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Objective: To examine the changes in total kidney volume (TKV) and total liver volume (TLV) before and after dialysis initiation in patients with autosomal dominant polycystic kidney disease. Patients and Methods: This was a retrospective, single-center cohort study to investigate the changes in TKV and TLV before and after dialysis initiation, along with influencing factors, using linear mixed models. We enrolled 95 patients with autosomal dominant polycystic kidney disease (85 receiving hemodialysis [HD] and 10 receiving peritoneal dialysis [PD]) who began receiving dialysis at Toranomon Hospital from January 1, 2008, to December 31, 2020. Results: The least squares mean TKV ratio (TKV at each time point/TKV at dialysis initiation) was 63.8% (95% confidence interval [CI], 54.7%-72.9%) at 6 years before dialysis initiation and 95.5% (95% CI, 82.9%-108.2%) at 6 years after dialysis initiation (P<.001). A multivariate linear mixed model analysis revealed that dialysis style (HD or PD) had the strongest effect on changes in TKV (P=.002). The least squares mean TLV ratio was 98.2% (95% CI, 88.4%-108.0%) at 6 years before dialysis initiation and 95.7% (95% CI, 85.2%-106.2%) at 6 years after dialysis initiation (P=.01). Although PD did not have significant effects on changes in TLV (P=.27), the changes in TLV were greater in patients on PD than in those on HD. Conclusion: The TKV increased until dialysis initiation and generally decreased after dialysis initiation. The TLV continued to increase even after dialysis initiation, however, changes in the TLV significantly decreased after dialysis initiation. The increases in TKV and TLV were greater in patients on PD than in those on HD.
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Background & Aims: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma. PLD most commonly develops in females, either as an extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) or as isolated autosomal-dominant polycystic liver disease (ADPLD). Despite known genetic causes, clinical variability challenges patient counselling and timely risk prediction is hampered by a lack of genotype-phenotype correlations and prognostic imaging classifications. Methods: We performed targeted next-generation sequencing and multiplex ligation-dependent probe amplification to identify the underlying genetic defect in a cohort of 80 deeply characterized patients with PLD. Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints. Results: Monoallelic diagnostic variants were identified in 60 (75%) patients, 38 (48%) of which pertained to ADPKD-gene variants (PKD1, PKD2, GANAB) and 22 (27%) to ADPLD-gene variants (PRKCSH, SEC63). Disease severity defined by age at waitlisting for liver transplantation and first PLD-related hospitalization was significantly more pronounced in mutation carriers compared to patients without genetic diagnoses. While current imaging classifications proved unable to differentiate between severe and moderate courses, grouping by estimated age-adjusted total liver volume progression yielded significant risk discrimination. Conclusion: This study underlines the predictive value of providing a molecular diagnosis for patients with PLD. In addition, we propose a novel risk-classification model based on age- and height-adjusted total liver volume that could improve individual prognostication and personalized clinical management. Lay summary: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe. However, it is currently difficult to predict clinical outcomes such as hospitalization, symptom burden, and need for transplantation in individual patients. In the current study, we aimed to investigate the clinical value of genetic confirmation and an age-adjusted total liver volume classification for individual disease prediction. While genetic confirmation generally pointed to more severe disease, estimated age-adjusted increases in liver volume could be useful for predicting clinical outcomes.
