10. Development of Nephron
The METANEPHRIC
MESENCHYME (MM)
becomes distinct from the
surrounding loose
mesenchymal cells and come
to lie adjacent to the
URETERIC BUD (UB).
Upon invasion of UB in the
loose MM, signals from MM
cause UB to branch into a T -
tubule
Signals from UB induce the
MM to condense along the
surface of UB

11.  After condensation a subset of the MM
aggregates inferior and adjacent to the
tips of the branching ureterIc bud,
forming the PERITUBULAR
AGREGATES.
 These undergo mesenchyme – to –
epithelial transformation and form the
RENAL VESICLE
 The Renal vesicle ultimately forms the
• Glomerulus
• Proximal Convoluted tubule
• Loop of Henle
• Distal Convoluted tubule
Renal
Vesicle

12. Renal Vesicle in contact with the
epithelium of the ureteric bud forms
the ‘COMMA SHAPE’
Glomerulus develops from the most
proximal end of the Renal Vesicle,
farthest from UB tip.
These cells develop into Podocytes.
Vascular cleft develops between
podocyte layes and the more
proximal cells – ‘S SHAPE’
Endothelial cells migrate into the
vascular cleft
Mesangial cell ingrowth follows the
endothelial cells into the vascular
cleft.

14. DDeevveellooppmmeenntt ooff tthhee CCoolllleeccttiinngg
SSyysstteemm
 TThhee ccoolllleeccttiinngg dduuccttss aarree aallll ddeerriivveedd ffrroomm tthhee UUrreetteerriicc BBuudd..
 TThhee uurreetteerriicc bbuudd iinniittiiaallllyy ppeenneettrraatteess tthhee mmeettaanneepphhrriicc mmeessooddeerrmm,,
aanndd tthheenn uunnddeerrggooeess rreeppeeaatteedd bbrraanncchhiinngg ttoo ffoorrmm tthhee uurreetteerrss,, rreennaall
ppeellvviiss,, mmaajjoorr ccaallyycceess,, mmiinnoorr ccaallyycceess,, aanndd ccoolllleeccttiinngg dduuccttss..
 TThhiiss bbrraanncchhiinngg iiss hhiigghhllyy ppaatttteerrnneedd

15. After the first few rounds of branching of the UB derivatives and
the concomitant induction of nephrons, the kidney begins to
become divided into an outer CORTICAL region (where
nephrons are being induced) and an inner MEDULLARY region
where the collecting system forms.
As growth continues successive groups of nephrons are induced
at the peripheral regions of the kidney, known as the
NEPHROGENIC ZONE.

16. Development of Vasculature
 VASCULOGENESIS – de novo
differentiation of previously non
vascular cells into structures that
resemble capillary beds.
 ANGIOGENESIS – sprouting of
cells from early capillary beds to
form mature vessel structures.
 Endothelial progenitors withing
the MM give rise to renal vessels
in situ, these capillaries form a
rich network around the
developing nephric tubules.

17. Renal Ascent
 a The fetal metanephros is located att vveerrtteebbrraall lleevveell SS11--SS22,,
wwhheerreeaass tthhee ddeeffiinniittiivvee aadduulltt kkiiddnneeyy iiss llooccaatteedd aatt vveerrtteebbrraall lleevveell
TT1122--LL33..
 From 6th to 9th weeks: kidneys ascend to a lumbar site just
below adrenals
 As the kidneys migrate, they are vascularized by a succession of
transient aortic sprouts that arise at progressively higher levels
 final pair forms in the upper lumbar region and becomes the
definitive renal arteries
 occasionally, a more inferior pair of arteries persists as accessory
lower pole arteries
 IInniittiiaallllyy tthhee kkiiddnneeyyss ffaaccee aanntteerriioorrllyy,, bbuutt dduurriinngg tthhee aasscceenntt,, tthhee
kkiiddnneeyyss rroottaattee 9900°°ccaauussiinngg tthhee hhiilluumm ttoo ffiinnaallllyy ffaaccee mmeeddiiaallllyy..

