Autosomal-dominante polyzystische Nierenerkrankung

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, and it is even one of the most common hereditary diseases in man. In 85% of the cases the disease is caused by mutations in the PKD1 gene, which encodes for the ciliary protein polycystin-1. A milder variant of the disease is caused by mutations in the PKD2 gene, which encodes for the calcium channel-related protein polycystin-2. The disease is characterized by the progressive development of innumerable cysts in both kidneys, which gradually replace the normal kidney tissue. In ADPKD patients the inexorable cyst growth leads to a progressive deterioration of renal function over decades, which ultimately can only be treated by renal replacement therapy or renal transplantation. Until now a causal treatment was not available, and treatment options were limited to regular clinical controls and treatment of complications (hypertension, cyst infections). Several promising clinical studies are currently examining new or even existing drugs as therapeutic options to retard cyst growth in ADPKD (vasopressin receptor-2 antagonists [V2RA], mammalian target of rapamycin [mTOR] inhibitors, somatostatin). It can be anticipated that ADPKD patients will benefit from these new treatment options in the near future.     

Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in the genes for polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2). Typical onset is in middle age, with gradual replacement of renal tissue with thousands of fluid-filled cysts, resulting in end-stage renal disease requiring dialysis or kidney transplantation. There currently are no approved therapies to slow or cure ADPKD. Mutations in the PKD1 and PKD2 genes abnormally activate multiple signaling proteins and pathways regulating cell proliferation, many of which we observe, through network construction, to be regulated by heat shock protein 90 (HSP90). Inhibiting HSP90 with a small molecule, STA-2842, induces the degradation of many ADPKD-relevant HSP90 client proteins in Pkd1^−/− primary kidney cells and in vivo. Using a conditional Cre-mediated mouse model to inactivate Pkd1 in vivo, we find that weekly administration of STA-2842 over 10 wk significantly reduces initial formation of renal cysts and kidney growth and slows the progression of these phenotypes in mice with preexisting cysts. These improved disease phenotypes are accompanied by improved indicators of kidney function and reduced expression and activity of HSP90 clients and their effectors, with the degree of inhibition correlating with cystic expansion in individual animals. Pharmacokinetic analysis indicates that HSP90 is overexpressed and HSP90 inhibitors are selectively retained in cystic versus normal kidney tissue, analogous to the situation observed in solid tumors. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.     

Aktuelle Erkenntnisse zur Pathogenese der ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent hereditary diseases. With a prevalence of up to 1:1000 approximately 5 million patients worldwide suffer from ADPKD, corresponding to about 100,000 patients in Germany. As a systemic disease ADPKD always affects both kidneys. During the course of the disease functional kidney tissue is replaced by liquid-filled cysts leading to a progressive loss of kidney function and end-stage renal disease at a median age of 50 to 60 years. Recent studies identified the primary cilium, an antenna-like structure projecting from the apical surface of almost all kidney epithelial cells, as the central organelle in the pathogenesis of ADPKD. The primary cilium is now recognized as an important sensory organelle that receives signals from the environment and regulates cellular programs. A detailed understanding of ciliary function and the molecular pathogenesis of ADPKD is of special interest. Based on this knowledge, novel therapeutic concepts for the treatment of this otherwise progressive disease are currently under development.     

Autosomal-dominante polyzystische Nierenerkrankung

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent human genetic kidney disease, affecting about 6 million people worldwide. It is characterized by progressive development of innumerable renal cysts that gradually replace normal kidney tissue, leading ultimately to the loss of renal function starting from the fourth decade of life. There is currently no causal therapy that slows or stops ADPKD progression. In animal models of polycystic kidney disease, a variety of potential therapies have been tested: vasopressin receptor-2 antagonists (VPV2RA), mammalian target of rapamycin inhibitors (mTORi), somatostatin and its analogs, inhibitors of CFTR, B-Raf, MEK, Src, tumor necrosis factor alpha, and cyclins. Currently the efficacy of VPV2RA, mTORi, somatostatin analogs, and inhibitors of the renin angiotensin aldosterone system is being clinically tested. It is hoped that this serious disease can be treated causally in the coming years.     

Mutational analysis of the PKD1 and PKD2 (type 1 and 2 dominant autosomal polycystic kidney) genes

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is caused by mutations in at least two different genes: PKD1 and PKD2. The study of mutations in these genes is very difficult nowadays. In this study we have analyzed the non reiterated region of the PKD1 gene and all the exons and intron exon boundaries of the PKD2 gene. The technique used to study these genes have been single strand conformation analysis and heteroduplex. We have found 25 differences within the DNA sequence of the PKD1 gene with respect to the published sequence. Seven of these changes correspond to nonsense, missense, frameshifting and splicing mutations. The rest of changes correspond to polymorphisms or rare DNA variants. In the PKD2 gene we have identified 8 new mutations and one polymorphism. Six of these mutations are frameshifting, one is missense and the other one is a large deletion of the PKD2 gene. The rate of mutation detection within the PKD1 gene has been 4% and the rate for PKD2 has been 100%. We have not observed any correlation between genotype and phenotype either in the PKD1 nor in the PKD2 gene. The mutation analysis of ADPKD genes is very difficult, specially for the PKD1 gene. The rate of mutation detection is higher in the PKD2 gene but the global efficacy of the technique is very low as PKD2 represents only 15% of ADPKD patients. Nowadays linkage analysis is still the most useful technique for the molecular diagnosis of ADPKD patients.     

Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.     

Recent advances in autosomal‐dominant polycystic kidney disease

Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease in adults, affecting one in every 1000 Australians. It is caused by loss‐of‐function heterozygous mutations in either PKD1 or PKD2 , which encode the proteins, polycystin‐1 and polycystin‐2 respectively. The disease hallmark is the development of hundreds of microscopic fluid‐filled cysts in the kidney during early childhood, which grow exponentially and continuously through life at varying rates (between 2% and 10% per year), causing loss of normal renal tissue and up to a 50% lifetime risk of dialysis‐dependent kidney failure. Other systemic complications include hypertensive cardiac disease, hepatic cysts, intracranial aneurysms, diverticular disease and hernias. Over the last two decades, advances in the genetics and pathogenesis of this disease have led to novel treatments that reduce the rate of renal cyst growth and may potentially delay the onset of kidney failure. New evidence indicates that conventional therapies (such as angiotensin inhibitors and statins) have mild attenuating effects on renal cyst growth and that systemic levels of vasopressin are critical for promoting renal cyst growth in the postnatal period. Identifying and integrating patient‐centred perspectives in clinical trials is also being advocated. This review will provide an update on recent advances in the clinical management of ADPKD.     

Polycystin 1 is required for the structural integrity of blood vessels

Autosomal dominant polycystic kidney disease (ADPKD), often caused by mutations in the PKD1 gene, is associated with life-threatening vascular abnormalities that are commonly attributed to the frequent occurrence of hypertension. A previously reported targeted mutation of the mouse homologue of PKD1 was not associated with vascular fragility, leading to the suggestion that the vascular lesion may be of a secondary nature. Here we demonstrate a primary role of PKD1 mutations in vascular fragility. Mouse embryos homozygous for the mutant allele (Pkd1(L)) exhibit s.c. edema, vascular leaks, and rupture of blood vessels, culminating in embryonic lethality at embryonic day 15.5. Kidney and pancreatic ductal cysts are present. The Pkd1-encoded protein, mouse polycystin 1, was detected in normal endothelium and the surrounding vascular smooth muscle cells. These data reveal a requisite role for polycystin 1 in maintaining the structural integrity of the vasculature as well as epithelium and suggest that the nature of the PKD1 mutation contributes to the phenotypic variance in ADPKD.     

