Renal Agenesis

Renal agenesis, or absent kidney development, can result from anomalous development of the wolffian duct, ureteric bud, and/or metanephric blastema. Bilateral agenesis occurs in 1 of every 4000 births and has a male predominance (Potter, 1965). Fetal demise occurs secondary to the lack of fetal urine production and subsequent oligohydramnios. Affected infants are born with immature lungs and pneumothorax, Potter facies (hypertelorism, prominent inner canthal folds, and recessive chin), and orthopedic defects secondary to intrauterine compression. Most cases of bilateral agenesis are sporadic, and many are associated with other congenital anomalies, including urogenital sinus defects.

Unilateral agenesis is more common, with an incidence of 1 in 450 to 1000 births (Kass and Bloom, 1992). Again, a wolffian duct abnormality is often the cause, and associated other wolffian and müllerian abnormalities may also be present, such as malformation of the ipsilateral uterine horn, fallopian tube or ovary in the female, or absence of the ipsilateral testis, vas deferens, or seminiferous tubules in the male. Mayer-Rokitansky-Küster-Hauser syndrome refers to a group of associated findings that include unilateral renal agenesis or renal ectopia, ipsilateral müllerian defects, and vaginal agenesis. Of men with unilateral or bilateral congenital absence of the vas deferens, 26% or 11%, respectively, had renal agenesis. Congenital bilateral agenesis of the vas deferens is also an expected finding in male patients with cystic fibrosis. Cystic fibrosis transmembrane-conductance regulator (CFTR) gene mutations frequently contribute to maldevelopment of the vas deferens, but vasal agenesis can occur without any evidence of CFTR defects. CFTR abnormalities are rarely detected in men with congenital absence of the vas deferens and renal anomalies (Schlegel et al, 1996).

Unilateral renal agenesis can also be associated with other urologic abnormalities in 48% of patients, including primary vesicoureteral reflux (28%), obstructive megaureter (11%), and ureteropelvic junction obstruction (3%) (Cascio et al, 1999). These findings are similar to those associated with unilateral multicystic kidney disease, suggesting the possibility that some absent kidneys represent involuted multicystic dysplastic kidneys.

Additional reading on renal agenesis may be found in Chapter 117.

Dysplasia

Definition

Renal dysgenesis is defined as maldevelopment of the kidney that affects its size, shape, or structure. It is composed of two primary subtypes, the first of which is dysplasia. The term dysplasia, while literally and most simply is defined as “abnormal tissue,” specifically, as it relates to the kidney, it can only truly be defined on the basis of histopathology. Dysplasia is a histologic diagnosis made by the presence of embryonic, immature mesenchyme, and primitive renal components. The differentiation of the metanephros into mature renal components halts at some point along the developmental pathway, often due to an error in the wolffian duct/ureteric bud/metanephric blastema interaction. Common histologic features include distortion of renal architecture, immature or primitive glomeruli, nephron precursors such as comma and S-shaped bodies, and cartilage and tubules encircled by collars of fibromuscular cells (referred to as primitive ducts) (Fig. 118–1). Ericsson and Ivemark (1958) considered these primitive ducts to be the sine qua non finding of all dysplasia. Cysts may or may not be present. The etiology for the development of dysplasia appears to be twofold: (1) a primary, inherent abnormality in the differentiation of the nephron and collecting duct, often with an underlying genetic cause, and (2) a secondary cause resulting from congenital urinary tract obstruction.

Figure 118–1 Primitive duct lined with columnar epithelial cells. Note concentric arrangement of spindle mesenchymal cells around the duct. Special staining is required to demonstrate smooth muscle cells.

Key Points: Dysplasia

• The hallmark of dysplasia is the “primitive duct,” a duct encircled by a collar of fibromuscular cells.

• Dysplasia in its truest form is a histopathologic definition, not a clinical one.

• Dysplasia often is associated with ureteric bud anomalies and/or urinary tract obstruction.

