Polycystic kidney disease
Encyclopedia
Autosomal dominant polycystic kidney disease ("ADPKD", "autosomal dominant PKD" or "Adult-onset PKD") is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels. Approximately 50% of people with this disease will develop end stage kidney disease
and require dialysis
or kidney transplantation
. Progression to end stage kidney disease usually happens in the 4th to 6th decades of life. Autosomal dominant polycystic kidney disease occurs worldwide and affects about 1 in 400 to 1 in 1000 people.
Defects in two genes are thought to be responsible for ADPKD. In 85% of patients, ADPKD is caused by mutation
s in the gene
PKD1
on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative.
Autosomal recessive polycystic kidney disease is a distinct disease that also leads to cysts in the kidneys and liver, typically presents in childhood, only affects about 1 in 20,000 people and has different causes and prognosis.
and the mouse Mus musculus have shed light on how PKD develops in human patients. Biochemist James Calvet writes: "These discoveries are a testament to the power of genetics and the importance of animal models. Who would have thought to look at cilia at all as a basis for ADPKD if the direction had not been pointed out by these genetic studies?"
All cilia and flagella are constructed and maintained, by the process of intraflagellar transport
, a cellular function that is also essential for the insertion of proteins at specific sites along cilia and flagella membranes. These inserted membrane proteins can initiate environmental sensing and intracellular signaling pathways. They play a special role in the cilia of renal epithelial cells, and are thought to be critical for normal renal cell development and function and are sorted out and localized to the cilia of renal epithelial cells by the aforementioned intraflagellar transport
mechanism. Ciliated epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programmed cell death (apoptosis
) of these renal epithelial cells, producing the characteristic multiple cysts of PKD. PKD may result from mutations of signaling and environmental sensing proteins, or failure in intraflagellar transport
.
Two PKD genes, PKD1 and PKD2, encode membrane proteins that localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel that allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulates polycystin-2's channel activity. The calcium ions are important cellular messengers, which trigger complicated biochemical pathways that 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.
) 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 relates to PKD was originally proposed 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
s, both genetic syndromes
and genetic diseases
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
root cause of the widely-varying, phenotypically
-observed disorders. Thus, PKD is a ciliopathy
. Other known ciliopathies include primary ciliary dyskinesia
, Bardet-Biedl syndrome
, polycystic liver disease
, nephronophthisis
, Alstrom syndrome
, Meckel-Gruber syndrome and some forms of retinal degeneration
.
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 gene
s, 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.
may prevent cyst formation. Although not well-proven, treatment of hypertension and a low protein diet may slow progression of the disease.
Between PKD1 and PKD2, the former has the worse prognosis.
End stage renal disease
End stage renal disease may refer to:* End-stage renal disease, also known as chronic kidney disease , specifically the fifth stage of CKD...
and require dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
or kidney transplantation
Kidney transplantation
Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ...
. Progression to end stage kidney disease usually happens in the 4th to 6th decades of life. Autosomal dominant polycystic kidney disease occurs worldwide and affects about 1 in 400 to 1 in 1000 people.
Defects in two genes are thought to be responsible for ADPKD. In 85% of patients, ADPKD is caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
PKD1
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative.
Autosomal recessive polycystic kidney disease is a distinct disease that also leads to cysts in the kidneys and liver, typically presents in childhood, only affects about 1 in 20,000 people and has different causes and prognosis.
Pathophysiology
Recent studies in fundamental cell biology of cilia and flagella using experimental model organisms such as the round worm Caenorhabditis elegansCaenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and the mouse Mus musculus have shed light on how PKD develops in human patients. Biochemist James Calvet writes: "These discoveries are a testament to the power of genetics and the importance of animal models. Who would have thought to look at cilia at all as a basis for ADPKD if the direction had not been pointed out by these genetic studies?"
All cilia and flagella are constructed and maintained, by the process of intraflagellar transport
Intraflagellar transport
Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface...