18. Speculated that the differential growth of the lumbar and
sacral regions of the embryo plays a role

19. Signaling Pathways in Kidney
Development
• From MM
– WT 1
• Hepatocyte Growth Factor(HGF) & MET
• Glial derived nuerotrophic factor(GDNF) & RET
• From Ureteric bud
• Bone morphogenic protein(BMP)
• Fibroblast growth factor(FGF)
• PAX-2
• WNT-4

20. WT1
• Wt1 is a transcription factor
• WT1 was originally identified as a gene involved in Wilms tumor, a pediatric cancer in
which kidney elements are incompletely differentiated and proliferate to form
tumors.
• Wt1 is first expressed in intermediate mesoderm prior to kidney development, and
then in the kidney, gonads and mesothelium.
• Makes MM tissue to respond to ureteric bud induction.

21. WT1 is expressed in the metanephric mesenchyme
but not the Wolfian duct or ureteric bud.
As the differentiation proceeds, WT1 expression is lost
in the cells of the proximal and distal tubules and retained
only in the glomerular podocytes.

22. GDNF- ret Signaling in Kidney Development
Ret is a tyrosine kinase receptor
Ret is expressed in the Wolfian duct and the ureteric bud.
For stimulation of ureteric bud branching
By the time the bud has branched several times, expression is restricted to the tips of the
branches.

23. Factors from Ureteral Bud
• Bone morphogenic protein(BMP)
• Fibroblast growth factor(FGF)
- Stimulate proliferation of metanephric mesenchyme
- Maintain production of WT 1.

24. Factors from Ureteral Bud
• PAX-2
• WNT-4
- Mainly cause mesenchyme to epithelialise in
prepation for excretory tubule differentiation.
- Production of Laminin and Type 4 Collagen to
form basement membrane.

25. Timeline of Kidney Embryology
• Week 4 : appearance of Wolffian or
Mesonephric Duct
• Day 28 : formation of Ureteric Bud (UB)
• Week 4-8 : Initial MM induction and UB
branching
• Week 8 : First nephrons are formed
• Week 6-8 : kidneys ascend from pelvis to
lumbar location
• Week 8-15 : Period of UB branching with
stochastic formation of UB ampulla and nephron units
• Week 10 : filtration begins
• Week 32-36: End of Nephrogenesis

26. Applied Aspects

27. Anomalies in number
• Renal agenesis When
ureteric bud fails to
contact MM
• Duplications When
ureteric bud splits early
before reaching MM
• Ectopic ureters When
two ureteric buds arise
from mesonephricduct

28. Anomalous Ascent
• When the kidney fails to
ascend properly, its location
becomes ectopic.
• The inferior poles of the
kidneys may also fuse,
forming a horseshoe
kidney and ascent is stopped
by inferior mesenteric artery
• Kidney may fuse to the
contralateral one and ascends
to the opposite side, resulting
in a cross-fused ectopy.

30. Anomalous position
• Malrotated Kidneys - Calyces face
anteriorly or antrolaterally. Have
some element of obstruction
causing inadequate drainage –
leading to infection & stone
formation
Other abnormal positions include-
• Ventral Position
• Ventromedial Position
• Dorsal Position
• Lateral Position

31. Mal rotated kidneys
• Calyces face anteriorly or
antrolaterally
• Have some element of
obstruction causing
inadequate drainage –
leading to infection & stone
formation
30-march, 2010, tuesday 31

32. Polycystic kidneys
• Hereditary – autosomal dominant
• Not manifested before 30
• Kidneys enlarged, studded with cysts
• Unyeilding capsule compresses renal
parenchyma causing atrophy
• Liver,lungs and pancreas may be affected
• Defact : not clear, many theories
30-march, 2010, tuesday 32

33. Polycystic kidneys
 Loin pain- weight dragging upon
peddicle or capsule stretch,
hemorhage in cyst, stone
 abdominal mass- confused with
cystic tumor
 hematuria- cyst rupture in
pelvis,moderate, episodic.
 hypertention, infection, &
uremia/CRF.
 Nonspecific symptoms:
anorexia, headache, vague
abdominal discomfort,
vomiting, drowsiness,
anemia.
 ESRD: suddenly in middle age,
survival without RRT ( dialysis/
transplant) unlikely
30-march, 2010, tuesday 33