Development+of+Urinary+System

=**Objectives**=


 * 1. List the germ layer(s) from which the urinary system develops.**

The metanephric kidney is derived from two sources: the metanephric diverticulum or ureteric bud, and the metanephric mass of intermediate mesoderm or metanephric blastema. The ureteric bud develops into the ureter, renal pelvis, calyces, and collecting duct. The metanephric blastema forms the nephron. However, the glomerulus is formed from the vascular system which is splanchnic mesoderm in origin.

The bladder forms from the the urogenital sinus after it is separated from the rectum by the urorectal septum. Thus, the bladder is formed mostly from hindgut endothelium. However, the trigone portion of the bladder is formed from exstrophy of the mesonephric duct which forms from the intermediate mesoderm. Lastly, in males, the distal portion of the penile urethra is formed by ectoderm from the glandular urethral plate.


 * 2. List/describe the structures that are contributed to by the pronephros, mesonephros, and the metanephros and their respective duct systems.**

__Pronephros__ Rudimentry, transitional, and non-functional kidneys that are present in the neck region early in week four. Develop from intermediate mesoderm. Pronephric ducts run caudally to the cloaca and degenerate rapidly.

__Mesonephros__ Functional interm kidneys, 40 units in crania-caudal sequence, but only 30 functional units at any one time. Mesonephros and mesonephric ducts form from the intermediate mesoderm and are signaled by LIM-2, PAX-2, and WT-1 transcription factors.

Within the intermediate mesoderm, nephric vesicles form and elongate to nephric tubules that enlarge and connect to the mesonephric duct. Mesonephric tubules differentiate into rudimentary adult nephrons. The medial end of the tubule enlarges to form Bowman’s capsule and wraps around a clump of capillaries from the dorsal aorta forming the glomerulus, to produce the renal corpuscle. Each renal corpuscle and nephric tubule is called the mesonephric excretory unit.

Mesonephric ducts from as solid longitudinal rods that condense in the intermediate mesoderm and are dorsalateral to the mesonephric tubules. They grow cranial --> caudal by proliferation of cells at the caudal tip and proliferate into the ventrolateral walls of the cloaca where they will become part of the trigone portion of the future bladder. After fusion with the cloaca, the two rods undergo canalization and open a passage from the excretory unit to the cloaca.

After 10 weeks, the units cease to function and degenerate. In the male, the mesonephric duct forms part of the male genital duct system.

__Metanephros__ Metanephric kidneys are formed from the ureteric budand the metanephric blastema. The ureteric bud eventually forms the ureter, renal pelvis, calyces, and collecting duct. The metabnephric bastema forms the nephron. There is reciprocal induction between these two parts of the metanephric kidney which form from intermediate mesoderm at the sacral level.

The initial part of the ureteric bud forms the ureter as an outgrowth of the distal mesonephric duct. Bifercation of the ureteric bud forms superior and inferior lobes and the renal pelvis. Then there are two sets of 4 bifurcations and fusions to produce the major and minor calyces. Bifurcation then continues to form the collecting ducts. Each ureteric bud is covered with a cap of metanephric blastema which differentiate to metanephric vesicles that elongate to metanephric tubules that form the nephron. The elongating metanephric tubules envelop capillary glomerulus at the distal end of the tubule and form the renal corpuscle. The rest of the tubule differentiates into the epithelium, forming the definitive nephron.

In the bladder, the mesonephric ducts with attached ureteric buds are incorporated into the posterior wall of the forming bladder by exstrophy. This brings the opening of the ureteric buds into the bladder wall, essentially connecting the ureters to the bladder.


 * 3. Describe the region of the embryonic body in which the mesonephros and metanephros develop.**

The mesonephros develop from the intermediate mesoderm at the thoracolumbar region. The metanephros develop from the intermediate mesoderm at the sacral level.


 * 4. Define/describe/explain the tissues or structures that combine to form the metanephric kidney.**

The ureteric bud develops into the ureter, renal pelvis, calyces, and collecting duct. The metanephric blastema forms the nephron. However, the glomerulus is formed from the vascular system which is splanchnic mesoderm in origin.


 * 5. Be able to list the parts of the uriniferous tubule (nephron & collecting ducts) that are derived from each tissue or structure.**

Uriniferous tubule is formed by the ureteric bud and the metanephric blastema. The ureteric bud develops into the ureter, renal pelvis, calyces, and collecting duct. The metanephric blastema forms the nephron.


 * 6. Be able to relate the role of the following substances in the development of the kidney, or in the formation of congenital defects:**

__WT-1__ Necessary for mesonephric tubule formation. It is also expressed by the metanephric blastema and regulates the synthesis of GDNF which is necessary to induce branching and growth for the formation of the ureteric bud.

