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I./1.2.: Embryonic development of kidney
(Dr. Nándor Nagy)
I./1.2.1.: General features
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The kidney and ureter develop from the intermediate mesoderm (gono-nephrotome, urogenital plate) connecting the axial and lateral mesoderms of the embryo. In higher vertebrates, development of the uropoetic organ occurs from three, partially overlapping, primordia: pronephros, mesonephros and metanephros.
These primordia were named after their position occupied along the cranio-caudal axis, and according to the time of their onset. During the development of the human embryo, the first anlage to appear is the most cranial pronephros, which is not functional in humans and soon regresses. The mesonephros of intermediate position is functional as an excretory organ only for a short period, however, one part of it (Kupffer duct) participates in the development of the kidney and the ureter. Finally, the most caudal metanephros gives rise to major part of the definitive kidney.
I./1.2.2.: Pronephros
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Pronephros is the kidney type of jawless vertebrates (Agnatha, including lampreys and hagfish). In humans, it appears in rudimentary form in the level of cervical somites 2-6, arising from the intermediate mesoderm. Segmentation characteristic for somites extends, exceptionally, also to the intermediate mesodermal tissue of this cervical region, forming the anlages termed pronephric nephrotomes. Caudally from cervical somite 6, the nephrotomes are already packed too closely to reveal any segmentation.
Through epithelial transdifferentiation of the mesoderm of nephrotomes, the pronephric anlage begins to develop on embryonic day 21, followed by development of pronephric swelling and its caudal prolongation: the pronephric duct. The pronephric swelling gives rise to primitive external glomeruli, invaginating into the celom. In the lowest part, the tissue of nephrotomes gets penetrated by vessels from the aorta, to form internal glomeruli, similar to those of the mesonephros and metanephros of later stages. These glomeruli soon (by the end of embryonic week 4) undergo regression together with the collecting and excretory ducts of pronephric origin. However, the caudal part of pronephric duct persists as the initial segment of the Wolffian duct, to play a decisive role in later stages of renal development.
I./1.2.3.: Mesonephros
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The next stage of renal development is mesonephros which starts to develop already at the time of the existing pronephros. Both the mesonephros and mesonephric duct arise from a set of intermediate mesodermal segments collectively termed unitary mesonephrogenic cord, extending from the somite of C6 to that of L3. On week 4 of embryonic development, the cells of mesonephrogenic cord aggregate under induction of the pronephric duct, and then they give rise to mesonephric vesicles with a lumen inside. The mesonephric vesicles come in contact with the laterally placed pronephric duct via tubules with epithelial lining, and, after fusing with it, they give rise to the Wolffian duct (mesonephric duct).
Like double sided cups, the medial ends of mesonephric tubules enclose the capillary loops arising from the aorta, and they form glomeruli. The epithelium of the mesonephric duct engulfing the capillary loops turns into the Bowman's capsule. Although differentiation of metanephric glomeruli is more advanced than that of pronephric glomeruli, yet development of the mesonephros is regressive, ending up in a rudimentary organ before the onset and function of the definitive kidney (metanephros), i.e. by the end of the second month. Nevertheless, the Wolffian duct escapes regression and, growing in a caudal direction, it opens into the cloaca, participating in the formation of several parts of the urogenital system.
I./1.2.4.: Metanephros
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The third stage of renal development is represented by the appearance of metanephros or definitive kidney, which starts to develop on embyronic week 5, partly from the intermediate mesoderm of the region of lumbar somites 3-5 (metanephrogenic mesoderm), and partly from the ureteric bud arising from the Wolffian duct. Thus, the tissues of metanephros originate from two separate primordia, coming in contact by a secondary process. Ureter, renal pelvis, calyces and collecting ducts derive from the ureteric bud, whereas nephrons are derivatives of the metanephrogenic tissue occupying the caudal part of intermediate mesoderm. Close to its caudo-dorsal entry to the cloaca, the Wolffian duct gives off the ureteric bud, growing gradually into the neighboring metanephrogenic mesoderm .
The latter produces the proteins HGF (hepatocyte growth factor) and GDNF (glial cell line-derived growth factor), which, by acting on the tyrosine kinase receptors Met and Ret, promote elongation and dichotomic branching of the ureteric bud. Mutation of the growth factors or receptors bring about anomalous development of metanephros. The ureteric bud penetrates the metanephrogenic anlage, boat-like swelling of its cranial end forming the renal pelvis. The tubular caudal segment of ureteric bud will correspond to the definitive ureter.
After being penetrated by the ureteric bud, the metanephrogenic tissue forms caps around the branching ureteric bud, giving rise, after rapid growth and further branchings, to the minor and major calyces of renal pelvis (primary and secondary branches), as well as to the collecting ducts (tertiary branches). The distal end of every primitive collecting duct can determine development of the surrounding metanephrogenic tissue. By inducive effect of the ducts, mesodermal cells differentiate into vesicles with epithelial lining (renal vesicles). A great deal of the molecular biological background of this complex developmental mechanism is known.
