Development of the Urinary System

The kidney develops from embryonic mesoderm in 3 successive forms from the nephrogenic cords as the cords elongate in a cranial-to-caudal direction.

Pronephros

• Appears in week 4 as a cluster of a tubule and a few cells (nephrotomes) 
• Develops in nephrogenic cords in the cervical region 
• Rudimentary and nonfunctional 
• Degenerates by the end of week 4 (persists < 1 week)
• Purpose unclear, though may be a “scaffold” off which the next structure (the mesonephros) develops

Mesonephros

• Begins to develop as pronephros regresses around week 5
• Most of the mesonephros regresses by week 10.
• Develops lower, in the thoracolumbar region
• Connects with the cloaca at the caudal end of the primitive gut tube
• Consists of:
  • A longitudinal mesonephric duct (also called the wolffian duct)
  • A series of tubules coming off that main duct, growing anteriorly toward the aorta 
• Small glomerular vessels grow posteriorly off the aorta toward the mesonephric tubules, forming primitive renal corpuscles:
  • Mesonephric tubules grow around the glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries, forming Bowman capsules (though these will ultimately regress).
  • Forms the primitive urinary system
• Filtration of blood begins: 
  • Blood flows down the aorta → glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries
  • Filtered through Bowman capsule 
  • Filtrate travels down the mesonephric tubule → mesonephric duct → cloaca → allantois
• Mesonephros is present only from weeks 5–10 (at which time the permanent kidney formed from the metanephros takes over).
• The mesonephric ducts persist in males and form part of the male reproductive system.

Metanephros

The permanent kidney is formed from the metanephros.

• Develops starting around the 5th week
• Cells in the intermediate mesoderm in the pelvic region begin to differentiate into a structure called the metanephric blastema, which:
  • Ultimately becomes the cells making up the nephrons
  • Releases growth factors that stimulate the development of an outpouching off the caudal portion of the mesonephric duct called the ureteric buds
• Ureteric buds grow toward and invade the metanephric blastema:
  • Elongating stalk of the ureteric bud develops into the ureter.
  • Within the metanephric blastema, the ureteric buds undergo a series of branchings to form the:
    • Renal pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis
    • Major calyces
    • Minor calyces
    • Collecting tubules
• Metanephric mesodermal cap: 
  • Mesoderm from the metanephric blastema sitting “on top of” the developing collecting ducts
  • Elongates, forming the tubular system The tubular system The kidneys regulate water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. After the filtration of blood through the glomeruli, the tubular system takes over and is responsible for adjusting the urine composition throughout the remainder of the nephron. The Tubular System of the nephrons → becomes known as the metanephric tubule
  • The metanephric tubule fuses with the collecting tubule, creating 1 continuous system.
• Bowman capsule: forms off the growing end of the metanephric tubule
• Glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries:
  • Develop off the common iliac arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries
  • Become associated with Bowman capsule at the end of the metanephric tubules → begin creating “urine” (Note: True waste products from the fetus are removed via the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity.)
• Nephrons are formed until birth.
• Nephron maturation continues after birth.

Position of the kidney and changes in vascularization

• The kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys are initially located in the pelvic region.
• As the caudal portion of the body grows downward, the relative location of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys “ascends” into the upper quadrants of the abdomen (failure to ascend results in a pelvic kidney).
• As the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys ascend, the original blood supply degenerates.
• New vessels (higher up) develop off the aorta and invade the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, becoming the mature renal arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries.
• If the original vessels fail to regress, they may persist as additional renal arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries or veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins.

Development of the bladder and urethra

Between the 4th and 7th weeks of development, the cloaca divides into:

• Urogenital sinus:
  • From the anterior portion of the cloaca
  • Connects to the ureters and mesonephric ducts
  • The urogenital sinus has 3 portions:
    • Proximal (largest) → urinary bladder 
    • Middle (narrow) → origin of prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands and prostatic and membranous urethra in males and the entire urethra in females
    • Distal → penile urethra in males
• Anal canal:
  • From the posterior portion of the cloaca
  • Connects to the developing hindgut
• Urorectal septum: 
  • Separates the urogenital sinus from the anal canal 
  • Starts at the superior/proximal portion of the cloaca → grows distally until it reaches the outside of the body, where it becomes the perineal body
  • Failure of the septum to form correctly can result in fistulas between the urogenital system and the anorectum.
• The allantois (drains the cloaca through the umbilical cord) → ultimately turns into the median umbilical ligament

