Introduction
The development of the urinary tract begins with the formation of the nephrogenic cord in week four, along which the pronephros, mesonephros and metanephros form. Although the metanephric kidneys act as functional excretory units as early as week eleven, nephrogenesis is not complete until week thirty-two when multiple branching events have formed one to three million collecting tubules. Complex orchestrated interactions between various embryonic tissues, the mesonephric duct, ureteric bud, and metanephric blastema ensure the correct development of the urinary tract. Disruptions to these intricate signaling pathways, either genetic or environmental, result in congenital abnormalities of the kidney and urinary tract (CAKUT) including renal agenesis and dysplasia, multicystic dysplastic kidney disease and polycystic kidney disease.
Development
Kidney Development
Embryonic folding during the fourth week of development marks the beginning of the urinary tract with the formation of a longitudinal mass known as the urogenital ridge. The ridge can divide into parts depending on the system it forms; the nephrogenic cord will form the urinary tract while the gonadal ridge will develop into the reproductive system. Beginning rostrally and progressing caudally, three kidneys will form over a few weeks within the nephrogenic cord: pronephros, mesonephros, and metanephros.
Pronephros development begins in the fourth week; however, they will not form functioning kidneys in humans. Pronephric ducts develop in the cervical region of the nephrogenic cord before extending and fusing with the cloaca. Adjacent to the pronephric ducts, the intermediate mesoderm will condense to form non-functional nephron units, known as pronephroi, which will regress by day 25.
The mesonephric duct, also known as the Wolffian duct, now begins development in the next most caudal region of the nephrogenic cord. Similarly, the adjacent intermediate mesoderm condenses to form mesonephroi. Although approximately 40 pairs of mesonephroi form, only those located between L1-L3 continue to differentiate to form functional excretory units.[1] Thus, approximately twenty nephrons form capable of excreting small amounts of fluid into the amnion between the sixth and tenth week of development. Similar to the pronephric duct, the mesonephros and mesonephric duct will later degenerate in females; however, in males, these embryonic structures persist and develop into the epididymis, vas deferens, seminal vesicles, and the ejaculatory duct.
The third and final kidney, the metanephric kidney, begins development during the fifth week and will continue to differentiate to form the permanent kidneys. The mesonephric duct extends to fuse with the cloaca, thus inducing the sacral intermediate mesoderm to form an aggregate known as the metanephric blastema. At the beginning of week five, the metanephric blastema secretes a protein known as glial-cell derived neurotropic Factor (Gdnf), thus inducing an outgrowth in the mesonephric duct known as the ureteric bud; Gdnf acts as a ligand for cell surface receptor RET and on its co-receptor, Gdnf Family Receptor alpha 1 (Gfr-alpha1) which are both strongly expressed in the mesonephric duct.[2]
During the sixth week of development, the ureteric bud begins a branching cascade which will subsequently create collecting tubules and the basic renal architecture. The first bifurcation occurs during the sixth week and forms the renal pelvis as well as the cranial and caudal lobes of the kidney. The next four bifurcations coalesce to form the major calyces, while the following four bifurcations coalesce in the seventh-week form the minor calyces. Branching gets induced by Gdnf acting on the RET expressing cells in the tips of the ureteric bud; each individual branch acquires a blastemal cap from which Gdnf gets secreted. This cascade continues until week 32, thus producing approximately 1 million to 3 million collecting tubules.[3]
Functional nephrons begin to develop when the tip of each collecting tubule induces the blastemal caps to form nephric vesicles. These will then develop into nephric tubules consisting of an S-shaped Bowman’s capsule, proximal and distal tubules, and the loop of Henle. Development of glomerulus begins when podocyte precursors lining the S-shaped body secrete VEGF2, thus attracting endothelial cells and generating a primitive vascular tuft [4]. This activity will form the afferent and efferent arterioles of the glomerulus. Contact between the podocyte precursors and the endothelial cells stimulate differentiation of podocytes, with the glomerular basement membrane forming at the boundary between the two. The distal end of the nephric tubule, the distal convoluted tubule, fuses with the collecting duct to form a uriniferous tubule.
During early development, the kidneys lie close together in the sacral region of the embryo. However, as the abdomen enlarges, the kidneys are drawn apart and ascend to their final position in the lumbar region between weeks six to nine. The kidneys receive vascular supply from branches of the dorsal aorta called renal arteries; during their ascent, the caudal branches degenerate, and the kidneys receive their blood from successively higher branches.
Bladder and Ureter Development
The development of the bladder begins during week four when the urogenital septum divides the cloaca into two parts, the rectum posteriorly and the urogenital sinus anteriorly. The urogenital sinus will continue to grow to form the bladder, with the inferior end forming the urethra. As the mesonephric duct fuses with the cloaca, part of the duct gets incorporated into the posterior wall of the bladder. Although the ureteric bud is an outgrowth from the mesonephric duct, it has a separate opening into the urinary bladder. As the kidneys ascend, the ureters elongate and open into the bladder superiorly, while the roots of the mesonephric ducts are carried inferiorly, before fusing to form the trigone region. Endodermal cells from the urogenital sinus soon replace the mesodermal cells epithelium of the trigone region, thus completing development.
