|Year : 2003 | Volume
| Issue : 3 | Page : 296-304
|Autosomal Dominant Polycystic Kidney Disease: An Update
Muhammad Ziad Souqiyyeh
Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia
Click here for correspondence address and email
|How to cite this article:|
Souqiyyeh MZ. Autosomal Dominant Polycystic Kidney Disease: An Update. Saudi J Kidney Dis Transpl 2003;14:296-304
| Introduction|| |
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent inherited disorders, with an incidence of 1 in 1000.  It is also the most frequent genetic cause of renal failure in adults. It accounts for approximately 10% of cases of endstage renal disease (ESRD). The disease is characterized by progressive cystic dilatation of the renal tubules leading to ESRD in adult life. Hepatic cysts, cerebral aneurysms and cardiac valve abnormalities may also be found. 
The disease is genetically heterogeneous and can be caused by a mutation in at least three different genes. Approximately 85% of the affected individuals have a mutation at the PKD1 locus on chromosome 16p13,3.  Other loci, PKD2 on chromosome 4q 13-23  and PKD3  have been reported. However, only few mutations have been found since the PKD1 gene was identified in 1994. , It is expected that the majority of mutations at the PKD1 locus will be small deletions, insertions and point mutations.
It is not known yet what function of the product from the PKD1 gene is, and how a mutation in this gene gives rise to the disease. The PKD1 product, polycystin, is not a member of previously described gene family, but contains several structural motifs that are present in proteins of known function. ,
Most of these domains are present in the extracellular parts of proteins involved in interaction with other proteins and carbohydrates. The PKD1 gene product also contains potential transmembrane sequences. The molecule is likely to be involved in cell-cell or cell-matrix interactions, which is consistent with the different manifestations of the polycystic disease. ,
| Pathogenesis|| |
The PKD1 gene is very large, consisting of 46 exons distributed over 52 kb of genomic DNA. , The gene encodes a 14.1-kb mRNA transcript that is translated into a protein composed of 4302 amino acids. Interestingly, the region of the gene extending from exon 1 to exon 33 is duplicated at six other sites on chromosome 16p. The duplicated genes are expressed as mRNA transcripts and may represent pseudogenes.  Their existence has hindered mutational analysis because it can be difficult to distinguish mutations of PKD1 from mutations of the duplicated genes. More recently, with the use of long-range polymerase chain reaction (PCR), denaturing high pressure liquid chromatography (DHPLC), and the protein truncation test, mutations in the duplicated region of the PKD1 gene have been identified. ,,
Different types of mutations have been observed including splice site, in-frame, and out-of-frame deletions and insertions, nonsense mutations, and missense mutations. The out-of-frame deletions/insertions and nonsense mutations are very likely to represent inactivating mutations. No correlations between specific mutations and specific clinical manifestations have been identified, but mutations in the 5Lend of the gene appear to be associated with earlier onset disease than mutations in the 3Leend. 
Cysts arise from the tubular portion of the nephron as well as the renal collecting system. However, although all cells of the nephron carry the same germline mutation, only a few cysts arise per nephron. Many nephrons appear completely normal.  Therefore, ADPKD is a focal disease that involves only a small fraction of cells in the kidney, even though all cells carry one copy of the mutated gene.
A two-hit model of cystogenesis has been proposed to explain the focal nature of ADPKD. In this model, a mutated PKD1 (or PKD2) gene is inherited from one parent and a wild-type gene is inherited from the unaffected parent. During the lifetime of the individual, the wild-type gene undergoes a somatic mutation and becomes inactivated. Complete loss of PKD1 (or PKD2) in cells
in which second mutations have occurred initiates cyst formation. Because somatic mutations are rare and will only occur in a relatively small number of cells, the formation of cysts will be focal 
If each renal cyst arises from a discrete second hit, then a relatively high rate of somatic mutagenesis would be required to explain the large number of cysts that are found in polycystic kidneys. The reason for the high rate of somatic mutagenesis in the kidney is not known. Homozygous mutations of PKD1 and PKD2 would be more deleterious than heterozygous mutations. Indeed, no humans with homozygous germline mutations of either PKD1 or PKD2 have been observed, presumably because homozygosity is lethal to the embryo.
| Animal models|| |
Similar genes to the human PKD1 and PKD2 genes exist in the mouse genome and knockout mice, that lack one or both copies of the PKD1 and PKD2 genes, have been created. ,, Heterozygous mice develop cysts in the kidney or liver late in life, whereas homozygous null mutant mice are embryonic lethal and develop severely cystic kidneys in utero. , Marker studies reveal that the cysts arise from all segments of the nephron and the renal collecting system. These results demonstrate that loss of PKD1 or PKD2 is sufficient to cause renal cysts and support the two-hit model.
