Development Of Kidney
The kidneys develop from the intermediate mesoderm, which is located on each side of the embryo between the paraxial (somitic) and lateral plate mesoderm. After the fourth week, during which the embryo undergoes a complex folding process, the intermediate mesoderm forms a lateral nephrogenic cord and a medial genital (gonadal) ridge. The nephrogenic cord gives rise to three successive kidney precursors, while the genital ridge gives rise to the gonads.
The three kidney precursors known as the pronephros, mesonephros, and metanephros, in order of appearance develop in a cranial-to-caudal sequence along the nephrogenic cord. Although the pronephros and mesonephros completely regress in utero, they are nonetheless essential for the normal development of the metanephros, which becomes the deﬁnitive kidney. The pronephros and mesonephros can be viewed as intermediate structures in the historical evolution of the kidney because they have more important roles in organisms such as ﬁsh and amphibians.
Many signaling pathways have been found to play roles in the development of the kidneys, with the already expansive list growing on a regular basis. A detailed discussion of these pathways, however, is beyond the scope of this text, which will instead focus on the anatomic changes that occur during development.
At the start of the fourth week, the cervical portion of the nephrogenic cords undergoes mesenchymal-to-epithelial conversion to form the paired pronephric ducts, which grow in a caudal direction. A series of pronephric tubules appear medial to the ducts and connect them to the coelom, the precursor to the peritoneal space. These tubules constitute the paired pronephroi.
A glomerulus-like structure, known as the glomus, projects from the dorsal aorta into the coelom. The glomus produces ﬁltrate, some of which enters the pronephric tubules and then passes into the pronephric ducts. The pronephric ducts, however, are blind-ended. Thus the pronephroi are not functional excretory organs during human development.
As the paired pronephric ducts continue to grow in a caudal direction, the pronephric tubules degenerate, becoming completely absent by day 25 of gestation. At the same time, however, the growing pronephric ducts continue to grow toward the caudal end of the embryo. These ducts, which become known as the mesonephric (wolfﬁan) ducts, induce the formation of about 40 pairs of mesonephric tubules from the dorsolumbar region of the nephrogenic cords. These tubules constitute the paired mesonephroi.
Each mesonephric tubule receives ﬁltrate from a glomerulus, which receives blood from a branch of the dorsal aorta and drains blood to the posterior cardinal vein. Some tubules drain urine into the mesonephric ducts.
Around the twenty-sixth day of gestation, the mesonephric ducts fuse with the cloaca, the precursor of the urinary bladder. At this point, the mesonephroi become functional excretory organs. The mesonephric tubules degenerate over subsequent months, however, and are almost completely absent by the fourth month of gestation. A small subset, however, persist into adulthood. In males, some of the most caudal tubules form the efferent ductules of the testes. Meanwhile, in females, some of the tubules form vestigial structures known as the epoophoron and paroophoron.
The paired metanephroi are the precursors of the deﬁnitive adult kidneys. They begin to form around the twenty-eighth day of gestation, shortly after the mesonephric ducts have fused with the cloaca. The caudal portion of each mesonephric duct sprouts a small diverticulum known as a ureteric bud. Each bud then grows toward a nearby mass of mesoderm known as the metanephric mesenchyme, which is located at the sacral end of the ipsilateral nephrogenic cord.
Once each ureteric bud enters its associated metanephric mesenchyme, it begins a process of iterative bifurcation that gives rise to the urine collecting system. The ﬁrst eight bifurcations of the ureteric bud give rise to the renal pelvis, major calices, and minor calices. These initial divisions later fuse to a considerable extent, resulting in the deﬁnitive appearance of the pelvicaliceal system. The next dozen bifurcations give rise to the collecting duct system.
As the collecting ducts are being formed, the sur- rounding metanephric mesenchyme differentiates into nephrons, each consisting of a glomerulus, proximal tubule, thin limb, distal tubule, and connecting tubule. The ends of these nephrons fuse with the developing collecting duct system. Throughout this process, the ureteric bud and metanephric mesenchyme provide essential inductive signals to one another. Thus, if either one is absent, the metanephros will not develop. The ﬁrst phase of nephron formation begins around the sixth or seventh week of gestation. The tips of the branching ureteric buds, known as ampullae, induce the condensation of adjacent mesenchymal cells. Some of the mesenchymal cells form caps over the ampullae, while others form clusters just lateral to the ampullae.
The clusters, also known as pretubular aggregates, are the nephron precursors.
Each pretubular aggregate undergoes mesenchymal- to-epithelial conversion to form a hollow vesicle. The proximal end of each vesicle fuses with the adjacent ampulla, the precursor of a collecting duct. Meanwhile, the distal end of each vesicle invaginates to form a cleft, the precursor of Bowman’s capsule. The formation and subsequent deepening of the cleft causes the vesicle to become a comma-shaped and then S-shaped body. The cells lining the inner part of the cleft are the precursors of the visceral epithelial cells (podocytes), while those lining the outer part are the precursors of the parietal epithelial cells.
In the S-shaped stage, endothelial cells appear within the cleft and become ﬂattened and fenestrated. The developing podocytes send foot processes over the endothelial cells, and the podocyte basement membrane fuses with that of the endothelial cells, forming the three-layered glomerular basement membrane. Mesangial cell precursors, derived from the metanephric mesenchyme, enter the cleft and form the scaffolding for the developing glomerular capillaries. Throughout this process, the entire primitive nephron lengthens, giving rise to distinct proximal and distal segments.
The second phase of nephron formation begins at approximately the fourteenth week of gestation. During this phase, the ampullae grow outward toward the cortex without further division. As nephrons form adjacent to the growing ampullae in the manner described previously, older nephrons attach to the connecting tubules of newer nephrons rather than directly to the ampullae. This process gives rise to nephron arcades, all joined by a single connecting tubule to a collecting duct. These nephrons become the long-looped (juxta-medullary) nephrons in the mature kidney.
The third phase of nephron formation begins at approximately the twentieth week of gestation. During this phase, the ampullae continue to grow toward the cortex without further division; however, as new nephrons are formed, they retain their individual attachments to the collecting duct system. These nephrons become the short-looped (cortical) nephrons in the mature kidney.
After the thirty-sixth week of gestation, no new nephrons form, but the existing nephrons continue to undergo structural changes. For example, portions of the proximal and distal tubules become increasingly tortuous and convoluted, while the loops of Henle grow deeper into the medulla.
The metanephroi begin to produce urine at 9 weeks of gestation, even as active nephrogenesis is ongoing. Such urination becomes essential for maintaining a normal volume of amniotic ﬂuid. The placenta, how- ever, is the organ responsible for removing waste products from the fetus.
The fetal kidney has a lobated surface appearance, which can be attributed to condensations of metanephric mesenchyme around the initial branches of the ureteric buds. This surface lobation, however, usually disappears around 4 or 5 years of age, as additional tissue ﬁlls in the sulcated areas. If fetal lobation persists into adulthood, it is an inconsequential anatomic variant; however, such lobations may be sometimes mistaken for cortical scarring.