Article: Polycystic kidney disease

Polycystic kidney disease (PKD) is a progressive, genetic disorder of the kidneys. It occurs in humans and other organisms. PKD is characterised 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 mater 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 monkey / human symptoms are hypertension, fatigue and mild to severe back or flank pain and urinary tract infections. The disease often leads to chronic renal failure and 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 recessive polycystic 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.

Polycystic kidneys

Genetics

The disease exists both in an autosomal recessive and an autosomal dominant form.

Autosominal dominant form

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 mutations in the gene PKD1 (chromosomal locus 16p13.3-p13.1); in 15% of patients mutations in PKD2 (chromosomal locus 4q21-q23) are causative.

• OMIM 173910, DDB 10262

Autosominal recessive form

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.

• OMIM 263200, DDB 10280

Other types

A 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.

Incidence/prevalence

Polycystic kidney disease is the most common life threatening genetic disease affecting over 12.5 million people worldwide. Autosomal dominant polycystic kidney disease affects about 1 in 500 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 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 proteins 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 proteins 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 apoptosis of these renal epithelial cells producing the characteristc multiple cysts of PKD. PKD may result from mutations of signaling and environmantal sensing proteins, 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 quiescence 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.

PKD and the "two hit" hypothesis:

The two hit hypothesis (aka Knudson hypothesis ) is often used to explain the manifestation of polycystic kidney disease later in life even though the mutation is present at birth. This term is borrowed from cancer research stating that both copies of the gene present in the genome have to be "silenced" before cancer manifests itself (in Knudson's case the silenced gene was Rb1) . In ADPKD the original "hit" is congenital (in either the PKD1 or PKD2 genes) and the subsequent "hit" occurs later in life as the cells grow and divide. The two hit hypothesis as it related to PKD was originally purposed by Reeders in 1992. Support for this hypothesis comes from the fact that ARPKD patients develop disease at birth, and somatic mutations in the "normal" copy of PKD1 or PKD2 have been found in cyst-lining epithelia

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.

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.

Reference

1. Nauli and Zhou BioEssays 26:844–856, 2004.

2. Grantham J.J et al The New England Journal of Medicine 354:2122-30, 2006.