Although the two-hit hypothesis explains many features of the disease, multiple mechanisms are likely to be involved. Mice with trans-heterozygous mutations of PKD1 and PKD2 exhibit more severe renal cystic disease than would be predicted by a simple additive effect of the cyst formation in singly heterozygous mice. 
A role for polycystin-1 in regulating exocytosis in kidney-derived cells has recently been proposed.  Several studies have suggested that polycystin-1 regulates G protein signaling.  G protein signaling pathways regulate processes that are important in cyst formation, such as fluid secretion, proliferation, cell polarity, and differentiation. 
A characteristic feature of cyst epithelial cells is an abnormally high rate of cellular proliferation.  Overexpression of fulllength polycystin-1 in MDCK cells inhibits cellular proliferation and suppresses cyst formation.  Recently, polycystin-1 was found to have a direct role in the regulation of the cell cycle by inducing cell cycle arrest at the G0/G1 transition. Progression through the cell cycle is controlled by cyclin-dependent kinases. 
Like polycystin-1, polycystin-2 is predicted to be an integral membrane protein. In the kidney, polycystin-2 like polycystin-1 is expressed in all nephron segments, with the possible exception of the thin limbs, but is absent from glomeruli. , The structure of polycystin-2 suggested that it might function as an ion channel, and single channel recordings as well as patch clamp analyses have shown that polycystin-2 is a nonselective cation channel that can conduct calcium ions. ,,
Polycystin-2 directly interacts with polycystin-1.  The interaction of polycystin-2 with polycystin-1 inhibits G protein signaling.  This may explain why mutations of either PKD1 or PKD2 produce diseases with identical clinical manifestations. Polycystin-2 is located in premedial Golgi compartments, primarily the endoplasmic reticulum and cell membrane, while polycystin-1 appears to be located in the plasma membrane. , Polycystin-2 activity increases cytosolic calcium, perhaps in local microenvironments, and that the isolated loss of the capacity to translocate calcium results in sufficient loss of function to cause polycystic kidney disease.
Polycystin-1 may function as a receptor for an as yet unidentified extracellular stimulus and signal to the cell interior through its interaction with polycystin-2. The signaling results in activation of calcium channels and increase in cytosolic calcium level that trigger exocytosis and changes in gene expression. A defect in exocytosis has been observed in cyst epithelial cells and may be responsible for the mislocalization of some basolateral membrane proteins to the apical membrane that has been found in PKD. ,
| Is PKD a Ciliary Disease?|| |
Renal tubular epithelial cells contain one to two primary cilia. Primary cilia have been identified in all segments of the nephron from Bowman's capsule to collecting ducts with the exception of intercalated cells. The primary cilia in the kidney are two to 10 µm in length and protrude from the apical cell membrane into the tubule lumen.  Immotile primary cilia may have a chemosensory or mechanosensory function.
Recent studies suggest that disorders of primary cilia may produce polycystic kidney disease. The involvement of cilia in ARPKD was first suggested by studies in the mouse.  There is a gene that encodes a novel protein, named polaris, which is expressed in ciliated cells and localizes to the ciliary axoneme and basal bodies.  Most cells in the kidney express polaris and studies suggest that mutations of polaris inhibit the assembly of primary cilia in kidney tubules and that this leads to polycystic kidney disease. The involvement of cilia in PKD is further supported by studies of the cpk mouse, which is a well- characterized, naturally occurring recessive mouse model of polycystic kidney disease. 
Recently polycystin-2 has been identified in the primary cilia of mammalian renal epithelial cells. In addition to localization in the endoplasmic reticulum, polycystin-2 colocalizes with ciliary tubulin in the cilia of cultured mouse and human kidney cells.  Furthermore, polycystin-1 is also expressed in renal cilia, where it co-localizes with cystin. These results further support the hypothesis that abnormalities of ciliary function play a role in the pathogenesis of PKD. The suggested functions of the primary cilia include facilitation of solute reabsorption, concentration of receptors for a urinary ligand, and monitoring of urinary flow. , Further studies are needed to elucidate the normal function of renal cilia and how alterations in ciliary structure and function lead to cyst formation.
No specific treatment for PKD currently exists, so it is hoped that a more complete understanding of the molecular pathogenesis of the disease will identify novel therapeutic strategies. Microtubule polymerization is an essential process in ciliogenesis. Taxanes such as paclitaxel inhibit cyst progression, and the salutary effects of these compounds are directly related to their ability to promote microtubule assembly in vitro.  This is consistent with the hypothesis that lack of cystin results in altered ciliary microtubule stability.
