Anomalies In Number Of Kidneys
Renal agenesis is deﬁned as the complete absence of one or both pairs of kidneys and ureters. It represents a failure of the ureteric bud and metanephric mesenchyme to engage in the process of reciprocal induction and differentiation required for metanephros formation. As a result, both the kidney and ureter fail to develop. Renal aplasia, in contrast, occurs when there is abnormal differentiation of the metanephric mesenchyme and ureteric bud that leads to involution of the kidney, but with persistence of a rudimentary collecting system.
Because numerous signaling molecules are involved in normal metanephros development, the range of genetic defects that may cause renal agenesis is vast and under active investigation. Recent evidence, however, suggests a prominent role for abnormalities in the GDNF-RET signaling cascade. GDNF (glial cell line-derived neurotrophic factor) is expressed in the masses of metanephric mesenchyme lying near the mesonephric (wolfﬁan) ducts. It binds to RET, a receptor tyrosine kinase, in the mesonephric ducts and induces formation of the ureteric buds. Mutations in the genes encoding these proteins prevent formation of the ureteric buds and have been noted in fetuses with renal agenesis.
In some cases, male fetuses with renal agenesis still develop normal mesonephric duct derivatives (i.e., the vas deferens, seminal glands [vesicles], and epididymis), indicating that the underlying developmental defect affected only ureteric bud branching or metanephric induction. Fetuses with broader defects, in contrast, have likely sustained insults to the intermediate mesoderm, which gives rise to both the nephrogenic cords and genital ridge (see Plate 2-1).
Bilateral renal agenesis. Bilateral renal agenesis, deﬁned as the complete absence of both kidneys and ureters, is a rare abnormality that occurs in approximately 1 : 5000 to 1 : 10,000 fetuses. Males are affected at least twice as often as females. There is evidence that a signiﬁcant number of affected fetuses have abnormalities in signaling cascades important to renal development, such as the GDNF-RET pathway described above. A subset of affected fetuses, however, also have associated abnormalities that suggest a more wideranging defect in caudal development, such as sirenomelia (fused lower extremities, imperforate anus, renal agenesis, and abnormal or absent genitalia).
Bilateral renal agenesis is typically diagnosed using prenatal ultrasound. Normally the fetal kidneys can be visualized starting at approximately the twelfth week of gestation. In bilateral renal agenesis, however, no renal parenchyma can be visualized either in the normal renal fossae or other ectopic locations, such as the fetal pelvis or thorax. The fetal adrenal glands are in normal position but may appear less ﬂattened because of the lack of normal compression from the kidneys. Finally, the fetal bladder appears empty, and the normal cycles of ﬁlling and emptying are not seen.
Severe oligohydramnios is a major consequence of bilateral renal agenesis and may be one of the more notable sonographic ﬁndings. Before 20 weeks of gestation, diffusion of ﬂuid into the amnion produces a signiﬁcant fraction of the amniotic ﬂuid, which there-fore may appear normal in volume even despite a lack of fetal renal function. After 20 weeks, however, the fetal kidneys are responsible for producing over 90% of the amniotic ﬂuid. Severe oligohydramnios at this stage of development is therefore a very sensitive sign of bilateral agenesis. It is not, however, particularly speciﬁc, and other possible causes including bilateral renal dysplasia, bilateral renal cystic disease, urinary outﬂow tract obstruction, premature rupture of membranes, and fetal demise must be ruled out.
Severe oligohydramnios, irrespective of the cause, has numerous adverse effects on the fetus. First, the increase in intrauterine pressure results in physical compression of the growing fetus, which leads to a blunted nose; low-set, ﬂattened ears that appear enlarged; micrognathia; prominent infraorbital folds; a prominent depression between the lower lip and chin; clubbed limbs; and dislocated hips. In addition, the lack of amniotic ﬂuid causes abnormal development of the skin, which appears loose and excessively dry. Finally, the increased pressure on the fetal thorax and decline in circulating amniotic ﬂuid leads to severe pulmonary hypoplasia. The cause-and-effect relationship between oligohydramnios and these various sequelae is known as the Potter sequence.
Bilateral renal agenesis is fatal. Forty percent of affected fetuses die in utero, and the remainder develop severe respiratory distress shortly after birth. There-fore, if the diagnosis is established using prenatal ultra- sound, therapeutic abortion is typically recommended. Because most cases of bilateral renal agenesis are sporadic, the risk of recurrence in a subsequent pregnancy is low.
