Urogenital disorders

I./1.3.: Developmental disorders of the uropoetic system and urinary passages

I./1.3.1.: Malformations of the kidney

About 3-4 % of all live births suffer from malformation of the kidney, brought about by various factors. Such factors can be of environmental origin (pharmaceuticals, chemicals), inherited (gene mutations, chromosomal aberrations), or diseases occurring during pregnancy.

Disorders of the kidney are extremely variable and often are combined with defects of other organic systems. Not infrequently, disorders of genital organs (vagina, uterus, vas deferens, seminal vesicle), adrenals, heart, brain and face are associated with those of the kidneys. Based on embryological factors, the malformations of the kidney belong to the following categories: numerical, parenchymatous, posititional, rotational, formational and fusional and vascular disorders.

I./1.3.1.1.: Numerical disorders

Congenital and bilateral lack of kidney (renal aplasia or agenesis) is a non-viable disorder, with prevalence of 1:3000 newborn infants. Lacking kidney on both sides, fetal excretion is absent, leading to olygohydramnios. Owing to bilateral renal agenesia and oligohydramnios, the fetus is compressed, with thoracic deformities, positional disorders of foot and hand and dislocation of the hip. The infants are small, with hypoplasia of lung and typical features characteristic for craniofacial malformations (wide-set eyes, flattened nose, collectively termed Potter sequence). The infants die within 24-48 hours due to pulmonary hypoplasia.

Unilateral renal agenesis occurs in ca. 0.1% of adult population, usually without symptoms. Concomitant aplasia or malformation of genital organs or the adrenal gland can be observed in about 10% of patients.

Renal agenesis can be explained by failure of inductive interaction between the ureteric bud and metanephrogenic blastem. The main reason is lack of ureteric bud but it is also possible that the ureter develops normally, yet an induction of kidney development fails. Normally, the cells of metanephrogenic blastem secrete the growth factors GDNF and HGF, interacting with the Ret and Met receptors of the ureteric bud. Such molecular interaction induces the growth of ureteric bud, and promotes its being embedded into the metanephrogenic mesoderm and dichotomic branching. Mutation of the genes involved in GDNF-Ret signal transduction can cause renal agenesis. The latter is often accompanied by developmental disorders of the ureter, genital and other organs.

Congenital supernumerary kidneys may derive either from the outgrowth of multiple ureteric buds, or, due to splitting of ureteric bud, several nephrogenic regions differentiate separately from the metanephrogenic mesoderm. For example, renal triplicity (three kidneys) means that two kidneys develop on one side. These supernumerary kidneys possess separate capsule and vascular supply, in addition to a supernumerary ureter.

I./1.3.1.2.: Developmental disorders of the renal parenchyme

Renal hypoplasia means that the kidney is smaller than its regular size by 50% and less than five calices are formed. This malformation is mostly free from symptoms and is detected only because of recurrent urinary infections. Hypoplasia on one side is usually compensated by hyperplasia of the other kidney. Prevalence of renal hypoplasia is 1%. The likely cause of congenital hypoplasia is the formation of a ureteric bud of aberrant origin. The amount of metanephrogenic tissue around the ectopic ureteric bud is insufficient to form a normal kidney; therefore, a vestigial uropoetic organ develops. In the kidneys of smaller size, a meshwork of interconnected mesenchymal areas and a lack of glomeruli and collecting ducts can be observed. A rarer disorder, hyperplasia renis means an enlargement of kidney due to an increased number of renal papillae. Cavities of varied size, lined by epithelium (cysts) occur very frequently in the kidney. Only traces of normal tissue are present around the multicystic or polycystic areas filling the renal parenchyme. Occasionally, the size of solitary cysts can exceed that of the renal pelvis. Similar to solitary cysts, multicystic kidneys are usually unilateral. Cystic kidneys occur more frequently in males, mainly in the left kidney. Bilateral cystic kidney is considered incompatible with viability.

A severe developmental disorder of the kidney, congenital polycystic kidney disease, occurs in the form of autosomal dominant disorder, 1:800 newborn infants, caused by mutation of the genes encoding polycystin-1,-2 (PKD-1 and PKD-2). Polycystin proteins participate in the cell proliferation and differentiation accompanying formation of the nephrons. Formation of the polycystic kidney involves irregular development of the metanephrogenic tubular system and the collecting ducts of ureteric bud origin. The tubules fail to come in contact with the ducts arising from the ureteric bud, preventing normal drainage of urine.

Owing to retention of urine, cysts of varied size (from a few mm to several cm) with an epithelial lining appear in the place of glomeruli. As a results, the size and weight of the kidney are also enhanced. Due to the increasing number and diameter of cysts, the parenchyme of the kidney gets damaged, followed by weakness and, eventually, failure of function. Polycystic kidney is often associated with disorders of the liver, lungs or cystic anomalies of pancreas.

A rare congenital disease, medullary sponge kidney represents cystic dilation of medullary collecting ducts. Usually both kidneys are affected, and the disease involves the formation of cysts with epithelial lining, filled with yellowish extracellular fluid, in the region of one or more papillae.

