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.
Pronephros
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.
Mesonephros
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.
Metanephros
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.