Etiology

Renal dysplasia is the primary cause of childhood end-stage renal disease and two main theories have been considered in its pathogenesis: (1) a primary failure of ureteric bud activity and (2) a disruption in renal development produced by fetal urinary outflow impairment (obstruction). Mackie and Stephens (1975) described the ureteric bud theory suggesting that ectopic (cephalad or caudal) ureteric bud formation leads to abnormal ureteric orifice location either laterally (often leading to vesicoureteral reflux) or distally (often leading to ureteral obstruction). Normal nephrogenesis is dependent upon the ureteric bud meeting the center of the metanephric mesenchyme so that nephrogenesis is appropriately induced by the ureteric bud. However, an abnormally located ureteric bud would be expected to penetrate into a peripheral, degenerating area of the metanephric blastema. The result is a marginal (i.e., hypoplastic or dysplastic) kidney. In cases of dysplasia that are associated with an ectopic ureter, it is not clear if it is the obstruction, aberrant ureteric bud/metanephros interaction, or some other factor that leads to the dysplasia. Dysplasia associated with vesicoureteral reflux would also be included in this category.

Currently, there is no direct experimental evidence to prove that an abnormal ureteric bud site leads to ureteric bud penetration at a peripheral area of the blastema. However, there is much data to support the idea that defects in genetic and apoptotic pathways can affect ureteric bud formation, branching morphogenesis within the metanephric blastema, and normal nephrogenesis (e.g., RET, RAR, BMP4, SLIT2-ROBO2, COX-2, AT2) (Mendelsohn et al, 1994; Norwood et al, 2000; Pope et al, 2001; Grieshammer et al, 2004; Thomas et al, 2005). The genetic defect at each point may be the same, but the downstream pathway associated with the defect may vary for each process.

Animal studies of fetal urinary tract obstruction generate some but not all of the anatomic and histopathologic features of human renal dysplasia. Findings in these animal studies include dilatation at various segments of the nephron and collecting duct, inhibition of nephron development in the nephrogenic zone, architectural disorganization, and the appearance of primitive glomeruli as well as S-shaped bodies and cysts. At times, obstruction in these animal models can even lead to dedifferentiation of certain cells. An example is the conversion of renal epithelial cells back into mesenchymal cells and even of mesenchymal cells into myofibroblasts (Peters et al, 1992; Nguyen et al, 1999; Matsell and Tarantal, 2002). Dysplasia arising from obstruction typically appears at the periphery of the kidney, at the nephrogenic zone, and frequently with subcapsular cysts. This type usually develops later in gestation, such as in the case of posterior urethral valves (PUVs) (Fig. 118–2).

Figure 118–2 Histologic specimen of a nonfunctioning reflux kidney in a patient with posterior urethral valves. Note presence of nests of cartilage (short arrows). Primitive ducts are scattered throughout the specimen (long arrow) (100×). The findings are compatible with dysplasia.

Dysplasia is associated with numerous genetic syndromes (Fraser syndrome, branchio-oto-renal (BOR) syndrome, renal-coloboma syndrome, Kallman syndrome, Simpson-Golabi-Behmel syndrome, Smith-Lemli-Opitz syndrome, HDR [hypoparathyroidism sensorineural deafness, and renal dysplasia] syndrome, and Townes-Brocks syndrome, to name a few). The kidney, in association with these conditions, may be composed mostly of normal functioning parenchyma with areas of dysplasia, or, alternatively, the entire kidney may be dysplastic or entirely absent.

On rare occasions, renal agenesis, renal dysplasia, multicystic dysplasia, and renal aplasia may appear in family members but heterogeneously. One family member may have renal agenesis while another has renal dysplasia, and still another has a multicystic dysplastic or aplastic kidney. When all or part of this group of anomalies is seen in one family, an encompassing term for these four entities is used: familial renal adysplasia.

Ultrasonographically, dysplastic kidneys have a distinct appearance. The kidney is typically small and is hyperechogenic when compared with the liver. There is loss of the typical corticomedullary differentiation, and there is minimal distinction of the renal parenchyma and the perirenal fat (Fig. 118–3A). Cysts can be seen in conjunction with parenchymal dysplasia (Fig. 118–3B). These cysts can also develop from either abnormal development of the metanephric blastema or from distal obstruction. Again, the exact etiology of the cyst formation can be unclear. The important point is that not all cysts are a result of dysplasia and not all dysplasia is associated with cysts.

Figure 118–3 Ultrasonographic appearance of renal dysplasia. A, Classic dysplasia with hyperechogenic appearance of the kidney relative to the liver, a loss of normal corticomedullary differentiation, and dysmorphic calyces. B, Renal dysplasia accompanied by cysts.

(Courtesy of Marta Hernanz-Schulman, MD.)