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BACKGROUND & AIMS: Polycystic liver disease (PLD) is characterised by increased autophagy and reduced miRNA levels in cholangiocytes. Given that autophagy has been implicated in miRNA regulation, we tested the hypothesis that increased autophagy accounts for miRNA reduction in PLD cholangiocytes (PLDCs) and accelerated hepatic cystogenesis. METHODS: We assessed miRNA levels in cultured normal human cholangiocytes (NHCs), PLDCs, and isolated PLDC autophagosomes by miRNA-sequencing (miRNA-seq), and miRNA targets by mRNA-seq. Levels of miR-345 and miR-345-targeted proteins in livers of animals and humans with PLD, in NHCs and PLDCs, and in PLDCs transfected with pre-miR-345 were assessed by in situ hybridisation (ISH), quantitative PCR, western blotting, and fluorescence confocal microscopy. We also assessed cell proliferation and cyst growth in vitro, and hepatic cystogenesis in vivo. RESULTS: In total, 81% of miRNAs were decreased in PLDCs, with levels of 10 miRNAs reduced by more than 10 times; miR-345 was the most-reduced miRNA. In silico analysis and luciferase reporter assays showed that miR-345 targets included cell-cycle and cell-proliferation-related genes [i.e. cell division cycle 25A (CDC25A), cyclin-dependent kinase 6 (CDK6), E2F2, and proliferating cell nuclear antigen (PCNA)]; levels of 4 studied miR-345 targets were increased in PLDCs at both the mRNA and protein levels. Transfection of PLDCs with pre-miR-345 increased miR-345 and decreased the expression of miR-345-targeted proteins, cell proliferation, and cyst growth in vitro. MiR-345 accumulated in autophagosomes in PLDCs but not NHCs. Inhibition of autophagy increased miR-345 levels, decreased the expression of miR-345-targeted proteins, and reduced hepatic cystogenesis in vitro and in vivo. CONCLUSION: Autophagy-mediated reduction of miR-345 in PLDCs (i.e. miRNAutophagy) accelerates hepatic cystogenesis. Inhibition of autophagy restores miR-345 levels, decreases cyst growth, and is beneficial for PLD. LAY SUMMARY: Polycystic liver disease (PLD) is an incurable genetic disorder characterised by the progressive growth of hepatic cysts. We found that hepatic cystogenesis is increased when the levels of miR-345 in PLD cholangiocytes (PLDCs) are reduced by autophagy. Restoration of miR-345 in PLDCs via inhibition of autophagy decreases hepatic cystogenesis and thus, is beneficial for PLD.
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BACKGROUND & AIMS: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, the frequency of truncating mutations to ADPLD genes in large, population sequencing databases is 1:496. With the increasing use of abdominal imaging, incidental detection of hepatic cysts and ADPLD has become more frequent. The present study was performed to ascertain the incidence and point prevalence of ADPLD in Olmsted County, MN, USA, and how these are impacted by the increasing utilisation of abdominal imaging. METHODS: The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center were searched to identify all subjects meeting diagnostic criteria for definite, likely, or possible ADPLD. Annual incidence rates were calculated using incident cases during 1980-2016 as numerator, and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator, and age- and sex-specific estimates of the population of Olmsted County on 1 January 2010 as denominator. RESULTS: The incidence rate and point prevalence of combined definite and likely ADPLD were 1.01 per 100,000 person-years and 9.5 per 100,000 population, respectively. Only 15 of 35 definite and likely incident ADPLD cases had received a diagnostic code, and only 8 had clinically significant hepatomegaly. The incidence rates were much higher when adding possible cases, mainly identified through radiology databases, particularly in recent years and in older patients because of the increased utilisation of imaging studies. CONCLUSIONS: Clinically significant isolated ADPLD is a rare disease with a prevalence <1:10,000 population. The overall prevalence of ADPLD, however, to a large extent not clinically significant, is likely much higher and closer to the reported genetic prevalence. LAY SUMMARY: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, we demonstrate that it is a relatively common disease, which is rarely (<1:10,000 population) clinically significant.
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OBJECTIVE: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). PATIENTS AND METHODS: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. RESULTS: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P<.001), prior cholecystectomy (OR, 12.2; 95% CI, 1.59-552; P=.008), duodenal diverticulum (OR, 13.5; 95% CI, 2.44 to not estimable; P=.004), type 2 diabetes mellitus (OR, 6.41; 95% CI, 1.01 to not estimable; P=.05), prior endoscopic retrograde cholangiopancreatography (OR, 14.0; 95% CI, 1.80-631; P=.005), and prior kidney transplant (OR, 8.06; 95% CI, 1.72-76.0; P=.004) were higher in patients with ADPKD-associated PLD with definite cholangitis compared to controls. CONCLUSION: Gallstones, prior cholecystectomy, duodenal diverticulosis, type 2 diabetes mellitus, prior endoscopic retrograde cholangiopancreatography, and prior kidney transplant constituted risk factors for cholangitis among patients with ADPKD-associated PLD.