I./1.3.1.3.: Positional disorders of kidney (dystopia renis)

During embryonic development the definitive kidney that has developed in the lesser pelvis migrates in a cranial direction to the abdominal cavity (ascent of kidney). Premature cessation or failure of ascent, as well as caudal or contalateral displacement may bring about different positional anomalies of renal development. Thus, the kidneys come to lie outside of their normal location (between the levels of thoracic vertebra 12 and lumbar vertebra 3), instead, they are situated in other regions of the abdomen or (usually) in the pelvis. By their location, sacral, lumbar and (rarely) thoracic dystopiae renis can be distinguished. In the case of sacral or thoracic dystopias, the kidney is situated in front of the sacrum or above the diaphragm, respectively.

Vascular supply of dystopic kidneys varies according to their position, it may arise from the common iliac or external iliac arteries, or even from the inferior mesenteric artery. Abnormal situs of renal anlages may be due to anomalous direction of the growth of the ureteric bud; migrating to the contralateral side, both kidneys develop on the same side (crossed dystopia). The latter is three times more frequent on the left side and, in 90% of cases, it involves fusion of the kidneys lying on top of each other. This anomaly often involves also a rotation of the kidneys, i.e. the hilum is directed forward rather than toward the midline. A very rare anomaly is symmetric crossed dystopia, which develops as a result of induction by the ureteric buds migrated to the contralateral side.

I./1.3.1.4.: Disorders of the fusion and formation of kidneys

Fusional disorders mean that the bilateral renal primordia merge into a single organic mass. In the case of cross-migrating kidneys, the primordia on top of each other undergo fusion, to form a columnar kidney. In such cases, by default of fusion of ureters, two separate ureters develop. The most characteristic form of merger of the kidneys is termed horseshoe kidney (ren arcuatus), arising from bilateral and asymmetrical primordia. This malformation takes place, when cranial growth of the ureteric bud and ascent of the kidneys are incomplete or failed. A frequent malformation, horseshoe kidney occurs in 1:600 newborn infants, its prevalence being twice as high in boys.

As evidenced by recent experiments on transgenic model animals, the site of developing renal blastema is determined by the growth factor named sonic hedgehog, produced by the notochord and the basal plate of neural tube. Following ablation of the notochord, or in sonic hedgehog knockout mutant mice this regulator molecule is missing, leading to the formation of horseshoe kidney. Usually, horseshoe kidney develops caudally from the normal level because the bilateral renal primordia fuse at their inferior pole (if they merge completely in the midline, it is termed pancake kidney).

The interconnected segment of the fused poles is called the isthmus, if it also contains renal parenchyme. Ascent of the fused pair of kidneys can be blocked at the isthmus by the inferior mesenteric artery emerging from the aorta. Arterial supply of horseshoe kidneys is highly variable; apart from the aorta, the inferior mesenteric artery above the isthmus or the common iliac artery laterally may also contribute. The arteries and veins of both dystopic and fusioned kidneys show large differences. A frequent vascular anomaly, supernumerary (accessory, polar) arteries arising from the aorta may directly course to the superior and inferior poles of the kidney. Those aberrant arteries that originate from the renal artery and pass to the inferior pole may, by crossing the ureter, cause obstruction and subsequent distension of renal pelvis (pyelectasia).

I./1.3.2.: Developmental disorders of the ureter

The most common form of malformation is duplication of the ureters, affecting nearly 1% of all newborn infants. In the case of ureter duplex (duplicated ureter), two (rather than a single) ureteric buds start to develop from the mesonephric duct, and the supernumerary ureter, once developed, has a separate opening in the bladder. According to the developmental rule by Mackie-Stevens, the supernumerary ureteric bud of cranial origin (when not opening in the bladder) may have an ectopic ending in the urethra, ejaculatory duct, vas deferens or vagina (ectopia ureteris). Conversely, supernumerary ureteric buds of caudal origin tend to open in the bladder, albeit in abnormal position. Such cases always lead to vesicourethral reflux (see below).

Duplicated ureter may occur uni- or bilaterally, accompanied by proportional duplication of the renal pelvis. The course of supernumerary ureters and the orifices generated in the wall of the bladder are described by the rule of Weigert-Meyer; the orifice of the ureter arising from the more cranial pelvis is situated medially and caudally, whereas the orifice of the ureter belonging to the more caudal pelvis is found higher (cranially) and laterally. Should there be double ureters on both sides, the trigone can take on a trapezoid shape.

When the pair of ureters fuse on one side, ureter fissus (bifid ureter) develops. Here, only one ureteric orifice is present in the bladder, and, rather than passing to the bladder, urine may flow via the fusioned segment back into the other ureter (urinary reflux). Aplasia of ureter (congenital lack of ureter) may occur on both sides, due to failure or partial defect of ureteric development. A rudimentary ureteric bud, ending blind, can lead to renal agenesis.