Renal Hypoplasia

Another form of renal dysgenesis is hypoplasia, which is defined as the underdevelopment of a tissue or organ, and is usually due to a deficiency in the number of cells. Renal hypoplasia is a condition in which there is a reduction in the size of the functioning renal mass. Use of the term hypoplasia should be restricted to kidneys that have less than the normal number of calyces and nephrons but are not dysplastic or embryonic. These are kidneys that are morphologically normal but have either a reduced number of nephrons or smaller nephrons, although a hypoplastic kidney may have a normal nephron density despite its small size. Hypoplasia may be bilateral or unilateral. In unilateral cases, the other kidney usually shows greater compensatory growth than is characteristic in patients with renal atrophy caused by acquired disease. A common cause of renal hypoplasia is vesicoureteral reflux, although the term reflux nephropathy is now used to describe the renal changes associated with reflux.

Hypodysplastic kidneys most often occur in conjunction with ectopic ureteric orifices, with the extent of dysplasia correlating with the degree of ectopia (Schwarz et al, 1981). However, hypodysplastic kidneys are seen in a few patients with normal ureteric orifices. In such cases, obstruction may or may not be present.

All forms of hypoplasia can be assessed by ultrasonography with measurement of the kidneys. The size will be reduced in all forms. Dilated calyces may also be seen. The collecting systems will be demonstrated by excretory urography if renal function is not sufficiently impaired to prevent this. Renal function is assessed biochemically and, if there is unilateral hypoplasia, by radionuclide studies.

Oligomeganephronia

First described in 1962 (Habib et al, 1962; Royer et al, 1962), oligomeganephronia is a type of renal hypoplasia that results from a quantitative defect of the renal parenchyma with a reduced number of nephrons and hypertrophy of each nephron. This condition differs histopathologically from simple hypoplasia in which the renal mass is reduced but the number of nephrons is normal. Oligomeganephronia may occur as a sporadic defect or in association with a number of syndromes. It is usually a bilateral condition, although a few instances of unilateral oligomeganephronia associated with contralateral renal agenesis have been reported (Griffel et al, 1972; Lam et al, 1982; Forster and Hawkins, 1994).

Histopathology

Meticulous histologic examination of the kidney is the only way to establish an absolute diagnosis of oligomeganephronia. There is a reduced number of nephrons, which are all elongated (sometimes fourfold) and widened, particularly at the proximal end (Fig. 118–4). Immature glomeruli are often present. Existing glomeruli and tubules are enlarged. As the disease progresses, segmental sclerosis and hyalinosis of glomeruli are present. Tubular atrophy with interstitial fibrosis occurs. The renal artery is small.

Figure 118–4 A, Mosaic photograph of two typical proximal tubules dissected from the kidney of a patient with oligomeganephronia. The silhouette in the top center is a diagrammatic representation to scale of an average proximal tubule from a kidney of an age-matched control. B, Enlargement of the inset in A showing the diverticula along the course of the nephron (arrows).

(From Fetterman GH, Habib R. Congenital bilateral oligonephronic renal hypoplasia with hypertrophy of nephrons [oligomeganephronia]. Am J Clin Pathol 1969;52:199–207.)

Ask-Upmark Kidney (Segmental Hypoplasia)

In 1929, Erik Ask-Upmark, a Swedish physician, described distinctive small kidneys in eight patients, seven of whom had malignant hypertension; six of these patients were adolescents. Subsequently, this problem was described histologically as focal renal hypoplasia resulting in a segmental renal scar. Segmental renal hypoplasia, or Ask-Upmark kidney, is an extremely rare anomaly, and the patients (usually young women and girls) most frequently present with hypertension. The lesions found in these kidneys are most likely acquired, possibly representing chronic atrophic pyelonephritis due to vesicoureteral reflux, although some appear to be congenital. Segmental vascular (arterial) anomalies have also been cited as a possible cause for these lesions.

Histopathology

The Ask-Upmark kidney is smaller than normal—12 to 35 g (Royer et al, 1971). Its distinctive feature is one or more deep grooves on the lateral convexity, underneath which the parenchyma consists of tubules resembling those in the thyroid gland. Usually, the hypoplastic segments are easily distinguished from adjacent areas. The medulla consists of a thin band, and remnants of the corticomedullary junction and arcuate arteries are seen. Arteriosclerosis is common, and juxtaglomerular hyperplasia may be seen (Bernstein, 1968; Meares and Gross, 1972; Kaufman and Fay, 1974; Arant et al, 1979) (Fig. 118–5).

