ARPKD is a significant hereditary

renal disease in childhood, with an estimated prevalence of 1 in

20,000 live births. A carrier frequency of up to 1:70 has been

reported. Mutations in a single gene, PKHD1, are responsible for all the

clinical presentations of ARPKD. PKHD1, localized on human chro-

mosome region 6p21.1–6p12.2, is one of the largest genes in the

genome, occupies ~450 kb of DNA, and contains at least 86 exons. It

produces multiple alternatively spliced transcripts. The largest tran-

script encodes fibrocystin/polyductin (FPC), which is a large receptor-

like integral membrane protein of 4074 amino acids. FPC has a single

transmembrane, a large N-terminal extracellular region, and a short

intracellular cytoplasmic domain. FPC is localized on the primary cilia

of epithelia cells of cortical and medullary collecting ducts and cholan-

giocytes of bile ducts, similar to polycystins and several other ciliopa-

thy proteins. FPC is also expressed on the basal body and plasma

membrane. The large extracellular domain of FPC is presumed to bind

to an as yet unknown ligand(s) and is involved in cell-cell and cell-

matrix interactions. FPC interacts with ADPKD protein PC2 and may

also participate in regulation of the mechanosensory function of the

primary cilia, calcium signaling, and PCP, suggesting a common

mechanism underlying cystogenesis between ADPKD and ARPKD.

FPC is also found on the centrosomes and mitotic spindle and may

regulate centrosome duplication and mitotic spindle assembly during

cell division. A large number of various mutations have been found

throughout PKHD1 and are unique to individual families. Most

patients are compound heterozygotes for PKHD1 mutations. Patients

with two truncation mutations appear to have an earlier onset of the

disease.

Clinical Features Classic ARPKD is generally diagnosed in utero

or within the neonatal period and characterized by greatly enlarged

echogenic kidneys in diseased fetuses. Reduced fetal urine production

CHAPTER 327

Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development2434

may contribute to oligohydramnios and pulmonary hypoplasia. About

30% of affected neonates die shortly after birth due to respiratory insuf-

ficiency. Close to 60% of mortality occurs within the first month of life.

In the classic group, most patients are born with renal insufficiency

and ESRD. However, infants often have a transient improvement in

their GFR; death from renal insufficiency at this stage is rare. Some

patients are diagnosed after the neonatal stage, which form the older

group. Morbidity and mortality in this group often involve systemic

hypertension, progressive renal insufficiency, and liver manifestations.

The hallmarks of ARPKD liver disease are biliary dysgenesis due to a

primary ductal plate malformation with associated periportal fibrosis,

namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic

bile ducts (Caroli disease). CHF and Caroli disease can then lead to

portal hypertension exhibiting hepatosplenomegaly, variceal bleeding,

and cholangitis. Some patients with the diagnosis of ARPKD at 1 year

of age with nephromegaly exhibit slowly declining renal function over

20 years with only minimally enlarged kidneys at ESRD and markedly

atrophic kidneys following renal transplantation. The slow progres-

sion of renal disease is likely due to increasing fibrosis rather than the

development of cysts. Systemic hypertension is common in all ARPKD

patients, even those with normal renal function.

Diagnosis Ultrasonography, CT, and MRI all can be used for diag-

PART 9 nosis. Ultrasonography reveals large, echogenic kidneys with poor

corticomedullary differentiation. The diagnosis can be made in utero

after 24 weeks of gestation in severe cases. Macrocysts generally are

not common at birth in ARPKD patients. The absence of renal cysts in

either parent, particularly if they are >40 years of age, on ultrasonogra-

Disorders of the Kidney and Urinary Tract

phy helps distinguish ARPKD from ADPKD in older patients. Clinical,

laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathol-

ogy demonstrating characteristic ductal plate abnormalities, family

history of affected siblings, or parental consanguinity suggestive of

autosomal recessive inheritance is helpful. The lack of mutational hot

spots and the large and complex genomic structure of PKHD1 make

molecular diagnosis difficult; however, presymptomatic screen of other

at-risk members in a family with already identified ARPKD mutations

is straightforward and inexpensive.

TREATMENT

Autosomal Recessive Polycystic Kidney Disease

There is no specific therapy for ARPKD. Appropriate neona-

tal intensive care, blood pressure control, dialysis, and kidney

transplantation increase survival into adulthood. Complications of

hepatic fibrosis may necessitate liver transplantation. Patients with

severe Caroli disease may need portosystemic shunting. Tolvaptan,

an approved drug, functions by inhibiting the vasopressin pathway

through the blockade of the vasopressin receptor 2 (V2). Preclinical

studies conducted on a rat model of PKD, wherein the causative

gene of ARPKD, PKHD1, is mutated, revealed promising results.

These studies demonstrated a reduction in kidney cyst formation,

decreased cyst cell growth, and preserved kidney function following

tolvaptan administration. These findings suggest that the vasopres-

sin pathway may contribute to the progression of renal manifesta-

tions in ARPKD. A multinational, multicenter phase 3 clinical

trial is evaluating the safety and efficacy of the drug tolvaptan in

treating infants and children with ARPKD. Upcoming therapies

may target abnormal cell signaling mechanisms, as described above

for ADPKD.

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