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Contains fulltext : 218555.pdf (Publisher’s version ) (Closed access)

Background: Predictive genetic screening and testing is available for accurate and early diagnosis of hereditary autosomal polycystic kidney disease. However, the complex ethical and psychosocial implications can make decision-making challenging and data on patients' perspectives are limited. We aimed to describe patient and caregiver perspectives on the value and risks of genetic screening and testing for autosomal polycystic kidney disease (ADPKD). Method(s): 154 participants (120 patients and 34 caregivers) from 8 centres in Australia, France and Korea participated in 17 focus groups. Transcripts were analysed thematically. Result(s): We identified five themes: financial constraints (insecurity in the inability to obtain life insurance, self-doubt in limited work opportunities, financial barrier of test); futility in unpredictability (accepting erratic and diverse manifestation of disease, inevitable disease progression, daunted by perplexity of results); lacking autonomy and support in decisions (overwhelmed by ambiguous information, medicalising family planning, appeasing the family, financial barrier); seizing control of wellbeing (gaining confidence through disease management, reassurance in family resilience, hope for health innovations to benefit the next generation, minimalising regret with preparation); and anticipating impact on quality of life (comforted by lack of symptoms, decisional uncertainty in risk of inheriting PKD, judging the value of life with PKD in family planning, guilt in foetal testing or abortion). Conclusion(s): For patients with ADPKD, genetic screening or testing provides an opportunity for them to take ownership of their health through family planning and preventive measures. However, they are also concerned and uncertain about the accessibility of these services, psychological sequelae of testing, and potential financial consequences. Patient-centred genetic counselling and education that addresses patients' concerns may support in

Item does not contain fulltext, BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, >/=60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m(2) of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m(2) were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m(2) (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m(2) (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m(2); 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin

Contains fulltext : 177029.pdf (publisher's version ) (Open Access), It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype. To study the role of PDE1A in a mammalian system, we used a TALEN pair to Pde1a exon 7, targeting the histidine-aspartic acid dipeptide involved in ligating the active site Zn++ ion to generate two Pde1a null mouse lines. Pde1a mutants had a mild renal cystic disease and a urine concentrating defect (associated with upregulation of PDE4 activity and decreased protein kinase A dependent phosphorylation of aquaporin-2) on a wild-type genetic background and aggravated renal cystic disease on a Pkd2WS25/- background. Pde1a mutants additionally had lower aortic blood pressure and increased left ventricular (LV) ejection fraction, without a change in LV mass index, consistent with the high aortic and low cardiac expression of Pde1a in wild-type mice. These results support an important role of PDE1A in the renal pathogenesis of ADPKD and in the regulation of blood pressure.

Item does not contain fulltext, BACKGROUND: Cyst infection is one of the complications of autosomal dominant polycystic kidney disease and polycystic liver disease. The diagnosis is typically made on a mix of clinical, laboratory and imaging abnormalities but the importance of individual items is uncertain. We aimed to perform a Delphi survey amongst physicians to achieve consensus on diagnostic criteria. METHODS: We retrieved diagnostic items from the literature and conducted physician and patient interviews. All items were combined to create the online questionnaire. Participants rated each item during 3 consecutive rounds. Items were rated for diagnostic helpfulness for hepatic and renal cyst infection on a 9-point scale with anchors, from extremely unimportant (n = 1) to extremely important (n = 9). We determined consensus with the disagreement index. The median rating of each item was calculated and categorized into inappropriate (/=6.5). By combining all items that reached an appropriate consensus rating, we developed a diagnostic algorithm based on expert consensus. RESULTS: We invited 58 physicians to participate in the survey. In total, 35 (60%) responded to round 1 of which 91% (n = 32) and 86% (n = 30) responded to round 2 and 3, respectively. The final panel included 23 nephrologists, 5 hepatologists, a nuclear medicine specialist and an infectious disease physician from 11 countries (male 67%, mean age 47 +/- 11 years, median clinical experience 21 years). The panel rated the diagnostic helpfulness of 59 potential items. Ultimately, 22 hepatic and 26 renal items were rated appropriate, including positive blood cultures and fluorodeoxyglucose positron-emission CT imaging. Ultrasonography and absence of intracystic bleeding were amongst those deemed uncertain or inappropriate. Subsequently, by combining items rated appropriate, we developed a clinical tool to diagnose hepatic and renal cyst infection. CONCLUSIONS: We identified diagnostic it

Item does not contain fulltext, BACKGROUND & AIMS: Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. METHODS: We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. RESULTS: We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). CONCLUSION: Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.

Item does not contain fulltext, Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1- or Pde3-knockout mice on the Pkd2(-/WS25) background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling (PDE1), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) -driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2(-/WS25) mice, knockout of Pde1a, Pde1c, or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase A-phosphorylated (Ser133) cAMP-responsive binding protein (P-CREB), activating transcription factor-1, and CREB-induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2(-/) (WS25);Pde1a(-/-), Pkd2(-) (/WS25);Pde1c(-/-), and Pkd2(-/) (WS25);Pde3a(-/-) kidneys. The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2(-/WS25);Pde3a(-/-) mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium- and calmodulin-dependent PDEs (PDE1A and PDE1C) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR-driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.