Figure 118–5 Typical microscopic pattern of segmental hypoplasia affecting the cortex with thyroid-like tubules, thick-walled arteries, and the absence of glomerulus. Note the sharp delineation from the surrounding normal kidney (bottom). Periodic acid–Schiff stain.

(From Babin J, Sackett M, Delage C, Lebel M. The Ask-Upmark kidney: a curable cause of hypertension in young patients. J Hum Hypertens 2005;19:315–6.)

Renal Hypodysplasia

Hypodysplasia may be associated with a wide spectrum of urologic diseases, such as primary obstructive megaureter and ureteropelvic junction obstruction, ureterocele, urethral obstruction, or prune-belly syndrome, to name a few. It has been previously mentioned that abnormal ureteric budding leads to abnormal renal development that often is manifested as hypodysplasia. Lateral ureteral ectopia usually leads to vesicoureteral reflux and its associated forms of hypodysplasia—be it a developmental anomaly, the result of chronic pyelonephritis, or a combination of both. Medial ureteral ectopia, with or without the presence of an ureterocele, can often result in hypodysplasia as well. The renal cortex may be thin, secondary to hydronephrosis, or severely dysplastic, and perhaps with numerous small cysts.

According to Osathanondh and Potter (1964), posterior urethral valves may be associated with two types of renal hypodysplasia. In the less severe form, there are small, usually subcapsular cysts and nearly normal renal function. In the second form, the cysts are larger and more widely distributed, and numerous islands of cartilage are present. This form usually is associated with earlier onset and more severe obstruction and reflux (see Fig 118–2).

The features of the prune-belly syndrome (absent abdominal musculature, triad syndrome) include grossly deformed kidneys, which may have various degrees of hypodysplasia. The ureters are wide and tortuous, often with large and laterally placed orifices. Urethral obstruction or atresia may be present in the most severe cases, but usually there is no lower urinary tract obstruction.

Classification

In this chapter, the classification of renal cystic disease as outlined in 1987 by the Committee on Classification, Nomenclature, and Terminology of the AAP Section on Urology is used. The primary distinction is between genetic (“inheritable”) and nongenetic (“noninheritable”) disease. Table 118–1 gives an overview of characteristics associated with the various forms cystic disease.

Table 118–1 Cystic Diseases of the Kidney

The terms multicystic and polycystic should not be confused, even though both terms literally mean “many cysts.” Multicystic typically refers to a dysplastic kidney resulting from aberrant renal development. Polycystic refers to renal units that developed in a normal fashion, all of which have no dysplasia and have nephrons throughout the kidney. The term polycystic kidney disease traditionally is used in reference to two conditions: ARPKD and ADPKD. Many of the polycystic kidney disease entities progress to renal failure as the nephrons become more diseased. In other conditions, such as tuberous sclerosis and VHL disease, there are hyperplastic cysts, and the individual nephrons are normal. Only occasionally do the nephrons become compressed by the cysts or by associated tumors, and only in such situations does renal failure ensue.

Among the noninheritable cystic diseases, benign multilocular cysts, cystic renal cell carcinoma, and other variants are considered neoplasms. Medullary sponge kidney is a disease principally of dilated ectatic collecting ducts, with cysts playing a lesser role, although the size of the ducts by definition makes them cysts. The nephrons initially are normal.

Inheritable Cystic Disease

Genetic (inheritable) cystic diseases can be classified based on their mode of transmission: autosomal dominant, autosomal recessive, X-linked, among others. Some of these disorders are caused by a single gene defect, some by an X-linked gene defect, and others by chromosomal defects. The modes of inheritance of these diseases and the specific gene or gene locus, where identified, are summarized in Table 118–2.

Table 118–2 Characteristics of Major Inheritable and Noninheritable Cystic Kidney Diseases

Genetics

Once the diagnosis of ARPKD is strongly suspected, referral for genetic evaluation and counseling is appropriate. A detailed history should be taken of at least three generations. Because the disease is transmitted as an autosomal recessive trait, siblings of either sex have a 1 in 4 chance of being affected.

