POLYCYSTIC KIDNEY
DISEASE
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
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
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.