Prevalence of Cysts in Seminal Tract and Abnormal Semen Parameters in Patients with Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Autosomal dominant polycystic kidney disease is a systemic disorder with a wide range of extrarenal involvement. The scope of this study was to analyze the prevalence of seminal cysts and to correlate these findings with the sperm parameters in patients with autosomal dominant polycystic kidney disease.Design, setting, participants, & measurements: A prospective study enrolled 30 adult men with autosomal dominant polycystic kidney disease. Of these 30 patients, 22 agreed to provide a semen sample for analysis, and 28 of 30 agreed to undergo an ultrasound rectal examination. Data obtained from the semen tests and from the ultrasound study were compared.Results: Cysts in the seminal tract were present in 10 (43.47%) of 28 individuals. Twenty of 22 patients showed abnormal semen parameters, with asthenozoospermia as the most common finding. No correlation between ultrasound findings and sperm abnormalities was observed.Conclusions: The presence of cysts in the seminal tract is remarkably high (43.47%); however, this finding does not correlate with sperm abnormalities, which are also a frequent finding, especially asthenozoospermia. This semen abnormality is probably related to the abnormal function of polycystins. More attention should be paid to reproductive aspects in the initial evaluation of patients with autosomal dominant polycystic kidney disease before their ability to conceive is further impaired by uremia.Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders, occurring in approximately one of 1000 individuals in the general population. ADPKD is a genetically heterogeneous disorder caused by mutations in either the PKD1 or the PKD2 gene, which encode for the proteins polycystin-1 and polycystin-2, respectively. Most ADPKD cases (>80%) are due to mutations of the PKD1 gene and are associated with an earlier onset and faster disease progression than the PKD2 phenotype. ADPKD has been widely studied during the past decade, having shed new light on polycystin structure and function. Polycystin-1 and -2 are highly conserved ubiquitous transmembrane proteins that, in the kidney, are located in epithelial cells of renal tubules, in particular in the primary cilia at the luminal side of the tubules, as well as in other areas of the renal cell epithelium. Polycystin-1 is a large protein with a long extracellular N-terminal region, 11 transmembrane domains, and a short intracellular C-terminal tail. Polycystin-2 is structurally related to the transient receptor potential channel family, and it is known to function as a nonselective cation channel permeable to Ca². Polycystin-1 and -2 form heteromeric complexes and co-localize in the primary cilium of renal epithelial cells. The primary cilium is a long nonmotile tubular structure located in the apical surface of epithelial cells in renal tubules. Its function was unknown for a long time; however, recent studies proposed a role of the primary cilium as a mechanoreceptor that may sense changes in apical fluid flow and may be able to transduce them into an intracellular Ca²⁺ signaling response (1). This model involves the participation of polycystin-1 as a mechanical sensor of ciliary bending induced by luminal fluid flow. Bending of the cilium would cause a conformational change in polycystin-1 that would in turn activate polycystin-2–associated Ca²⁺ channel, increasing the intracellular Ca²⁺ concentration and triggering intracellular signaling pathways leading to normal kidney development.Many extrarenal features are well known in ADPKD. Hepatic cysts are the most common extrarenal manifestation of ADPKD. More than 75% of individuals who have ADPKD and are older than 60 yr have hepatic cysts (2). The prevalence of intracranial aneurysms is approximately 10%, and the prevalence of pancreatic cysts is 6 to 9%; however, other extrarenal organ involvement, such as aortic abdominal aneurysms, colonic diverticulae, and cardiac valve abnormalities, has been questioned for ADPKD. Other rare associations have been reported, but their prevalence remains unknown. This could be the case for thoracic aortic aneurysm, hernias, and seminal tract cysts.There have been several case reports on cysts in epididymis, seminal vesicles, prostate, and testes in patients with ADPKD. Also some cases of infertility have been reported. Even a structural abnormality in the sperm from some patients with ADPKD has been reported; however, ADPKD is not a disease that is considered to cause infertility. Fewer than 10% of cases are sporadic, and in the remaining 90%, the disease has been inherited independently from the mother or the father. Moreover, large pedigrees are frequent. The aim of this study was to determine the prevalence of cysts in the seminal tract and to correlate it with sperm parameters.     

Cardiovascular polycystins: insights from autosomal dominant polycystic kidney disease and transgenic animal models

Mutations in the PKD1 and PKD2 polycystin genes are responsible for autosomal dominant polycystic kidney disease (ADPKD), one of the most prevalent genetic kidney disorders. ADPKD is a multisystem disease characterized by the formation of numerous fluid-filled cysts in the kidneys, the pancreas, and the liver. Moreover, major cardiovascular manifestations are common complications in ADPKD. Intracranial aneurysms and arterial hypertension are among the leading causes of mortality in this disease. In the present review, we summarize our current understanding of the role of polycystins in the development, maintenance, and function of the cardiovascular system.     

Polycystic liver disease without autosomal dominant polycystic kidney disease

Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.     

Historia natural de la poliquistosis renal autosómica dominante en Córdoba: utilidad de una base de datos para agrupar familias y mutaciones

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease. Today, the knowledge of its genetic base has made it possible to develop strategies that prevent the transmission of the disease.ObjectivesThe objective of the study was to analyze the natural history of ADPKD in the Province of Córdoba and to design a database that allows families and different mutations to be grouped.Patients and methodsAll patients (n = 678) diagnosed with ADPKD followed up in the Cordoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed.ResultsThe prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (Log-rank p = 0.000). We have genetically identified 43.8% of the population, detecting mutations in PKD1 in 61.2% and in PKD2 in 37.4% of cases. The most frequent mutation was detected in PKD2 (c.2159del) in 68 patients belonging to 10 different families. The one with the worst renal prognosis was detected in PKD1 (c.9893G>A). These patients required RRT at a median age of 38.7 years.ConclusionsThe renal survival of ADPKD in the Province of Córdoba is similar to that described in the literature. Mutations in PKD2 were detected in 37.4%. Our strategy allows us to know the genetic bases of our population with a great saving of resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis.     

Hepatic and renal manifestations in autosomal dominant polycystic kidney disease: a dichotomy of two ends of a spectrum

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder. It is the most common genetic cause of end-stage renal disease. One frequent extra-renal manifestation is hepatic cyst formation. The majority of ADPKD patients develop complications as a result of renal cyst formation; however, a small proportion develop extensive hepatic disease with minor renal features. Both phenotypes seem to represent the spectrum of ADPKD. This review discusses the current understanding of the pathogenesis of the disease, its manifestations and the mechanisms of cyst formation. Furthermore, it focuses on monitoring the disease and the treatment options currently available.     