Despite the clinical variability of ARPKD, it appears that only mutations of a single gene, named PKHD1 and located on chromosome 6 (6p12), are responsible for the disease. The gene produces a protein called fibrocystin (also known as polyductin) (Onuchic et al, 2002; Ward et al, 2002). This protein is a member of a larger family of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion. More specifically, dysfunction of this protein mediates cystogenesis through dysfunction of the primary cilia of renal epithelial cell. It is highly expressed in the kidney, with levels also present in the liver and pancreas. It is localized to the branching ureteric bud, collecting ducts of the kidney, and biliary ducts, consistent with the phenotype seen in ARPKD, and it is often absent in the patients with ARPKD (Wilson, 2004; Al-Bhalal and Akhtar, 2008).

Clinical Features

Affected children typically present in utero with enlarged, echogenic kidneys. Oligohydramnios is common because of the lack of normal urine production by the fetus. The infant often displays Potter facies and deformities of the limbs and may have respiratory distress as a consequence of pulmonary hypoplasia. The affected newborn usually has enormous, kidney-shaped, nonbosselated flank masses that are hard and do not transilluminate. In some cases, the kidneys are large enough to impede delivery. The infant’s serum creatinine and BUN concentrations are those of the mother’s at birth but soon begin to rise. Thirty to 50 percent of the affected individuals die shortly after birth as a result of uremia or respiratory failure (Kaplan et al, 1989c; Capisonda et al, 2003; Guay-Woodford, 2003). The earlier the age at which the disease is identified, the more severe the disease. No matter what the severity of the renal disease, all patients with ARPKD have liver involvement in the form of congenital hepatic fibrosis and vary in the degree of biliary ectasia and periportal fibrosis (Habib and Bois, 1973; Kissane and Smith, 1975).

Patients who survive the neonatal period have a milder form of the disease and are likely to survive into adulthood. Some diagnosed as neonates can live beyond age 3 or 4 years before going into renal failure (Cole et al, 1987; Avni et al, 2002). Hypertension and renal insufficiency are the major manifestations in surviving children, with liver disease becoming more prevalent in older patients. The exact cause of hypertension remains unclear. Consequences of chronic renal insufficiency (i.e., growth failure, anemia, osteodystrophy, etc.) become more apparent as the children age. Renal calcifications occur commonly in patients with ARPKD.

Patients whose disease appears later in life develop renal failure and hypertension more slowly. In general, their clinical problems are the consequence of liver disease rather than the renal disease, with hepatic fibrosis leading to portal hypertension, esophageal varices, and hepatosplenomegaly. Hepatocellular function is rarely abnormal, with liver enzymes typically remaining normal. The kidneys in these patients are often normal in appearance.

No association of ARPKD with renal neoplasms has been reported to date.

Histopathology

The kidneys are symmetrically enlarged (up to 20 times their normal size) and retain a reniform configuration. The parenchyma exhibits small subcapsular cysts, representing generalized fusiform dilations of the collecting tubules radiating from the medulla to the cortex with their long axis perpendicular to the renal surface (Bisceglia et al, 2006). Almost 100% of collecting ducts are affected in the most severe cases. The cortex is crowded with minute cysts (Fig. 118–7A). The renal pedicle is normal, as are the renal pelvis and ureter.

Figure 118–7 Newborn with abdominal mass and pulmonary hypoplasia. Neither parent had a history of renal cysts. A, Renal histology demonstrates dilated ducts radiating out to the periphery of the kidney. B, On liver histology, ectatic biliary ducts are seen in the left half of the figure, and periportal fibrosis is seen at the upper edge. These findings confirm the diagnosis of autosomal recessive polycystic disease.

ARPKD affects both the kidneys and the liver in approximately inverse proportions (Torres and Grantham, 2008). The disease may be viewed as a spectrum ranging from severe renal disease and mild liver changes at one extreme to mild renal damage and severe liver disease at the other. The form with severe renal disease is the most common and the one typically seen at or near the time of birth. The form with less severe renal disease and more significant liver damage is present in older children. All children with ARPKD have lesions in the periportal areas of the liver (Habib and Bois, 1973; Kissane and Smith, 1975) (Fig. 118–7B). Congenital hepatic fibrosis is characterized by enlarged and fibrotic portal areas with apparent proliferation of bile ducts, absence of central bile ducts, hypoplasia of the portal vein branches, and sometimes prominent fibrosis around the central veins. Bulbar protrusions from the walls of dilated ducts also occur, and bridges sometimes form. This malformation has been found to occur occasionally as an isolated event (Caroli disease), but most often it is associated with ARPKD (Torres and Grantham, 2008).