Therapy directed at increasing microtubule stability is unlikely to affect the mechanosensory defect hypothesized for the polycystins in the cilia. On the other hand, if the role of cilia in ADPKD is confirmed and if polycystin-2 is delivered to the ciliary membrane in the absence of polycystin-1, agonists of polycystin-2 channel activity that are filtered at the glomerulus could play a role in treating the most common form of ADPKD, the one caused by mutations in polycystin-1.
| Analysis of large families|| |
A recent survey found that only 7% of transplant recipients with ADPKD have used living related renal donors, and 13% of US transplant centers would not perform living related transplantations for patients with ADPKD.  The primary aim in screening potential living related kidney donors for ADPKD is not to diagnose ADPKD, but to firmly exclude the possibility that the donor will develop the disease in the future.  It is desirable that a screening test for ADPKD in familial donors has a negative predictive value (NPV) that is extremely close to 100%.
Ultrasound is a sensitive, inexpensive, and a non-invasive screening test for polycystic kidney disease. The standard ultrasound criterion for diagnosis of ADPKD is the finding of two or more cysts on one kidney, with at least one cyst on the contralateral kidney as well.  Ultrasound has a demonstrated NPV of 100% when used to screen patients aged older than 30 years with a family history (i.e., at 50% risk) of ADPKD. However, even applying this narrow ultra-sonographic standard, there is a 10% false-negative rate in relatives aged between 20 and 30 years for ADPKD.  Computed tomography (CT) and magnetic resonance imaging (MRI) can also be used for renal cyst detection. Because of their increased anatomic resolution, many investigators believe they are more sensitive than ultrasound in screening for ADPKD. ,
As an alternative to anatomic imaging, genetic linkage analysis is a highly sensitive method of donor screening, with 99% accuracy in the diagnosis of ADPKD and an NPV of almost 100%. Unfortunately, testing of at least two or more known affected family members and two to three generations is required to establish a linkage. ,
This greatly complicates the screening of potential familial kidney donors as members who do not wish to donate may also decline to undergo genetic testing. Genetic screening has a very high NPV, but currently is not practical for donor screening in most instances. Although the genes for the major forms of PKD have been identified, multiple mutations can occur in each gene, and any single mutation may or may not be associated with the clinical disease. 
If we are to increase the availability of living related renal transplantation for patients with ADPKD, we must develop a screening test with an NPV of 100% for potential donors who are aged younger than 30 years. Such single screening test is not available at present.
| Risk Factors and management before end-stage renal failure|| |
Hypertension, which is a common finding in patients with ADPKD, often occurs before the onset of renal insufficiency and is associated with a faster progression to ESRD and increased cardiovascular mortality.  Patients with proteinuria have higher blood pressures and lower creatinine clearances than non-proteinuric patients.  However, there are no long-term, prospective, randomized studies showing the impact of reduction of blood pressure and/or proteinuria on the progression of ADPKD.
Although the early detection and effective treatment of hypertension may be very important to both slow the renal progression and decrease the cardiovascular mortality in patients with ADPKD, there is no consensus about the type of anti-hypertensive agent most appropriate for patients with ADPKD. Activation of the renin-angiotensin-aldosterone system caused by cyst expansion and local renal ischemia is believed to have an important role in the development of hypertension in patients with ADPKD. In this regard, the use of angiotensin-converting enzyme (ACE) inhibitors may be the optimal therapy.  Calcium channel blockers, especially non-dihydropyridines, are alternatives to ACE inhibitors.
Some reports have suggested that ESRD may occur in patients with ADPKD with uncontrolled hypertension as early as at 45 years of age.  Thus, early intervention with appropriate anti-hypertensive therapy may have the potential of altering the rate of progression to ESRD in patients with ADPKD.
| Renal replacement therapy and prognosis|| |
ADPKD accounts for approximately 8 to 10% of patients receiving dialysis or renal transplantation for ESRD in the United States and Europe.
There are multiple extrarenal manifestations that include cystic involvement of other organs and connective tissue abnormalities. Major extrarenal manifestations are liver cysts, intracranial aneurysms, cardiac valvular disease, and perhaps diverticulosis. , Many other vascular abnormalities, including thoracic, iliac, and abdominal aortic aneurysms; coronary artery aneurysms; intracranial arterial dolichoectasia; intracranial arterial dissection; and megadolichobasilar artery have been reported in ADPKD patients.  These entities are uncommon, and their natural history is unknown.
There has been no formal or prospective analysis of this assumption. Paradoxically, survival on dialysis of ADPKD patients surpasses that of general dialysis patients. 
Mortality rates after attainment of ESRD are lower in patients with ADPKD than in non-diabetic control ESRD patients matched for age, gender, and year of development of ESRD. The survival advantage is evident across all principal causes of death categories. 
Cardiovascular disease, primarily coronary artery disease, and infections are the leading causes of death in ADPKD patients on renal replacement therapy. The extrarenal aspects of ADPKD did not contribute to morbidity and perhaps mortality in excess of that resulting from the development of ESRD. 
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Muhammad Ziad Souqiyyeh
Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh, 11417
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