For example, the metanephrogenic mesenchyme can react to the inducive effect of ureteric bud only if it expresses the gene WT-1 (Wilms tumor suppressor 1; zinc finger transcription factor). In addition, this WT-1 gene regulates and maintains secretion of the growth factors GDNF and HGF in the metanephrogenic tissue. Nephrogenic competition of the metanephrogenic mesoderm is followed by alteration of extracellular matrix proteins and cell adhesion molecules; appearance of laminin (characteristic for epithelial cells), collagen type IV and, on the surface of mesenchymal cells, expression of the adhesion molecules syndecan and E-cadherins, necessary for condensation and epithelial transformation of these cells.
The renal vesicles tranform into S-shaped tubules. One end of these grows around the capillary glomerulus like a cap, and differentiates into a nephron. At the proximal end of nephrons, the epithelial cells of the tubular cap form the Bowman's capsule, while the distal end gives rise to uriniferous tubules. Continually growing segments of these tubules form the proximal convoluted tubules, loops of Henle and distal convoluted tubules. In the beginning, the uriniferous tubules are not connected to the excretory duct system but later the cell layer separating them gets perforated, enabling the passage of urine.
The anlage of metanephros begins to grow in the pelvic region under the bifurcation of aorta. With later growth of the lumbosacral region, the kidneys ascend into the abdomen (ascent of kidney). In the course of this migration, vascular supply undergoes changes (see also previous chapter). In the beginning, it comes from the pelvic rami of the aorta and then, toward the end of migration, new vessels arise from higher segments of the aorta, while the lower ones tend to regress.
I./1.2.5.: Developmental disorders of the kidney
I./1.2.5.1.: Displacement of the kidneys
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Several malformations occur due to abnormal development of the kidney. For example, the kidney may lie outside of its normal position (between the12th thoracic and the third lumbar vertebrae): in other other parts of the abdomen (dystopic kidney, dystopia renis) or in the lesser pelvis (pelvic kidney). This disorder, caused by deficiency or failure of cranial growth of the ureteric bud and the ascent of kidneys, is often accompanied by distorsion of the kidney, i.e. the hilum is directed ventrally rather than toward the midline. Another example of abnormal migration of renal anlages: both kidneys are situated on the same side. The left or right anlage migrates to the other side during ascent.
I./1.2.5.2.: Horseshoe kidney, pancake kidney
Likewise, a disorder of ascent may give rise to horseshoe kidney (ren arcuatus) or pancake kidney. Mostly, horseshoe kidneys are situated caudally from the normal level because the bilateral renal anlages are drawn together by their blood vessels, leading to fusion of their lower poles (or total fusion, in the case of pancake kidney). The fused part of the poles of horseshoe kidney are termed isthmus, provided that it contains renal parenchyme. Ascent of the fused pair of kidneys can be blocked at the isthmus by the root of inferior mesenteric artery, emerging from the aorta. Vascular supply of horseshoe kidneys is highly variable, it may include, apart from the aorta, the inferior mesenteric artery (above the isthmus) or the common iliac artery (laterally). A common developmental disorder, prevalence of the horseshoe kidney is 1:600 live births, twice as frequent in boys.
I./1.2.5.3.: Polycystic kidney disease
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The most severe congenital developmental disorder of the kidney, polycystic kidney disease occurs once in every 800 newborn infants. A polycystic kidney gradually ceases to function because the parenchyme is getting filled by hundreds of thousands of continually growing vesicles (called cysts), which overgrow intact parenchyme by taking the place of nephrons. Polycystic kidney occurs mostly in an autosomal dominant form, caused by mutation of the genes (PKD-1 and PKD-2) encoding the proteins polycystin-1 and -2. Polycystin proteins participate in the proliferation and differentiation of nephrons. Mutation of these proteins leads to the formation of cysts.
I./1.2.5.4.: Numerical variations
The size of fully developed kidney may be smaller than normal (renal hypoplasia) or greater than normal (renal hyperplasia). Lack of kidney on both sides (bilateral renal agenesis) or one side (unilateral renal agenesis) can also occur. Supernumerary kidneys may be generated from the metanephrogenic mesoderm as a result of induction by the split ureteric bud. Renal triplicity (three kidneys) means development of two kidneys on the same side. Bilateral congenital renal agenesis or aplasia is a non-viable disorder occurring 1 in every 3000 newborn infants. Since both kidneys are missing, there is no excretion of urine in the fetus, leading to oligohydrammnios. Unilateral renal agenesis is not infrequent, usually without symptoms, occurring in about 0.1% of adult population.
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The disorders involving lack of kidney can be ascribed to failure of interaction between the ureteric bud and metanephrogenic tissue. In most cases, the ureteric bud is missing, too, but it is also possible that, although the ureteric bud is present, it fails to induce development of the kidney. In normal cases, the growth factor GDNF arising from metanephrogenic mesoderm acts on the RET receptor of the cells of the ureteric bud, promoting and maintaining growth and branching of the ureteric bud. This explains the fact that 50% of all renal agenesis cases are elicited by mutation of GDNF or RET genes. Renal agenesis is often accompanied by malformations of the ureter or the genital and other organs. Ectopic development of the growth factor GDNF may also lead to the formation of supernumerary renal anlages.
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