Clinical Relevance

Disorders of urinary development

• Horseshoe kidney: developmental defect of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys in which the inferior poles are fused together. As the kidney attempts to migrate superiorly during development, it is blocked by the superior mesenteric artery. The vascular supplies and collecting system of the kidney also tend to have various degrees of distortion. Individuals are typically asymptomatic, with incidental diagnosis made on imaging. Other presentations include infection, obstruction, hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis, and calculi. 
• Duplications of the collecting system: known as a “duplex system.” Duplications of the collecting system are the most common congenital anomaly of the urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract. In these cases, a kidney will have 2 separate pelvicaliceal systems and 2 ureters. Ureteral insertion into the bladder from the duplicated system is often abnormal as well. Most individuals are asymptomatic, though recurrent urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections (UTIs) or obstruction may occur.
• Renal agenesis: congenital absence of a kidney, specifically, renal parenchymal tissue. This absence results from disruption of metanephric development. Most individuals are asymptomatic (because they have another normally functioning kidney) and are diagnosed incidentally on imaging. Renal agenesis is often associated with additional congenital anomalies.
• Posterior urethral valves: persistence of the urogenital membrane, resulting in urethral obstruction in males. Affected infants often present in utero with severe bilateral hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis seen on ultrasonography that causes pressure necrosis of renal tissue and CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease in these children. There is a high likelihood that renal transplantation will be necessary.
• Urachal fistula: persistence of the urachus. The urachus is known as the allantois earlier in development, and it connects to the bladder. Babies with a urachal fistula may leak urine from their umbilicus at birth.

Congenital anomalies of the reproductive system

• Gartner duct cysts: benign cysts that can be seen on either side of female reproductive organs (typically the upper vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor). These cysts represent remnants of the mesonephric ducts and are usually asymptomatic.
• Müllerian anomalies: abnormal fusion of the müllerian/paramesonephric ducts can result in a variety of uterine, cervical, and vaginal anomalies. Individuals are often asymptomatic, though they may present with infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility or issues related to menstruation.

• Hymen anomalies: The hymen is the membrane where the vaginal plate met the urogenital sinus. Normally, the hymen ruptures prior to birth, however a number of anomalies are possible. An imperforate hymen will not allow efflux of any uterine fluid, and it typically presents with pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain at the onset of menses. Management is surgical.

• Hypospadias: congenital anomaly of the male urethra that is characterized by an abnormal location of the urethral meatus on the ventral surface of the penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis. The meatus may be located anywhere on the glans, penile shaft, scrotum, or perineum.

Disorders of sexual development

Disorders of sexual development (DSDs) are a group of conditions characterized by atypical sexual development in an individual, which may involve abnormalities in the structure and/or function of the internal reproductive organs and/or external genitalia. 

• Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia: Increased formation of male sexual hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview ( androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens) with virilization of the external female genitals. Characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia.
• Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome (AIS): Mutations in the androgen receptors cause partial or complete resistance to testosterone. Genotypically, affected individuals have a 46,XY karyotype and testes present internally. Testosterone levels are elevated, and some of this testosterone is converted to estrogen peripherally. Clinically, individuals with complete AIS will present with no sexual hair and have normal-appearing external female genitalia. Individuals are usually assigned female gender at birth and will present at puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty with amenorrhea.
• Aromatase deficiency Aromatase deficiency Aromatase deficiency is a very rare genetic condition with autosomal recessive inheritance. Aromatase deficiency is characterized by congenital estrogen deprivation with increased levels of testosterone due to decreased levels of the aromatase enzyme. Aromatase Deficiency: results in an inability to convert testosterone to estrogen, primarily causing virilization of the external genitalia in females.
• 5α-reductase deficiency:  autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder that impairs conversion of testosterone to DHT, preventing full development of the external genitalia in males. This disorder results in ambiguous genitalia in 46,XY individuals at birth. 
• Pure gonadal dysgenesis: results in nonfunctional gonads. In 46,XX individuals, pure gonadal dysgenesis presents with premature ovarian insufficiency (i.e., premature menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause) in otherwise normal-appearing females. In 46,XY individuals, the condition is known as Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome; without functional testes, testosterone and MIF are not produced, so individuals have external female genitalia and normal müllerian structures. Affected individuals present in adolescence with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and lack of all secondary sex characteristics.  
• Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome: Chromosomal aneuploidy characterized by the existence of ≥ 1 extra X chromosomes in a male karyotype (e.g., 47,XXY or 48,XXXY). Symptoms are not usually observed during childhood. During adulthood, individuals are typically tall males who present with gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility related to hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism. Educational difficulties are also common.
• Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome: chromosomal aneuploidy characterized by the absence of an X chromosome in a female karyotype (e.g., 45,X0). Clinical manifestations include a characteristic phenotype (short stature, webbed neck, widely spaced nipples) and multiple anomalies usually involving the cardiac, renal, reproductive, skeletal, and lymphatic systems. Gonadal dysgenesis and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility are likely.
• True hermaphroditism True hermaphroditism True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. True Hermaphroditism: presence of an ovotesticular gonad that contains both ovarian and testicular elements. Affected individuals are usually born with ambiguous genitalia, and the internal structures depend on the adjacent gonadal tissue. The most common karyotype is 46,XX.