Evaluation

The diagnosis may be suspected from in utero ultrasound examination and may be associated with oligohydramnios, a finding secondary to low urinary output. In both fetus and newborn, ultrasonography identifies bilateral, very enlarged, diffusely echogenic kidneys, especially when compared with the echogenicity of the liver (Fig. 118–8A). The increased echogenicity is due to the presence of numerous microcysts (created by tightly compacted, dilated collecting ducts) that result in innumerable interfaces. Compared with normal newborn kidneys, in ARPKD, the pyramids are hyperechogenic because they blend in with the rest of the kidney, and the kidneys typically have a homogeneous appearance (see Fig. 118–8A). In ADPKD, the cysts, if apparent in newborns, are usually diffuse and large (see Fig. 118–8B). Also included in the differential diagnosis is severe bilateral hydronephrosis (the kidneys are enlarged with hypoechogenic calyces), multicystic kidney (hypoechogenic cysts lie within a nonreniform mass that has very little parenchyma), sporadic glomerulocystic kidney disease, bilateral mesoblastic nephroma, Wilms tumor, and bilateral renal vein thrombosis. If the diagnosis is in doubt, computed tomography is valuable because it is more sensitive to inhomogeneity (and therefore to tumor) within abdominal masses.

Figure 118–8 Ultrasonographic appearance of the kidneys in neonates with autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) can be similar. A1 and A2, Newborn with ARPKD. Note the large size and hyperechogenic, homogeneous appearance of the renal parenchyma. A2 is a cross-sectional cut of the baby’s abdomen showing both kidneys to be quite large and occupying a large portion of the abdominal cavity. B1 and B2, Newborn with ADPKD. Again note the abnormal renal architecture and the hyperechogenic appearance of the kidneys. The parenchyma consists of multiple tiny cysts, with some being slightly larger than others.

(Courtesy of Marta Hernanz-Schulman, MD.)

Considerable overlap in clinical presentation and imaging findings can occur between ADPKD and ARPKD. Occasionally, a newborn with severe ADPKD can also have enlarged, homogeneously hyperechogenic kidneys. Age at onset can overlap, and typically, when ADPKD manifests at birth, cysts are apparent on the sonographic image. Macrocysts are rare in newborns with ARPKD but do increase in frequency as the child gets older, sometimes producing an appearance similar to that of the dominant disease. Cysts less than 1 cm appear more often than large cysts (Avni et al, 2002) (Fig. 118–9). Hepatic fibrosis can rarely occur in patients with ADPKD, as can brain aneurysms with ARPKD (Cobben et al, 1990; Neumann et al, 1999). The correct diagnosis of ARPKD depends on the overall clinical data: positive family history with a recessive mode of inheritance, a positive liver biopsy, and the lack of the extrarenal malformations often associated with other renal cystic diseases.

Figure 118–9 A1 and A2, MR images of an 8-month-old child with autosomal recessive polycystic kidney disease (ARPKD) demonstrating multiple renal cysts. A1, On T1-weighted image, fluid content of cysts appears dark. A2, On T2-weighted image, the fluid content appears white. B, CT scan of a child with ARPKD. Horizontal cuts showing contrast puddling in collecting ducts. C, Coronal cut. Note the kidneys are enlarged, and the enhancing renal parenchyma is effaced by nonenhancing cysts and represents the progression/normal history of the disorder.

(A, Courtesy of Walter Berdon, MD. B, Courtesy of Marta Hernanz-Schulman, MD.)

Treatment

No cure has been found for ARPKD. Respiratory care can ease or extend the child’s life. Severely affected neonates may require unilateral or bilateral nephrectomy, because of respiratory and nutritional compromise. Patients who survive may require treatment for hypertension, congestive heart failure, and renal and hepatic failure. Portal hypertension may be dealt with by decompressive procedures such as a splenorenal shunt. Esophageal varices may be managed, at least temporarily, by gastric section and reanastomosis. Endoscopic sclerotherapy is widely employed in pediatric and adults with bleeding varices. Hemodialysis and renal transplantation must eventually be considered in many patients.