Isolated polycystic liver disease as a distinct genetic disease,unlinked to polycystic kidney disease 1 and polycystic kidney disease 2

Polycystic liver disease (PLD) is proven to occur either sporadically or in association with autosomal dominant polycystic kidney disease (ADPKD), whereas the existence of an isolated (i.e., without any kidney cyst) familial form is disputed. We describe a family with definitely isolated PLD transmitted through three generations and exclude the linkage of the disease to the genetic markers of PKD1 and PKD2, the two main loci responsible for ADPKD. These findings strongly support the existence of PLD as a genetic disease distinct from the known forms of ADPKD. (Hepatology 1996 Feb;23(2):249-52)     

The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.     

Autosomal-dominante polyzystische Nierenerkrankung

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease and is the underlying cause for renal failure in 15% of patients receiving a kidney transplant in Germany. The diagnosis is made by ultrasound and family history and genetic testing does not play any role in routine clinical practice. Half of the affected individuals will require renal replacement therapy between 50 and 60 years of age. The most common complications are cyst infections and cyst-related pain and the most severe but rare complication is rupture of an intracranial aneurysm. The mainstay of ADPKD therapy is blood pressure control and modification of risk factors as well as management of complications. This review surveys the current literature on ADPKD and special attention is given to novel observations on the early course of ADPKD in children, new data on intracranial aneurysms and results from clinical intervention trials.     

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??Abstract??Autosomal dominant polycystic kidney disease (ADPKD) is a common single-gene inherited kidney disease??and it is also the fourth leading cause of end-stage renal disease (ESRD).Currently??no effective treatment exists to delay ADPKD progression.The present strategy is to inhibit ADPKD progression and control complications.In recent years??with the development of radiological and molecular genetical techniques??researchers were focusing on using imaging methods to evaluate ADPKD progression??and promising therapies included blockade of RAAS??inhibition of cell proliferation and abnormal cyst fluid secretion??and other new diagnostic and treatment strategies.Further investigations of these issues will help to elucidate the pathogenic mechanisms of ADPKD and lay the basis for clinical cure of this disease in the future.     

Aktuelle Therapiestudien für die Indikation zystischer Nierenerkrankungen

Inherited cystic kidney diseases are a heterogeneous group of rare diseases. Based on molecular biological findings approved drugs have already been recently tested for the new indications for autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex. For ADPKD it is important to note that renal function remains stable for decades so the effectiveness of treatment is determined by renal size as a surrogate marker of disease burden. In a 3-year study of 1,445 ADPKD patients tolvaptan, an aquaretic agent, decreased the growth of kidneys, renal function loss and kidney pain. The long-acting somatostatins octreotide and lanreotide moderately decreased liver and kidney size in patients with ADPKD and polycystic liver disease. The mTOR inhibitors sirolimus and everolimus were ineffective for the indications of ADPKD while these drugs shrunk the renal angiomyolipomas associated with tuberous sclerosis. Health authorities will decide this year on the approval of tolvaptan for ADPKD and of everolimus for the indications for tuberous sclerosis complex.     

Documento de consenso de poliquistosis renal autosómica dominante del grupo de trabajo de enfermedades hereditarias de la Sociedad Española de Nefrología. Revisión 2020

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6–10% of patients on kidney replacement therapy (KRT).Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.     

Chronic pancreatitis with polycystic kidney disease: A rare coincidence?

IntroductionIn children, chronic pancreatitis (CP) is usually associated with anatomical anomalies of the pancreas and biliary tract or is genetically determined. Autosomal dominant polycystic kidney disease (ADPKD) may present with extrarenal cyst formation, sometimes involving the pancreas. Large enough, these cysts may cause pancreatitis in ADPKD patients.Case presentationHerein, we present a case of a 12-year-old Caucasian girl with recurrent pancreatitis with no identifiable traumatic, metabolic, infectious, drug, or immunologic causes. Structural anomalies of the pancreas, including cysts, were ruled out by imaging. However, bilateral cystic kidneys were found as an incidental finding. Her family history was negative for pancreatitis, but positive for polycystic kidney disease. Molecular analysis of ADPKD-causing mutations revealed a novel c.9659C>A (p.Ser3220*) mutation in the PKD1 gene confirming the clinical suspicion of ADPKD. Although CP may rarely occur as an extrarenal manifestation of ADPKD with pancreatic cysts, it is unusual in their absence. Thus, molecular analysis of pancreatitis susceptibility genes was performed and a homozygous pathologic c.180C>T (p.G60=) variant of the CTRC gene, known to increase the risk of CP, was confirmed.ConclusionThis is the first reported case of a pediatric patient with coincidence of genetically determined CP and ADPKD. Occurrence of pancreatitis in children with ADPKD without pancreatic cysts warrants further investigation of CP causing mutations.