Contains fulltext : 153987.pdf (publisher's version ) (Closed access), BACKGROUND: Polycystic liver disease is associated with impaired health-related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease. AIM: To determine whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease. METHODS: We pooled data from two randomized, double-blind, placebo-controlled trials that evaluated HRQL using the Short-Form 36 (SF-36) in 96 polycystic liver disease patients treated 6-12 months with somatostatin analogues or placebo. The SF-36 contains a summarizing physical and mental component score and was administered at baseline and at the end of treatment. We used random effect models to delineate the effect of somatostatin analogues on HRQL. We determined the effect of demographics, height-adjusted liver volume, change in liver volume, somatostatin analogue-associated side effects with change in HRQL. In patients with autosomal dominant polycystic kidney disease, we estimated the effect of height-adjusted kidney volume and change in kidney volume in relation to HRQL. RESULTS: Physical component scores improved with somatostatin analogues, but remained unchanged with placebo (3.41 +/- 1.29 vs. -0.71 +/- 1.54, P = 0.044). Treatment had no impact on the mental component score. Large liver volume was independently associated with larger HRQL decline during follow up (-4.04 +/- 2.02 points per logarithm liver volume, P = 0.049). In autosomal dominant polycystic kidney disease, patients with large liver and kidney volumes had larger decline in HRQL (5.36 +/- 2.54 points per logarithm liver volume; P = 0.040 and -4.00 +/- 1.88 per logarithm kidney volume; P = 0.039). CONCLUSION: Somatostatin analogues improve HRQL in symptomatic polycystic liver disease. Halting the progressive nature of polycystic liver disease is necessary to prevent further decline of HRQL in severe hepatomegaly.

Item does not contain fulltext, BACKGROUND & AIMS: Polycystic liver disease (PLD) follows a progressive course ultimately leading to severe hepatomegaly and mechanical complaints in a subset of patients. It is still unknown to what extent this compromises health-related quality of life (HRQL). Our aim was to determine HRQL in PLD patients and investigate its association with concurrent abdominal symptoms and liver volume. METHODS: Pooled data of 92 severe PLD patients from two randomized clinical trials were used for our cross-sectional analysis. HRQL was assessed using the generic short-form health survey (SF-36) resulting in eight scale scores and the summarizing physical (PCS) and mental component score (MCS). Subsequently, these were compared with the general population. Abdominal symptoms were measured with a standardized, 7-point scale questionnaire in 54 patients. We dichotomized symptoms for absence or presence and compared them with the component scores. Finally, a possible correlation between liver volume and HRQL was explored. RESULTS: Demographics showed severe polycystic livers (mean 4906 +/- 2315 ml). PCS was significantly lower compared with the general population (P < 0.001), in contrast with a similar MCS (P = 0.82). PLD patients had statistically significant (P < 0.05) diminished physical functioning, role physical, general health, vitality and social functioning scores. Upper- and lower abdominal pain and dyspnoea were significantly associated with a reduced PCS (P < 0.01). No correlation was found between liver volume and HRQL. CONCLUSION: Polycystic liver disease patients had significantly lower HRQL in the physical dimension compared with the general population. Abdominal pain and dyspnoea had a significant impact on this physical dimension of HRQL.

Item does not contain fulltext, BACKGROUND & AIMS: Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy. METHODS: We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment. RESULTS: The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022). CONCLUSIONS: Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group.

1 december 2011, Item does not contain fulltext, Mutations in the PKHD1 gene, which encodes fibrocystin, cause autosomal recessive polycystic kidney disease (ARPKD). Unfortunately, the lack of specific antibodies to the mouse protein impairs the study of splicing, post-translational processing, shedding, and temporal and spatial expression of endogenous fibrocystin at the cellular and subcellular level. Here, we report using a knock-in strategy to generate a null Pkhd1 strain and a strain that expresses fibrocystin along with two SV5-Pk epitope tags engineered in-frame into the third exon, immediately C-terminal to the signal-peptide cleavage site in a poorly conserved region. By 6 mo of age, the Pkhd1-null mouse develops massive cystic hepatomegaly and proximal tubule dilation, whereas the mouse with epitope-tagged fibrocystin has histologically normal liver and kidneys at 14 mo. Although Pkhd1 was believed to generate many splice forms, our western analysis resolved fibrocystin as a 500 kD product without other forms in the 15-550 kD range. Western analysis also revealed that exosome-like vesicles (ELVs) secrete the bulk of fibrocystin in its mature cleaved form, and scanning electron microscopy identified that fibrocystin on ELVs attached to cilia. Furthermore, the addition of ELVs with epitope-tagged fibrocystin to wild-type cells showed that label transferred to primary cilia within 5 min. In summary, tagging of the endogenous Pkhd1 gene facilitates the study of the glycosylation, proteolytic cleavage, and shedding of fibrocystin.

1 juli 2010, Contains fulltext : 89294.pdf (publisher's version ) (Closed access), Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation-sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, PolyPhen, and pMut and sift. We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.