Genetics

There are two major genetic forms of ADPKD caused by mutation in the genes PDK1 and PDK2 (Reeders et al, 1985; Breuning et al, 1987; Ryynanen et al, 1987; Pieke et al, 1989). PDK1 has been localized to the short arm of chromosome 16, with its gene product being polycystin-1. Mutations in the PDK1 gene account for 85% of ADPKD cases. These patients typically have a more rapidly progressive form of the disease, with cysts usually developing by the age of 20 years (64% of children have cysts by the age of 10 years and 90% by the age of 20 years) and ESRD occurring in their 50s (Chakraborty and McHugh, 2005). The PKD2 gene has been mapped to the long arm of chromosome 4 (Peters et al, 1992), and it encodes the protein polycystin 2. PDK2 mutations account for about 15% of ADPKD cases, and in these patients, the disease progresses more slowly. ESRD usually does not occur until these patients are in their 70s (Hateboer et al, 1999). The presence of a third locus (PKD3) is now accepted as the cause of disease in a very small percentage of patients who have been found to have neither a PKD1 nor a PKD2 gene defect (Dauost et al, 1993). When either the PKD1 or the PKD2 gene is abnormal, cystic kidneys can develop. Because defects of PKD1 and PKD2 manifest similarly, it has been suggested that the gene product of each is involved in the same pathway and that an abnormality of either product results in similar manifestations of the disease (Qian et al, 1996).

Every cell of the nephron and collecting duct has the PDK1 or PDK2 mutation; however, only 1% to 2% of these glomerular units are affected by cyst formation. Only those nephrons that undergo a disruption of a second allele undergo cystic enlargement. This is the “second hit” of the Knudson theory, which has been proposed to explain the focal nature of the cysts (Knudson, 1991). In this model, a mutated PKD1 (or PKD2) gene is inherited from one parent, and a wild-type gene is inherited from the unaffected parent. During the lifetime of the individual, the wild-type gene undergoes a somatic mutation and becomes inactivated. Loss of heterozygosity owing to somatic mutations of the PKD1 and PKD2 genes has been identified in the cells lining the cysts in both the kidney and liver (Qian et al, 1996; Watnick et al, 1998). The phenomenon of genetic anticipation is seen as well; it is manifested by progressively earlier presentation and increased severity in subsequent generations of patients with ADPKD (Fick et al, 1994; Zerres et al, 1994). Genetic testing for PDK1 and PDK2 are commercially available through polymerase chain reaction amplification and direct DNA sequencing.

Occasionally, the classic ADPKD phenotype is seen in conjunction with tuberous sclerosis. This association is a classic example of a “contiguous gene syndrome,” which is a disorder due to deletion of multiple gene loci that are adjacent to one another. Contiguous gene syndromes are characterized by multiple, apparently unrelated, clinical features caused by deletion of the multiple adjacent genes. Due to the fact that the PDK1 gene is immediately adjacent to the TSC2 gene (the most important gene in tuberous sclerosis) on chromosome 16, large deletions in this area can involve both the PDK1 and TSC2 genes. Thus these patients have the classic features of tuberous sclerosis in addition to the renal cystic phenotype of ADPKD.

Pathogenesis

The PDK1 and PDK2 proteins, polycystin 1 (PC1) and polycystin 2 (PC2), are transmembrane proteins that in all likelihood form a functional complex. When working properly, PC1 and PC2 inhibit cell proliferation by several pathways. Polycystin 1 functions as a mechanoreceptor located on the primary cilium of renal tubular cells. These cilia project from the surface of the cell into the lumen of the ducts and tubules. Mutations that block the assembly of these cilia are known to cause many cystic diseases of the kidney. The products of the ADPKD, ARPKD, and nephronophthisis genes are at least partially localized to these primary cilia. Polycystin 1 is linked to polycystin 2, which contains a calcium (Ca⁺⁺) channel. When the mechanoreceptor of polycystin 1 is stimulated by calcium-containing urine flowing through the tubule, the calcium channel of polycystin 2 opens and calcium enters the cell (Nauli et al, 2003; Braun, 2009). This process regulates the proliferative state of the renal tubular cells through a variety of signaling pathways (cAMP, extracellularly regulated kinase [ERK], mammalian target of rapamycin [mTOR], etc.). The cilia likely serve as organization centers for this signal transduction (Pazour, 2004).

In ADPKD, the polycystins do not function properly, and these proliferative pathways are unopposed and cyst formation occurs to varying degrees.