__c-ret__ In metanephric kidney development, it is the receptor for GDNF and is found in the ureteric bud and necessary for bifurcation; if this receptor is missing, renal agensis and bifid ureters will occur.

__PDK-1 & PDK-2__ In metanephric kidney formation, PDK-1 gene mutation on chromosome 16 is responsible for epithelial hyperplasia and autosomal dominant polycystic kidney disease; usually presents during 4-5 decade of life. If PDK-2 is affected, autosomal recessive polycystic kidney disease occurs and presents in childhood.

__Mox-1__ Required in metanephric kidney formation for nephron differentiation and glomerulus formation.

__N-myc__ Required in metanephric kidney formation for nephron differentiation and glomerulus formation.

__LIM-2__ Induces aggregation of mesenchyme cells into nephric duct.

__Pax-2__ In the mesonephric kidney, it induces conversion of intermediate mesoderm into epithelial tubules. If not expressed, kidney development stops. In the metanephric kidney, Pax-2 is needed to induce ureteric bud formation and transform mesenchymal cells into epithelial cells.

__BMP-7__ Growth factor in metanephric kidney development that is needed to signal blastema mesenchyme to aggregate.

__Wnt-4__

__Wnt-11__

__Hoxc-9__ Required in metanephric kidney formation for nephron differentiation and glomerulus formation.

__NGF__ Growth factor in metanephric kidney development that is expressed in the blastoma and is necessary for formation of nephrogenic tubules.

__IGF__ Overexpression during metanephric kidney development can result in Wilm’s tumors.

__Cadherins__ Makes tight junctions in forming epithelial tubes.

__Laminin__ Necessary for diapedesis to occur as cells migrate.

__Integrin__ Necessary for diapedesis to occur as cells migrate.


 * 7. Describe the development of the vascular supply to the definitive kidney. Explain the occurrence of "accessory renal arteries."**

The blood supply to the kidney changes as it “ascends” during development. Essentially, it gets its blood from its nearest vessels, beginning the common iliac arteries. As it ascends, the kidney starts getting segmental branches off the aorta; normally, the caudal branches degenerate and leave the kidney with a single renal artery branching off the aorta for each kidney. However, if segmental branches persist, accessory renal arteries can remain that can be superior or inferior to the renal artery. Obstruction of the ureter can occur if the accessory artery crosses anterior to the ureter. This can cause hydronephrosis – dilation of the renal pelvis and calyces due to backup of urine that can lead to kidney failure.


 * 8. Define/describe/explain fetal lobulation of kidney, renal agenesis, renal duplication, and Potter's syndrome.**

__Fetal Lobulation of Kidney__ The bifurcation of the ureteric bud forms the renal pelvis. Bifurcation continues and by the 6th week, the bifurcation forms the superior and inferior lobes separated by sulcus. Two sets of 4 bifurcations and fusions produce the major and minor calyces. By week 16, 14-16 lobes have formed and the external appearance is lobulated. Continued bifurcation forms 1-3 million collecting ducts.

__Renal Agenesis & Potter’s Syndrome__ Unilateral renal agenesis is probably due to a lack of ureteric bud and is usually asymptomatic due to hypertrophy of the remaining kidney.

Bilateral renal genesis is usually multifactorial in cause (due to failure in ureteric bud or meanephric bud to form). There is no excretion of urine into the amniotic sac, resulting in decreased amnionic fluid and early rupture of membranes during gestation. This is associated with Potter’s Syndrome which also has facial abnormalities.

__Renal Duplication__ Supernumary kidney is an extra kidney on one side with two ureters. Two ureteric buds instead of one form during early development.

Supernumerary kidney with bifid ureters is usually caused by complete division of the ureteric bud.


 * 9. Explain the formation of a "horseshoe" kidney and its positional relationship with surrounding organs and vessels.**

Horseshoe kidney is a U-shaped kidney in the pelvis. The inferior poles are fused together to form one U-shaped kidney. The kidney starts to ascend but gets held up by the inferior mesenteric artery so its stuck in the pelvis.


 * 10. Define/describe/relate polycystic kidney to its morphology and pathogenesis.**

Polycystic kidney disease is characterized by numerous cysts throughout the kidney containing clear fluid or blood and is prone to recurrent infections. A gene mutation in PDK-1 or PDK-2 on the 16th chromosome causes epithelial hyperplasia and cyst formation.

PDK-1 mutation results in autosomal dominant polycystic kidney disease and presents later in life (4-5 decade). Mutation in PDK-2 results in autosomal recessive polycystic kidney disease and presents at childhood.

