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Basic development of nephron and Kidney
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DEVELOPMENT OF
KIDNEY
- Dr. Garima Aggarwal- DM Nephrology
- Amrita Institute of Medical Sciences- Kochi, India
Created – September, 2013
OBJECTIVES
Stages of Kidney DevelopmentDevelopment of NephronDevelopment of the Collecting SystemDevelopment of VasculatureMolecular BiologyTimeline of EventsApplied Aspects
Basic Concepts
INTERMEDIATE MESODERM
The 3 embryonic germ layers
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
Stages of Kidney Development• The Human Kidney
develops in 3 successive stages (rostral to caudal)
PRONEPHROSMESONEPHROSMETANEPHROS They are aligned adjacent
to the
Wolfian / Nephric Duct
PronephrosPronephros The PRONEPHROS The PRONEPHROS
develops from the cranial develops from the cranial most part of urogenital most part of urogenital ridge.ridge.
It is transitory and It is transitory and regresses completely by 5 regresses completely by 5 weeks of gestationweeks of gestation
Forms the kidney in Forms the kidney in larval stages of larval stages of amphibians and fishamphibians and fish
It is non functional in It is non functional in Humans. Humans.
MesonephrosMesonephros 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 theAdrenal glandsGonads
METANEPHROS, third METANEPHROS, third and final stage of Kidney and final stage of Kidney developmentdevelopment
It results from Reciprocal It results from Reciprocal inductive signals between inductive signals between the Metanephric the Metanephric Mesenchyme (MM) and Mesenchyme (MM) and the Ureteric Bud (UB) at the Ureteric Bud (UB) at the caudal end of the the caudal end of the Urogenital bridge.Urogenital bridge.
Ureteric bud is an Ureteric bud is an outgrowth at the distal end outgrowth at the distal end of the Wolfian duct, first of the Wolfian duct, first visible at approx. 5 weeks visible at approx. 5 weeks of gestation.of gestation.
MetanephrosMetanephros
Development of Nephron
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
The METANEPHRIC MESENCHYME (MM) becomes distinct from the surrounding loose mesenchymal cells and come to lie adjacent to the URETERIC BUD (UB).
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
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.
Development of the Collecting Development of the Collecting System System
The collecting ducts are all derived from the Ureteric Bud.The collecting ducts are all derived from the Ureteric Bud. The ureteric bud initially penetrates the metanephric mesoderm, The ureteric bud initially penetrates the metanephric mesoderm,
and then undergoes repeated branching to form the ureters, renal and then undergoes repeated branching to form the ureters, renal pelvis, major calyces, minor calyces, and collecting ducts.pelvis, major calyces, minor calyces, and collecting ducts.
This branching is highly patternedThis branching is highly patterned
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.
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.
Renal Ascent The fetal metanephros is located at vertebral level S1-S2, The fetal metanephros is located at vertebral level S1-S2,
whereas the definitive adult kidney is located at vertebral level whereas the definitive adult kidney is located at vertebral level T12-L3. T12-L3.
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
Initially the kidneys face anteriorly, but during the ascent, the Initially the kidneys face anteriorly, but during the ascent, the kidneys rotate 90°causing the hilum to finally face medially.kidneys rotate 90°causing the hilum to finally face medially.
Speculated that the differential growth of the lumbar and sacral regions of the embryo plays a role
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
• 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.
WT1
As the differentiation proceeds, WT1 expression is lost in the cells of the proximal and distal tubules and retained only in the glomerular podocytes.
WT1 is expressed in the metanephric mesenchyme but not the Wolfian duct or ureteric bud.
GDNF- ret Signaling in Kidney Development
Ret is a tyrosine kinase receptorRet is expressed in the Wolfian duct and the ureteric bud. For stimulation of ureteric bud branchingBy the time the bud has branched several times, expression is restricted to the tips of the branches.
Factors from Ureteral Bud
• Bone morphogenic protein(BMP)• Fibroblast growth factor(FGF)
- Stimulate proliferation of metanephric mesenchyme- Maintain production of WT 1.
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.
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
Applied Aspects
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
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.
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
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
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
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
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