Increased levels of cAMP have been noted in multiple animal models of ADPKD, and biochemical processes that alter cAMP appear to affect the presence and size of renal cysts. For example, cAMP is broken down by phosphodiesterases. Caffeine and methylxanthine products, such as theophylline, interfere with phosphodiesterase activity, raise cAMP in epithelial cell cultures from patients with ADPKD, and increase cyst formation in canine kidney cell cultures (Mangoo-Karim et al, 1989; Belibi et al, 2002). The abnormal response to cAMP is directly linked to alterations in Ca⁺⁺ channel activity and results in the abnormal response of cyst-derived cells. This has also been shown to be regulated by cAMP stimulation of the mitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling pathways, which leads to abnormal cellular proliferation of the PKD renal epithelial cells.

Upregulation of the vasopressin V2 receptor has also been shown to increase cAMP levels. In genetically produced polycystic animals, two antagonists of the vasopressin V2 receptor (VPV2R), OPC31260 and OPC41061 (tolvaptan), decreased cAMP and ERK, prevented or reduced renal cysts, and preserved renal function (Gattone et al, 2003; Wang et al, 2005). Not surprisingly, simply increasing water intake decreases vasopressin production and the development of polycystic kidney disease in rats (Nagao et al, 2006). Polycystic kidney (PCK) animals with no vasopressin activity had virtually no cAMP or renal cysts, whereas animals with increasing amounts of vasopressin had progressively larger kidneys with more numerous cysts. Administration of synthetic vasopressin to PCK rats that totally lacked vasopressin re-created the full cystic disease (Wang et al, 2008; Braun, 2009). Finally, the absence of polycystin permits excessive kinase activity in the mTOR pathway and the development of renal cysts (Shillingford et al, 2006). The mTOR system can be blocked by rapamycin, which has been shown to slow PKD progression in rats (Wahl et al, 2006).

Clinical Features

Phenotypes associated with ADPKD are highly variable in penetrance. This variability related to the severity of renal disease can range from fetal demise and neonatal death to adequate renal function into old age. Characteristics of the associated liver disease and extrarenal manifestations can also be quite variable. PDK1 and PDK2 gene mutations are obviously critical, but intrafamilial variability also indicate that genetic background and environmental factors can also affect ultimate clinical expression of the disease (Rossetti and Harris, 2007). Now that the families of ADPKD patients are being screened by ultrasonography, large numbers of asymptomatic children with renal cysts are being identified before full-blown disease develops. Bilateral renal involvement is the usual presentation, but 17% of cases are asynchronous/asymmetrical, especially in children. These extreme forms of asymmetry are referred to as “unilateral ADPKD” with the involvement in the contralateral kidney becoming apparent at a much older age (Strand et al, 1989; Bisceglia et al, 2006).

Typically, signs or symptoms first occur between the ages of 30 and 50 years (Glassberg et al, 1981). These include microscopic and gross hematuria, flank pain, gastrointestinal symptoms (perhaps secondary to renomegaly or associated colonic diverticula), renal colic (secondary either to clots or stones), and hypertension. Microscopic or gross hematuria is seen in 50% of patients, and, in 19% to 35%, it is the presenting symptom (Milutinovic et al, 1984; Delaney et al, 1985; Zeier et al, 1988; Gabow et al, 1992). Because patients with ADPKD have increased renal mass, erythropoietin levels are increased, making anemia unusual even when ESRD is present (Gabow, 1993).

Pain (flank and/or abdominal) is the most common presenting symptom in adults. This results from a number of possible factors: mass effect (cysts impinging on abdominal wall or neighboring organs), bleeding into the cysts, urinary tract infection (including infected cysts), and nephrolithiasis. Twenty to 30 percent of patients with ADPKD develop stones (Fick et al, 1994), and these are treated by conservative means if possible (i.e., urine alkalinization, spontaneous stone passage, extracorporeal shock wave lithotripsy). Uric acid stones and calcium oxalate stones are equally prevalent. The finding of hydronephrosis, which helps make the diagnosis of stones, may not be as useful in ADPKD patients because of the number of cysts camouflaging the findings (Choyke et al, 1995). Urinary tract infections are more frequent in female patients. Cyst aspiration for both diagnostic and therapeutic reasons should be considered in the setting of suspected cyst infection.

As blood pressure screening has become more widespread, hypertension has become a very common form of presentation (Zeier et al, 1988). Hypertension is present in roughly 50% of patients 20 to 35 years old having ADPKD with normal renal function. Virtually 100% of patients with ESRD will have hypertension (Kelleher et al, 2004

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