It is postulated that the mutation affects the cilium of the kidney epithelial cells. Normally, these non-motile cilia detects movement of fluid and flux through the tubules. Somehow, the mutation causes the cilium to stop detecting fluid movement and results in signaling proliferation of epithelial cells that form cysts.


 * 11. Explain the formation of ureters, renal pelvises, and calices. Explain the bifid ureter and common clinical findings associated with it.**

The initial part of the ureteric bud forms the ureter as an outgrowth of the distal mesonephric duct. Bifercation of the ureteric bud forms superior and inferior lobes and the renal pelvis. Then there are two sets of 4 bifurcations and fusions to produce the major and minor calyces. Bifurcation then continues to form the collecting ducts.

Bifid ureter can present with several congenital abnormalities of the kidney but are usually associated with the ureteric bud failing to divide completely. In a divided kidney with bifid ureter, the ureteric bud divides incompletely, resulting in the kidney having two pelvises with a ureter attached to both. Supernumerary kidney with bifid ureters is also caused by failure of the ureteric bud to completely divide.


 * 12. List and describe the developmental history of the 3 portions of the urogenital sinus. What definitive structures are derived from each?**

The urogenital sinus is formed from the cloaca as it is divided from the rectum by the urorectal septum. As a result, the epithelium of the lower urinary tract is derived from hindgut endoderm. However, the smooth muscle and connective tissue walls are derived from the surrounding mesenchyme. The urogenital membrane covers the inferior opening.

The urogenital sinus is subdived ito three parts: the vesical, pelvic, and phallic portions. The vestical part is superior and continuous with the allantois. The pelvic part forms the middle portion and the phallic part forms the inferior portion. Each part forms different definitive structures.


 * **Urogenital Sinus Portion** || **Male** || **Female** ||
 * Vesical Part || Most of the Bladder || Most of the Bladder ||
 * Pelvic Part || Membranous and prostatic urethra || Complete urethra (because its shorter) ||
 * Phallic Part || Proximal penile urethra || Vestibule of the vagina ||


 * 13. Explain how exstropy of the bladder occurs.**

When the septation of the cloaca is occurring, the mesonephric ducts with attached ureteric buds are incorporated to the posterior wall of the forming bladder by exstrophy (eversion of a hollow organ). This brings the opening of the ureteric buds into the bladder, effectively connecting the ureters to the bladder. The opened mesonephric ducts continue farther inferiorly to the opening of the urethra, forming a triangular area called the trigone on the posterior wall.

Defects in this process can misdirect the ureters into opening directly into the urethra in males or into the vestibule in females.

Extrophy of the bladder can occur when the anterior abdominal wall and anterior wall of the bladder fail to close. This results in the eversion of the urinary bladder on the surface with the posterior wall of the bladder protruding onto the abdominal surface. Occurs 1/10,000 – 1/40,000 births.


 * 14. Explain the development of the urethra.**

In males, the //distal// portion of the penile urethra is formed by the glandular urethral plate; thus, it is derived from ectoderm and grows to merge with the urethra developing from the phallic portion. The proximal penile urethra has transitional epithelium, but the distal portion has stratified squamous mucosal type eptithelium because of this change in embryological origin.

In the female, the complete urethra is derived from the pelvic part of the urogenital sinus. This is because the female urethra is much shorter than the male urethra.


 * 15. Be able to relate the timing and chronology of above events to each other.**

__4th Week__
 * Pronephric kidney develops early and degenerate.
 * Mesonephric kidney mesonephros and associated mesonephric ducts develop around the 4th week.
 * Ureteric bud of the metanephric kidney being to form as an outgrowth of the distal mesonephric duct.
 * Ureteric bud bifurcation begins.

__5th Week__
 * Cranial mesonephric excretory units begin to degenerate.
 * Metanephric kidneys being development.

__6th Week__
 * Longitudinal rods of the mesonephric duct reach the ventrolateral walls of the cloaca and being canalization during the middle of the 6th week.
 * Mesonephric excretory units functional from 6-10th week.
 * Ureteric bud has bifurcated into superior and inferior lobes separated by sulcus. The first set of 4 bifurcations and fusion occurs to form the major calyces

__7th Week__
 * Ureteric bud initiates the second set of 4 bifurcations and fusion to form the minor calyces

__9th Week__
 * Metanephric kidney “ascension” and 90 degree medial rotation completes, placing the kidney in the normal adult position (T12-L3).

__10th Week__
 * Mesonephric excretory units no longer functional and have degenerated; in males, the mesonephric ducts forms part of the male genital duct system.
 * Metanephric kidney reaches adult configuration.

__16th Week__
 * Ureteric bud has bifurcated into 14-16 lobes.

__32nd Week__
 * The Ureteric bud completes its bifurcation process, forming 1-3 million collecting ducts.