Unilateral renal agenesis. Unilateral renal agenesis, deﬁned as the complete absence of one kidney and its associated ureter, occurs in approximately 1 : 1000 to 1 : 1200 individuals. Males are affected nearly twice as often as females. The underlying cause is thought to be abnormal interaction between a ureteric bud and its associated metanephric mesenchyme; however, it is unclear why some patients develop unilateral agenesis, whereas in others both sides are affected.
Like bilateral agenesis, unilateral renal agenesis is often discovered using prenatal ultrasound, which reveals an empty renal fossa without evidence of ectopic renal parenchyma, such as a pelvic kidney. Unlike in bilateral agenesis, however, urine production is normal, and therefore oligohydramnios does not occur. As a result, affected infants are typically born with a normal appearance and normal pulmonary function.
Many patients with unilateral renal agenesis have associated abnormalities in other organ systems. Indeed, the absence of a kidney may not even be discovered until an associated abnormality is investigated. Many of these abnormalities occur in structures derived from the mesonephric or paramesonephric ducts, suggesting a defect in the intermediate mesoderm early in development. In males, the ipsilateral mesonephric duct derivatives (vas deferens, seminal gland [vesicle], and epididymis) may be absent or rudimentary (i.e., a seminal gland [vesicle] cyst). Meanwhile, in females, a common associated anomaly is a unicornuate uterus, in which the side ipsilateral to the absent kidney is missing. Associated abnormalities may also occur in the cardiovascular system (e.g., septal or valvular defects) or gastrointestinal systems (e.g., imperforate anus).
Nearby musculoskeletal abnormalities may also be seen. In a smaller subset of patients, unilateral renal agenesis may be associated with a genetic syndrome that affects numerous organ systems, such as BOR (branchio-oto-renal) syndrome, Turner syndrome, Fanconi anemia, Kallmann syndrome, VACTERL (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal ﬁstula, renal defects, limb defects), and others.
With a solitary kidney, renal function typically remains normal, although for unclear reasons there is an increased risk of vesicoureteral reﬂux, ureteropelvic junction obstruction, and ureterovesical junction obstruction. Later in life, some patients may develop renal insufﬁciency and proteinuria, likely secondary to hyperﬁltration of the solitary kidney causing focal segmental glomerulosclerosis (see Plate 4-10). Their survival rate, however, appears to remain similar to that of normal individuals.
A supernumerary kidney is a very rare congenital anomaly. Unlike a kidney with a duplicated collecting system, which is far more common, a supernumerary kidney is a distinct mass of renal parenchyma with its own capsule, vessels, and collecting system. It is typically small and located just cephalad or caudal to the normally positioned kidney on the same side. Less commonly, it is located in a variety of other positions, such as the pelvis or midline. In some cases, the supernumerary kidney and normally positioned kidney may be loosely attached to each other by either ﬁbrous tissue or a bridge of renal parenchyma.
In half of cases, the ureter associated with a supernumerary kidney fuses with that of the normally positioned ipsilateral kidney, as seen in the illustration; in the other half, the ureter has its own separate insertion into the bladder. In such cases, the Weigert-Meyer rule is usually obeyed, meaning that the ureter associated with the more caudally positioned kidney has an oriﬁce located more superior and lateral than that of the cranially positioned kidney. The vessels to the supernumerary kidney usually originate from the aorta and inferior vena cava, although their origin is more variable with more caudally positioned kidneys.
The embryologic basis of the supernumerary kidney is not known but likely represents early division of the metanephric mesenchyme. A supernumerary kidney with a ureter that has its own insertion into the bladder likely reﬂects early division of the mesenchyme before insertion and branching of the ureteric bud (see Plate 2-2). The ureter to the supernumerary kidney probably represents a second ureteric bud that sprouted from the adjacent mesonephric duct, either by coincidence or as a direct effect of the divided mesenchyme. A supernumerary kidney with a ureter that fuses with that of the normal kidney likely reﬂects later division of the meta-nephric mesenchyme, perhaps in response to a ureteric bud that divided before insertion.
Supernumerary kidneys are often asymptomatic and do not affect overall renal function. Thus a signiﬁcant number of such kidneys may never be discovered or may be noted only as incidental ﬁndings during the workup of another unrelated complaint. In some patients, however, supernumerary kidneys present as palpable abdominal masses or cause symptomatic nephrolithiasis or an upper urinary tract infection. Because of the rarity of this condition, affected patients are often not diagnosed until their fourth decade, if at all.