1. Development of the kidney - malformations
Ágnes Nemeskéri
2016
Semmelweis University
Department of Anatomy, Histology and Embryology

2. Intermediate mesoderm (IM)PM IM
The specification of renal progenitor cells is influenced by Retinoic Acid (RA) signals emanating from the paraxial mesoderm (PM).
RA - diffusible morphogen – effects through concentration dependent activity

3. Embryonic origin of the urogenitalis system ?
intermedier mesoderm
- between paraxial and lateral mesoderm
- after lateral folding: ventral position
Urogenital ridge
- paired longitudinal ridges developing in the dorsal body wall 
on either side of the dorsal mesentery and aorta
medial gonadal ridge and lateral nephrogenic ridge
nephrogenic ridge develops into  three sets of tubular nephric structures (from head to tail):
pronephros mesonephros metanephros
/jpg/urogenital_ridge_ ADADE72D060CF5.jpg
urogenital ridge
Gray19_with_color.png‎ (670 × 228 pixels, file size: 153 KB, MIME type: image/png)

4. Pronephros (Greek: first kidney) pronephric duct pronephric tubules
Pronephros
(Greek: first kidney)
pronephric tubules
coelom
pronephric duct
it develops during the 4th week in the cervical region of the intermediate mesoderm
the nephrogen tissue is segmented into nephrotomes – epithelialization – vesicle – pronephric tubules – nephrostome: opening into the coelom
from the aorta: glomus – coiled capillary network
segmental vesicles elongate and fuse to form the pronephric duct –that grows caudally towards the cloaca
until the level of somites
the pronephric duct cannot filter materials outside the embryo
pronephro kidney is vestigial in humans thus it degenerates soon on the 5th week

5. Pronephros (Greek: first kidney) Pax8 (Paired box gene 8)
- the earliest determinants of pronephric fate
- both are under control of RA signaling
- its depletion leads to a complete absence of pronephric tubule
- pax8 overexpression leads to an enlargement of pronephros
pteg (Proximal tubules-expressed gene protein)
- an early pronephric marker
- direct target of the RA signaling
- essential factor for pronephric specification

6. 2. Mesonephros (Middle kidney) Temporary excretory organ
Starts to develop at the end of 4th week
Functions between 6th and 10th weeks
Mesonephric nephrons do not form any part of the mature kidney !
Nephron – „excretory mesonephric unit”
- a single glomerulus – arising from the lateral branches of dorsal aorta
- a Bowman’s capsule
- a mesonephric tubule – enters the mesonephric duct
Next to the mesonephric duct the intermediate mesoderm differentiates into mesonephric vesicle
This vesicle elongates to form mesonephric tubules attaching to the mesonephric duct
An artery extends towards the mesonephric tubule – contact each other – Bowman’s capsule
On the medial side of the mesonephric duct , from the 6th cervical to 3rd lumbar segments a series of mesonephric tubules develop
Mesonephric tubules collectively constitute the mesonephros

7. 2. Mesonephros (Middle kidney) C C C Function of mesonephros
- produces urine
- as the more caudal nephrons form, the more cranial
nephrons are already degenerating
- in females some vestigial structures remain: Gartner’s
duct, epoophoron, paroophoron
- in males the more caudal tubules survive and give
rise to efferent tubules of testis, epididymis, vas
deferens, seminal vesicle + vestigial structures:
appendix epididymis, paradidymis C C C

8. 3. Metanephros (definitive kidney)
Primordia of permanent kidney starts to develop on the 5th week
- become functional on the 9th week
Definitive kidney develops from 2 sources
1. Metanephric diverticulum – ureteric bud
2. Metanephrogenic blastema – metanephric mesenchyme

9. Ureteric bud
Ureteric bud – outgrowth from the mesonephric duct near its entrance into the cloaca
 reciprocal induction - retinoic acid dependent
Cranial-caudal patterning establishes  a “renogenic” region within the intermediate mesoderm in the tail of the embryo
–this renogenic mesoderm is the METANEPHRIC BLASTEMA
The METANEPHRIC BLASTEMA secretes growth factors that induce growth of the URETERIC BUD from the caudal portion of the mesonephric duct.
The URETERIC BUD proliferates and responds by secreting  growth factors that stimulates proliferation and then differentiation of the metanephric blastema into glomeruli and kidney tubules (i.e. induces the blastema to undergo mesenchymal-to-epithelial transition ).

10. Ureteric bud -reciprocal inductive signals!!! Ureteric bud
- elongates and penetrates the blastema
1. Caudal part
-the stalk develops to ureter
-reciprocal inductive signals!!!
2. Cranial part
- undergoes a number of dichotomous branching events
to form the urinary collecting tubule system
-the first 4 generations of tubules enlarge to form the major calyces
- second 4 generations fuse to form the minor calyces
- the end of each arched tubule induces clusters of blastema cells to form small metanephric vesicles

11. Metanephrogenic blastema
- derives from the caudal part of
the nephrogenic cord
Metanephric Mesenchyme
- is induced to undergo a mesenchymal-to- epithelial transformation
- to form the nephron:
from the epithelial glomerulus to the distal tubule
Nephrons: on average 900,000–1 million in humans

12. Nephron formation

13. CHRONOLOGICAL ORDER OF THE DEVELOPMENT OF PRO-, MESO- AND METANEPHROS
20. day of
embryonic life
25. day of
embryonic life
35. day of
embryonic life
Cytokeratin fluorescence immunostaining
of mouse embryo. Cytokeratin is present
in nephric duct and its derivates.

14. „Ascent„ of the kidneys

15. Malformations of the kidney
Perturbations of inductive events (e.g. mutations of either metanephric or ureteric factors or disruption of retinoic acid signaling) may cause inhibition of ureteric bud growth and renal hypoplasia or agenesis. 
Conversely, duplication or overproliferation of structures can occur if there is a gain of function of the inductive factors.
Gain-of-function mutations, also called activating mutations, change the gene product such that its effect gets stronger

16. Horseshoe kidney (1:400) recent studies abnormal fusion
result of a teratogenic event
-abnormal migration of posterior nephrogenic cells,
-coalesce to form the isthmus
Horseshoe kidney (1:400)

17. Congenital polycystic disease of kidney
(1:800 live birth), PKD1 and PKD2 mutation
Cyst formation is tied to cilia-mediated signaling that is irregular
polycystin-1 and 2 proteins appear to be involved in both autosomal and recessive polycystic kidney disease due to defects in both proteins
- both proteins have communication with calcium channel proteins this causes reduction in resting (intracellular) calcium and endoplasmic reticulum storage of calcium

18. The fetal kidneys regulate the amount of amniotic fluid.
Renal agenesis
Oligohydramnion
(insuficient amniotic fluid)
Polyhydramnios
(excess of amniotic fluid)
FATE OF EXCRETED URINE
IN FETAL LIFE
urine is expelled into the amniotic fluid
- amniotic fluid is partially swallowed by
the fetus and partially is absorbed by
maternal tissues.
- swallowed amniotic fluid is absorbed
by the digestive system of the fetus into
the circulation
- through the umbilical arteries it enters
the placenta where waste products leave
the fetus for the maternal blood.
Potter’s face

20. Ureter duplex
From our dissecting room