Article Update

Sunday, November 3, 2019


Polycystic kidney disease is an inherited disorder that exists in both autosomal dominant and autosomal recessive forms (ADPKD and ARPKD, respectively). Both diseases are characterized by the bilateral, diffuse formation of renal cysts that replace normal parenchyma and cause progressive renal insufficiency.


ADPKD is a relatively common condition, with a prevalence of 1 : 400-1 : 1000, and it is responsible for approximately 5% to 10% of end-stage renal disease (ESRD). Most cases reflect autosomal dominant inheritance of the mutated gene from an affected parent, with complete penetrance; however, about 5% of patients have parents with normal kidneys, suggesting a de novo genetic mutation.
ADPKD is caused by mutations in the genes PKD1 (chromosome 16p13.3) or PKD2 (chromosome 4q21). PKD1 mutations account for 85% of cases, whereas PKD2 mutations account for the remainder. PKD1 encodes polycystin-1, an integral membrane protein thought to play a role in cell-cell and cell-matrix interactions, while PKD2 encodes polycystin-2, a cation channel involved in calcium signaling. Although polycystin-1 and polycystin-2 appear to interact with each other at primary cilia, the precise mechanism by which mutations in these proteins cause cyst formation remains unclear. It is generally accepted, however, that cystogenesis follows a two hit model. Although most renal tubules possess epithelial cells that contain one mutated allele and one normal allele, a small subset possess cells in which the normal allele also becomes mutated, which is the second “hit” that permits cyst formation.
There is a wide range of clinical phenotypes associated with ADPKD, ranging from a complete lack of symptoms to progression to ESRD. When symptomatic, the disease usually first presents in the third to fifth decade as flank pain and hematuria (reflecting either traumatic or atraumatic cyst rupture, nephrolithiasis, or infection), hypertension, and progressive renal insufficiency. Extrarenal disease manifestations are common, and they include hepatic cysts (in approximately 80%), pancreatic cysts (in approximately 10%), intracranial aneurysms (in approximately 10%), and mitral valve prolapse (in approximately 20%).
To some extent, the rate at which renal insufficiency progresses is dependent on the specific underlying mutation. Patients with PKD1 mutations, for example, develop ESRD at a mean age of 54 years, whereas those with PKD2 mutations develop ESRD at a mean age of 74 years. Even within the subgroup of patients with PKD1 abnormalities, those with mutations near the 5’ end of the gene generally have a slightly faster progression to ESRD than those with mutations located near the 3’ end (53 years versus 56 years, respectively).
ADPKD can be diagnosed using several imaging modalities-such as ultrasound, CT, or magnetic resonance imaging-which reveal enlarged kidneys that possess diffuse, fluid-filled cysts. The cysts are variable in size, ranging from several millimeters to several centimeters, and are present in both cortex and medulla. The differential diagnosis should include other entities such as simple cysts (see Plate 2-14), especially when few cysts are seen; renal cyst formation secondary to other genetic syndromes, such as von Hippel-Lindau syndrome or tuberous sclerosis; medullary cystic kidney disease complex (see Plate 2-18); acquired cystic disease; and ARPKD, especially if cysts are noted early in life. The specific diagnosis of ADPKD can generally be reached based on the radiographic appearance of the kidneys, the presence of associated abnormalities (e.g., hepatic cysts), and a family history consistent with auto-somal dominant transmission. Recent work has proposed the following sonographic criteria for the diagnosis of ADPKD in at-risk patients with families of unknown genotype: at least three unilateral or bilateral cysts in those 15 to 39 years of age; at least two cysts in each kidney in those 40 to 59 years of age; and four or more cysts in each kidney in those greater than 60 years of age. Due to the size and complexity of the PKD1 and PKD2 genes, genetic testing is not commonly performed.
At present, no directed treatment is available to prevent or slow further cyst formation, although several experimental therapies are being studied. Instead, treatment is chiefly directed at reducing the morbidity associated with complications of the renal cysts, such as pain, hemorrhage, infection, and hypertension. If pain becomes severe, some centers offer laparoscopic unroofing of cysts or percutaneous aspiration of cyst fluid and injection of sclerosing material. Hepatic cysts are usually asymptomatic, but in rare cases portal hypertension  may  occur. About  10%  of those with ADPKD and intracranial aneurysms will die of subarachnoid hemorrhage; however, screening for intra-cranial aneurysms is generally not performed unless there is a family history of aneurysm rupture, the patient has a high-risk occupation (e.g., pilot), or there are concerning neurologic symptoms.
If progression to ESRD occurs, dialysis or renal transplantation is required. Before transplantation, nephrectomy may be necessary not only to relieve symptoms associated with the enlarged kidneys, but also to provide space for the graft.

ARPKD is a much rarer condition than ADPKD, occurring in approximately 1 : 20,000 live births. It is caused by mutations in the gene PKHD1 (located on chromosome 6p21), which encodes a protein known as fibrocystin. Fibrocystin is localized to the primary cilia of epithelial cells in the thick ascending limb and collecting duct, as well as to epithelial cells lining the hepatic biliary ducts. Although fibrocystin appears to interact with polycystin-2, it is uncertain how abnormalities in this system result in cyst formation.
As with ADPKD, there is a wide range of clinical phenotypes, but patients present much earlier in life. All patients with ARPKD have congenital hepatic fibrosis, and some patients also have dilation of the intraductal biliary ducts (Caroli disease). In general, there is an inverse correlation between the severity of the renal disease, which typically presents during the neonatal period, and hepatic disease, which typically presents during late childhood or adolescence.
In patients with severe renal disease, the diagnosis is first apparent using prenatal ultrasound. The kidneys appear enlarged and hyperechogenic owing to the presence of innumerable cysts. Unlike in ADPKD and most other cystic diseases, however, the individual cysts are generally too small to be visualized. If renal dysfunction is severe enough, oligohydramnios may also be present. During delivery, the enlarged kidneys may cause dystocia. Shortly after birth, the neonate may experience respiratory distress if pulmonary hypoplasia has occurred secondary to oligohydramnios or if the kidneys are large enough to cause restrictive lung disease. Patients with milder renal disease may not present until childhood, when renal insufficiency manifests as electrolyte disturbances or hypertension. Unlike in ADPKD, hematuria and infection are not common features.
Patients with the mildest renal disease often present in late childhood or adolescence with symptoms referable to hepatic disease. In these patients, progressive hepatic fibrosis can result in portal hypertension, which can manifest as bleeding varices or splenic enlargement with cellular sequestration. Intrahepatic biliary duct dilation, if present, may also present as cholangitis.
The diagnosis of ARPKD is generally established based on the sonographic appearance of the kidneys, described previously, in association with evidence of hepatic fibrosis and a family history that demonstrates autosomal recessive transmission. If the diagnosis is in doubt, or if family members wish to establish their carrier status, genetic testing is available. Renal biopsy is seldom performed, but the major feature is the presence of elongated cortical and medullary cysts that arise predominantly from collecting ducts.
As with ADPKD, no directed treatment is available to prevent or slow cyst formation, and thus care should be directed toward managing complications of renal or hepatic dysfunction. Patients who present early in life with renal dysfunction require aggressive support to maintain adequate nutritional status and avoid sus-tained fluid or electrolyte abnormalities. Patients who have portal hypertension complications may require intervention, such as portosystemic shunting or variceal sclerotherapy. The timing of ESRD onset is variable, but when it occurs dialysis and renal transplantation become the only remaining therapeutic options.

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