Polycystic kidney disease

Polycystic kidney disease (PKD) is a progressive, genetic disorder of the kidneys. It occurs in humans and other animals. PKD is characterized by the presence of multiple cysts (polycystic) in both kidneys. The disease can also damage the liver, pancreas and rarely the heart and brain. The two major forms of polycystic kidney disease are distinguished by their patterns of inheritance.

Autosomal dominant polycystic kidney disease (ADPKD) is generally a late onset disorder characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. Kidney manifestations in this disorder include renal function abnormalities, hypertension, renal pain, and renal insufficiency. Approximately 50% of patients with ADPKD have end-stage renal disease (ESRD) by age 60 years. ADPKD is, however, a systemic disease with cysts in other organs such as the liver, seminal vesicles, pancreas, and arachnoid membrane and non-cystic abnormalities such as intracranial aneurysms and dolichoectasias, dilatation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias.

Initial human symptoms are hypertension, fatigue and mild pain and urinary tract infections. The disease can lead to total loss of kidney function - chronic renal failure and end stage renal disease (ESRD).

Autosomal recessive polycystic kidney disease (ARPCD)is much rarer that ADPRD and is often lethal. The signs and symptoms of the condition are usually apparent at birth or in early infancy.

Genetics

The disease exists both in an autosomal recessive and an autosomal dominant form. called ADPKD (autosomal dominant PKD or "Adult-onset PKD") is much more common but less severe. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 (chromosomal locus 16p13.3-p13.1); in 15% of patients mutations in PKD2 (chromosomal locus 4q21-q23) are causative.

The recessive form, called ARPKD (autosomal recessive polycystic kidney disease) is the less common variant, mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.

A very small number of families with polycystic kidney disease do not have apparent mutations in any of the three known genes. An unidentified gene or genes may also be responsible for this disease.

Polycystic kidney disease is one of the most common inherited disorders caused by mutations in a single gene. It affects about 500,000 people in the United States. The autosomal dominant form of the disease is much more common than the autosomal recessive form. Autosomal dominant polycystic kidney disease affects 1 in 400-1,000 people, while the autosomal recessive type is estimated to occur in 1 in 20,000-40,000 people.

Biology

Recent studies in fundamental cell biology of cilia/flagella using experimental model organisms like green algae Chlamydomonas, round worm Caenorhabditis elegans and mouse Mus musculus shed light on the understanding of how PKD develops in the patients. Now the cellular signaling pathways initiated from the receptor proteins on the cilia are thought to be critical for normal renal cell development. Two PKD genes, PKD1 and PKD2, encode membrane proteins which localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel which allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulate its channel activity. The calcium ions are important cellular messengers which, in turn, trigger complicated biochemical pathways which lead to cell proliferation and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD.

Diagnosis

A definite diagnosis of ADPKD relies on imaging or molecular genetic testing. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations who are younger than age 30 years. Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis.

Molecular genetic testing by linkage analysis or direct mutation screening is available clinically; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. In the research setting, mutation detection rates of 50-75% have been obtained for PKD1 and ~75% for PKD2. Clinical testing of the PKD1 and PKD2 genes by direct sequence analysis is now available, with a detection rate for disease-causing mutations of 50-70%.

Genetic counseling may be helpful for families at risk for polycystic kidney disease.