, a cellular function that is also essential for the insertion of proteins at specific sites along cilia and flagella membranes. These inserted membrane proteins can initiate environmental sensing and intracellular signaling pathways. They play a special role in the cilia of renal epithelial cells, and are thought to be critical for normal renal cell development and function and are sorted out and localized to the cilia of renal epithelial cells by the aforementioned intraflagellar transport
Intraflagellar transport
Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface...
mechanism. Ciliated epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programmed cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
) of these renal epithelial cells, producing the characteristic multiple cysts of PKD. PKD may result from mutations of signaling and environmental sensing proteins, or failure in intraflagellar transport
Intraflagellar transport
Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface...
.
PKD and the "two hit" hypothesis
The two hit hypothesis (aka Knudson hypothesisKnudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes...
) 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 relates to PKD was originally proposed by Reeders in 1992. Support for this hypothesis comes from the fact that ARPKD patients develop disease at birth, and somatic mutations
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the "normal" copy of PKD1 or PKD2 have been found in cyst-lining epithelia
Relation to other rare genetic disorders
Recent findings in genetic research have suggested that a large number of genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s, both genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
root cause of the widely-varying, phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
-observed disorders. Thus, PKD is a ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
. Other known ciliopathies include primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, Bardet-Biedl syndrome
Bardet-Biedl syndrome
The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.-Summary of the...
, polycystic liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Alstrom syndrome
Alstrom syndrome
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in...
, Meckel-Gruber syndrome and some forms of retinal degeneration
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
.
Diagnosis
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
. 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
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
; 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
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
by linkage analysis or direct mutation screening is available clinically; however, genetic heterogeneity is a significant complication to molecular genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
. 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
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
and PKD2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, as well as marked allelic heterogeneity
Allelic heterogeneity
Allelic heterogeneity is the phenomenon in which different mutations at the same locus cause the same disorder. For example, β-thalassemia may be caused by several different mutations in the β-globin gene. It is a type of genetic heterogeneity....
, present obstacles to molecular testing by direct DNA analysis. In the research setting, mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
detection rates of 50-75% have been obtained for PKD1
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
and ~75% for PKD2. Clinical testing of the PKD1
PKD1
Polycystin-1 is a protein that in humans is encoded by the PKD1 gene.-Gene product:-Function:Polycystin-1 is a glycoprotein which contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail...
and PKD2 genes by direct sequence analysis
Sequence analysis
In bioinformatics, the term sequence analysis refers to the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alignment, searches against biological...
is now available, with a detection rate for disease-causing mutations of 50-70%.
Genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
may be helpful for families at risk for polycystic kidney disease.
Treatment
Although a cure for PKD is not available, treatment can ease the symptoms and prolong life.- PainPainPain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
: Over-the-counter pain medications, such as paracetamolParacetamolParacetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
can relieve pain. For most but not all cases of severe pain, surgery to shrink cysts can relieve pain in the back and flanks. However, surgery provides only temporary relief and usually does not slow the disease's progression toward kidney failure.
- Urinary tract infectionUrinary tract infectionA urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s: Patients with PKD tend to have frequent urinary tract infections, which can be treated with antibioticAntibioticAn antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s. Early treatment is important, because infection can spread from the urinary tract to the cysts in the kidneys. Cyst infections are difficult to treat because many antibiotics do not penetrate into the cysts. However, some antibiotics are effective.
- High blood pressure: Keeping blood pressure under control can slow the effects of PKD. Lifestyle changes including low salt diet and various medications especially ACE inhibitors and angiotensin receptor blockers can lower high blood pressure.Recommended target BP in these patients is 130/80 mm Hg or lower.
- End-stage renal disease: There are two options for replacing kidney functions: dialysisDialysisIn medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
or transplantation. Healthy (non-PKD) kidneys transplanted into PKD patients do not develop cysts.
Prognosis
Despite significant research, prognosis of this disease has changed little over time. It is suggested that avoidance of caffeineCaffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
may prevent cyst formation. Although not well-proven, treatment of hypertension and a low protein diet may slow progression of the disease.
Between PKD1 and PKD2, the former has the worse prognosis.
External links
- Photo demonstrating size of polycystic kidneys
- http://kidney.niddk.nih.gov/kudiseases/pubs/polycystic/index.htm
- http://www.ncbi.nlm.nih.gov/disease/PKD.html
- The Polycystic Kidney Disease Foundation website - more details on trials, treatments, nutrition, and support.
