Polycystic kidney disease

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

Autosomal dominantpolycystic 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 materand non-cystic abnormalities such as intracranial aneurysmsand dolichoectasias, dilatation of the aortic rootand dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias.

Initial human symptomsare hypertension, fatigueand mild painand urinary tract infections. The disease often leads to chronic renal failureand may result in total loss of kidney function, known as end stage renal disease(ESRD) which requires some form of renal replacement therapy(e.g. dialysis).

Autosomal recessivepolycystic kidney disease (ARPKD) is much rarer that ADPKD 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 recessiveand an autosomal dominantform. The 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 mutationsin 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/flagellausing experimental model organismslike the green algae Chlamydomonas, the round worm Caenorhabditis elegans and the mouse Mus musculus have shed light on how PKD develops in patients. All cilia and flagella are constructed and maintained, including localizing of protiens inserted into ciliary and flagellar membranes, by the process of intraflagellar transport. Environmental sensing and cellular signaling pathways initiated from proteins inserted into ciliary/flagellar membranes are thought to be critical for normal renal cell development and functioning. Membrane protiens which function in developmental and physiological environmental sensing and intracellular signalling are sorted to and localized to the cilia in renal epithelial cells by intraflagellar transport. These epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programed cell death or apoptosisof these renal epithelial cells producing the characteristc multiple cysts of PKD. PKD may result from mutations of signaling and environmantal sensing protiens, or failure in intraflagellar transport. 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 echogenickidneys 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 hepaticcysts, and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis.

Molecular genetic testingby linkage analysisor direct mutation screeningis 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, mutationdetection rates of 50-75% have been obtained for PKD1 and ~75% for PKD2. Clinical testing of the PKD1 and PKD2 genes by direct sequence analysisis now available, with a detection rate for disease-causing mutations of 50-70%.

Genetic counselingmay be helpful for families at risk for polycystic kidney disease.

In cats

Polycystic Kidney Disease (PKD) is also prevalent in Persian, Himalayan, and Exotic Cats.

There are 3 possible genotypes for PKD: 1) N/N (2 copies of the normal allele) 2) N/P Heterozygote (1 normal copy and 1 copy of the PKD mutation), or 3) P/P (2 copies of the PKD mutation)

PKD DNA testing is available to identify these genotypes to help cat breeders make more informed decisions about mating patterns[1].

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It uses material from the http://en.wikipedia.org/wiki/Polycystic+kidney+disease Wikipedia article Polycystic kidney disease.