Molecular Level
Recent studies have found three signaling molecules necessary for correct patterning of the kidneys: Lim1, Pax2/8, and Odd1. Lim1 is essential for proper patterning the pronephric duct, mesonephric duct, and mesonephros. Pax2 has been found to be a potent initiator of nephron development, therefore is the only molecule capable of specifying renal tissue wherever it gets expressed in the intermediate mesoderm and ectopically. Hence, Pax2/8 mutant embryos fail to express Lim1 and show a complete absence of kidney development.[5]
In addition to the Gdnf-RET pathway, Bone Morphogenic Protein 4 (Bmp4) and Gremlin regulate the development of the ureteric bud. Bmp4 released by the metanephric blastema suppresses ureteric bud development while stimulating ureteric stalk elongation. On the other hand, the ureteric bud secretes Gremlin, which inhibits Bmp4, thus ensuring it continues to develop. Therefore, these reciprocal interactions ensure that a single ureteric bud develops from each nephrogenic cord.[6]
Clinical Significance
Congenital abnormalities of the kidney and urinary tract (CAKUT) occur in approximately 1 in 500 live births and are responsible for 40 to 50% of childhood end-stage renal disease. Research has revealed known genetic causes of CAKUT, such as mutations in Pax2 and BMP4, but also highlighted several environmental factors such as maternal diabetes and intrauterine exposure to ACE-inhibitors. CAKUT encompasses a broad spectrum of disorders leading to abnormal development which are covered below.[7][8]
Renal agenesis is the congenital absence of renal tissue affecting one side (unilateral), or less commonly, both kidneys (bilateral). It is often associated with abnormalities of the heart, reproductive system in males, and the gastrointestinal tract.[9] Bilateral renal agenesis prevents the production of sufficient amniotic fluid, known as oligohydramnios, which leads to Potter’s Syndrome; these fetuses will display a range of physical abnormalities, most notably Potter’s facies, which includes low set ears, flattened nose, recessed chin, and infraorbital creases. Fetuses with bilateral renal agenesis are unlikely to survive and usually die within a few days of birth. However, children born with unilateral renal agenesis can survive as the remaining kidney undergoes compensatory hypertrophy. Research has shown a few genes associated with bilateral renal agenesis, including ANOS1, EYA1, and RET; however, further studies are necessary.[10]
Multicystic dysplastic kidney disease (MCDK) is characterized by impaired renal function due to the presence of irregular cysts on the affected kidney. It affects approximately 1 in 4300 live births worldwide and is more common in males. The majority of cases get diagnosed via a prenatal ultrasound. Fetuses with bilateral MCDK die in utero whereas those with unilateral MCDK are healthy and simply require regular imaging to monitor any size changes in the affected kidney. Occasionally a nephrectomy may be carried out to remove the affected kidney. The causes of MCDK are currently unknown, although it is thought to be caused by a defect in the genes involved in the Gdnf-RET signaling pathway between the ureteric bud and the metanephric blastema.[11]
Polycystic kidney disease (PKD) is a genetic disorder which causes fluid-filled cysts to form on the kidneys and progressively compromise renal function. There are two types of PKD, autosomal dominant PKD, and autosomal recessive PKD, with autosomal dominant PKD being the most common inherited kidney disease. Autosomal dominant PKD is thought to be caused by heterogeneous mutations in PKD1 in 85% of cases, with the remaining 15% due to PKD2 mutations.[12] Symptoms include abdominal pain, hypertension, and haematuria. However, individuals born with autosomal PKD do not tend to display symptoms until the cysts grow enough to disrupt normal kidney function; this tends to occur after the age of thirty. On the other hand, individuals with autosomal recessive PKD, caused by mutations in PKHD1, display symptoms shortly after birth. Up to 50% of affected neonates die due to pulmonary hypoplasia as a result of oligohydramnios; the remaining individuals have a shorter life expectancy and face other comorbidities including systemic hypertension and end-stage renal disease as they progress to adulthood.[13]
In addition to structural abnormalities of the kidney itself, failure of the kidneys to ascend can also result in malformations, the two most common being an ectopic kidney and a horseshoe kidney. An ectopic kidney, also known as a pelvic kidney, occurs when a kidney fails to begin or complete its ascent into its final position in the lumbar region. A horseshoe kidney occurs when both kidneys fuse at their inferior poles to form a U-shape, similar to a horseshoe, just below the inferior mesenteric artery. In both cases, the affected individual tends not to show symptoms, and only discovers it when they are having investigations for an unrelated health issue.
Embryology, Kidney, Bladder, and Ureter