Research Background
Polycystic Kidney Disease is a genetic disease that equally affects men, women and children, regardless of age, race, geography or ethnic origin. It comes in two forms: Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). ADPKD is the most common hereditary renal disease resulting from mutations in the PKD1 or PKD2 genes. It affects between 1 in 400 and 1 in 1,000 individuals or approximately 600,000 people in the United States and an estimated 12.5 million world-wide. A parent with ADPKD (the dominant form of the disease) has a 50% chance of passing the mutated gene to each of his/her children.
ARPKD is a relatively rare form of PKD that results from mutations in the PKHD1 gene. It affects 1 in 10,000 to 20,000 infants and often leads to death in the first month of life. Both parents of an ARPKD child carry the mutated gene, and they have a 25% chance of passing the disease to each of their children.
ADPKD is a systemic disorder with multiple extra-renal manifestations including mitral valve prolapse, intracranial aneurysms, liver cystic disease, diverticulitis and inguinal and ventral hernias. Risk factors for progression to ESRD have been identified in ADPKD individuals and include gene type, male gender, diagnosis in the first year of life, early age of onset of hypertension, increased renal volume or structural involvement, presence of certain gene polymorphisms, proteinuria or a history of gross hematuria, and three or more pregnancies in affected women. Current ongoing studies of rigorous blood pressure control demonstrate both reduction in proteinuria and a slower rate of loss of renal function. Although renal function may remain normal for many years of adulthood, by age 60, 50% of PKD patients (all mutations) are at Stage 5 renal function. They comprise 4.7% of those on dialysis.
Although there currently are no treatments to stop or slow disease progression in PKD, there are several drugs in Phase II/III clinical trials that have shown promising effects in cystic animal models: Tolvaptan (Otsuka), Rapamycin (Rapamune, Sirolimus, Everolimus), Octreotide (somatostatin). Learn more about PKD clinical trials.
Cyst formation and growth requires the involvement of at least three primary pathogenetic mechanisms: Abnormal regulation of epithelial cell growth. These cells exhibit abnormal responses to known growth stimulants and suppressors. In addition, increased proto-oncogene expression and dedifferentiation occur.
Abnormal trans-epithelial transport: Some studies have suggested that trans-epithelial fluid transport results in accumulation of fluid resulting in cyst expansion and growth. Translocation and alteration in function (aberrant, increased or diminished) of multiple transporters have been identified in epithelia lining cyst walls and play a role in the active trans-epithelial fluid transport found.
Remodeling of extra-cellular matrix: Some studies have suggested multiple components of the extra-cellular matrix surrounding cysts are present in increased or decreased amounts and demonstrate altered binding and adhesive abilities. These alterations may contribute to the extra-renal manifestations seen in this disorder.
ADPKD is a genetically heterogeneous disorder with two causative genes, PKD1 and PKD2, identified. PKD1 accounts for approximately 85% of all ADPKD families, PKD2 for the majority of the remainder. PKD1 is located on chromosome 16p13.3. It is a large gene comprised of 46 exons and encodes a ~14 kb transcript. Over 100 mutations have been identified to date with a different mutation in most families; no hot spots have been found. Mutational analysis of PKD1 has been hampered by complexity in the genomic organization, including highly homologous reduplication of parts of the gene elsewhere on chromosome 16. Expression of the ~4,300 amino acid integral membrane protein product of PKD1, polycystin-1, appears to be developmentally regulated and is necessary for normal renal growth and development. Functional studies have been hampered by difficulties in expressing the full-length protein and immunocytochemical studies have been complicated by low levels of expression and by differences in binding specificity of the reagents used. Homozygous Pkd1 knockout mice display abnormalities in kidney, pancreas and vascular development and die during the embryonic/neonatal period. Pkd1 heterozygous mice show late onset development of renal and hepatic cystic abnormalities. The function of polycystin-1 is at present not completely understood. Functional homologues have been identified in humans, mouse, fish, sea urchin, drosophila, and the nematode, C. elegans.
PKD2 is located on chromosome 4q21-23. It has 15 exons and encodes an integral membrane glycoprotein of 968 amino acids. Over 50 mutations in a majority of identified affected families have been described to date and, again, no hot spots have been found. Pkd2 knockout mice die during embryogenesis with abnormalities present in kidney, pancreas and heart development. Heterozygous Pkd2 mutant mice carrying a second unstable Pkd2 allele have offered an adult mouse model of ADPKD that most closely resembles the human disease phenotype. Polycystin-2, the PKD2 gene product, appears to work as a cation channel subunit. Two additional PKD2-gene family members have been identified in humans and several have been found in other species as well. Indirect evidence suggests that polycystin-1 and polycystin-2 interact at their carboxy terminals cytoplasmic domains. Polycystin-1 and polycystin-2 have been localized in primary cilia, a small organelle projecting from the surface of the cell, suggesting that this polycystin protein complex may play a role in monitoring flow in kidney tubules.
Autosomal recessive polycystic kidney disease (ARPKD) involves a single gene, PKHD1, located on chromosome 6p21-p12. This gene has recently been identified and encodes a protein of 4074 amino acids that has been named fibrocystin. Most patients are compound heterozygotes and two truncating mutations are associated with severe disease. ARPKD has an estimated incidence of 1:20,000 live births. Most cases present in infancy with the characteristic fetal phenotype of enlarged, echogenic kidneys, and oligohydramnios due to poor renal output in utero. As a result, approximately 40% of affected neonates have profound respiratory insufficiency and die within the first few hours of life. In those infants who survive the perinatal period, the clinical course is quite variable. Disease-related clinical characteristics of these children include hypertension, progressive renal insufficiency and portal tract fibrosis. At the present time, there are no precise prognostic markers for disease progression, either in utero or post-natally, and the molecular pathogenesis of ARPKD is largely undefined.
Mutations of other genes, in addition to the mutations of the genes responsible for ADPKD and ARPKD, can cause polycystic kidney disease in humans and other animal species. Furthermore variations in other genes ("modifier genes") can influence the severity of polycystic kidney disease. Further identification and understanding of these genes at a molecular level is important for the elucidation of the mechanisms involved in cystogenesis and the development of potential therapies.
Autosomal dominant polycystic liver disease (ADPLD) is a distinct entity that can occur independently from ADPKD. ADPLD, like ADPKD is genetically heterogeneous. One of the genes responsible for ADPLD, PRKCSH, has been recently identified. PRKCSH encodes a previously described human protein termed protein kinase C substrate 80K-H or non-catalytic beta-subunit of glucosidase II. Putative functions of this protein include the regulation of protein N-glycosylation in the endoplasmic reticulum and of Fibroblast Growth Factor signal transduction.