Another common malformation is constriction of the ureter at the border of renal pelvis. Due to this constriction, the passage of urine is strongly reduced, leading to stagnation. The segment above the narrowing gets distended, with enlarged musculature and gradually decreasing excretion of urine (glomerular filtration). The pelvis and calices merge into a uniform cavity, the kidney parenchyme gets thinner, gradually regressing, and finally a saccular structure filled with urine takes the place of kidneys (hydronephrosis).

Ureterokele (herniation of ureter) represents a cystic mucosal bulge of the terminal ureteric segment, which narrows the ureteric orifice, thereby hampering or obstructing the flow of urine. In a progressive stage, this may lead to abnormal distension of the ureter and renal pelvis. Ureteric stenosis, caused by malformation (hypoplasia) of the smooth muscle in the wall of ureter, can also give rise to obstruction of urinary passage.

A rare form of developmental disorder, prolapse of ureter (IMAGE) is caused by bulging smooth muscle layers of the bladder wall and distal ureter, leading to obstruction. This disorder is usually associated with other anomalies such as duplicated ureter or megaloureter. Congenital swelling of the ureter (megaloureter) occurs mostly in the lower segments but, in severe cases, robust swelling of the entire ureter can also be observed. Megaloureter can be explained, first of all, by defective development of the smooth muscle in the wall of ureter, also involving enlargement of connective tissue layers. Thus, owing to muscular weakness, megaloureter is characterised by the lack of peristalsis, also giving rise, sooner or later, to disturbance of the passage of urine.

Megaloureter may also be caused by ureteric orifice of abnormal shape, or by developmental disorder of the trigone. A compound developmental disorder of the ureteric orifice, terminal segment of ureter and the musculature of trigone is termed congenital vesicoureteric reflux. Under normal conditions, reflux of the urine from the bladder into the ureter or the kidney is prevented by the valve-like ureteric orifice, blocking the way from high pressure of the bladder or from ascending infections. Developmental disorders of the ureteric orifice may cause vesicoureteric reflux, i.e. there is continuous backflow of urine from the bladder into the ureter or the renal pelvis, leading to hydroureter and hydronephros.

I./1.3.3.: Developmental disorders of the urinary bladder and the urethra

These malformations often involve not only the bladder and the urinary passages but also the entire caudal region of the embryo. Exstrophy of the bladder (open, extra-abdominal bladder) is a compound disorder, occurring 1:30 000-50 000 live births, three times more frequently in boys.

This disorder results from failure of fusion of the ventral body wall, and from combined malformations of the urogenital sinus, cloaca membrane, umbilicus and pelvis. The disorder is characterised by an open abdominal defect stretching from the umbilicus to the symphysis, with a concomitant lack of the ventral bladder wall. The ureters open freely onto the abdominal wall. Ectopia vesicae involves fission of the pelvic wall around the symphysis, whilst the bladder remains closed although it is adherent to the ventral body wall.

Of the malformations of the bladder, total lack of bladder (agenesis of bladder) is very rare and is always associated with other severe defects incompatible with viability. The ureters tend to end blind in the lesser pelvis. Hypoplasia of bladder means the development of a vestigial bladder from the urogenital sinus. Partial or total duplicated bladder is another rare disorder. Partial duplication of bladder is brought about by invasion of a sagittal connective tissue septum, whereas total duplication of bladder can be accompanied by duplication of the urethra.

Diverticulum (outpocketing) of bladder is a disorder caused by saccular evagination of the bladder mucosa near the ureteric orifices. Given their position in the vicinity of the ureters, such diverticula can affect ureteric function, too.

Congenital disorders of the urachus occur twice as frequently in males. Patency of the urachus (connective tissue cord remaining from regressing cloaca and allantois) persists in 70% of newborn infants because the cavities with epithelial lining of urachus and bladder come in contact. Failure of closure of the urachus leads to an urachus fistule. This means that communication between the bladder and the navel remains open through the previously existing allantois, resulting in urination through the navel. Should the distended cavity with epithelial lining persist only in the vicinity of the bladder, the name of the disorder is urachus diverticulum. Conversely, those isolated swellings of the lower one-third of the urachus, which do not communicate with the bladder are termed urachus cysts.

Dorsal urethral valve is a frequent disorder of the lower urinary passage, with an incidence of 0.5-1:10000, only occurring in boys. A valve-like mucosal fold in the dorsal urethra, it obliterates the passage of urine, also causing stagnation and, potentially, other disorders of the ureter and kidney. Urethral stenosis or deficiency of a larger urethral segment may also cause hindrance to urinary passage. Total lack of urethra or supernumerary urethra (two urethrae emerging from the bladder) are very rare anomalies, accompanied by other developmental disorders.

The most frequent disorder of the urethra is termed hypospadiasis (abnormal opening of urethra). This disorder is caused by the failure of closure of the urogenital fissure, leading to ectopic opening of the urethra on the ventral side of pars spongiosa. The prevalence of mild or severe hypospadiasis is on average 1:200-400 live births, exclusive to boys. A less frequent disorder (1:100 000 in isolated cases, 1:50 000 in association with bladder exstrophy), epispadiasis (ectopic opening of urethra on the dorsal side of the penis) is mostly associated with malformations of variable degree of the penis, bladder, symphysis and the abdominal wall.