Polycystic Liver Disease Research Articles

Liver cyst penetration of antibiotics at the target site of infection: a randomized pharmacokinetic trial.

The EASL cystic liver disease guideline states that drug penetration at the site of infection (liver cyst) is essential for successful treatment, but pharmacokinetic (PK) data on cyst penetration are limited. This study aims to investigate tissue penetration of four antibiotics in non-infected liver cysts and explores influencing factors. We performed a prospective, randomized single-dose PK-study. Before percutaneous drainage of a non-infected liver cyst, an intravenous (IV) dose of either ciprofloxacin and piperacillin/tazobactam (group 1); or co-trimoxazole (trimethoprim/sulfamethoxazole) and doxycycline (group 2) was given. Cyst fluid was collected during drainage. Blood samples were obtained before, during and after drainage (within 12 h). Drug concentrations were measured with a validated LC-MS/MS. Primary outcome was liver cyst penetration, defined as the cyst-fluid-to-plasma concentration ratio (%) expressed as median (IQR). We included 20 patients, and 21 liver cysts were drained (group 1: n = 11, group 2: n = 10). Median drained cyst volume was 700 mL. Median time between infusion and drainage was 139 min (IQR 120-188 min). Median cyst-fluid-to-plasma concentration ratio was 4.2% (IQR 1.6%-8.9%) for ciprofloxacin, 0.3% (IQR 0.0%-1.3%) for piperacillin, 0.2% (IQR 0.0%-1.3%) for tazobactam, 12.2% (IQR 6.3%-16.1%) for trimethoprim, 0.4% (IQR 0.2%-3.8%) for sulfamethoxazole and 1.6% (IQR 0.9%-2.3%) for doxycycline. Time between trimethoprim infusion and cyst drainage was correlated with increased cyst-fluid-to-plasma concentration ratio (P < 0.01). Trimethoprim and ciprofloxacin have the highest penetration ratios amongst antibiotics tested. We found that liver cyst penetration varies widely between drugs after a single IV dose. NTR8499The trial was originally registered in the Netherlands Trial Register (ID: NL7290), which was converted to the International Clinical Trials Registry Platform in 2022.

Clinical and genetic analysis of autosomal dominant polycystic liver disease

Objective: To analyze and clarify the clinical and pathogenic gene variation and genetic etiology of polycystic liver disease. Methods: The proband clinical data and family history were collected. Whole-exome sequencing technology was used to detect the proband gene variations. Fluorescence quantitative PCR validation was performed on the proband and his family to screen out pathogenic gene variation. Results: A multiple liver cyst was found in an 18-year-old male proband during a physical examination. There were no abnormalities in his liver function, and both his father and grandfather had multiple liver cysts without any obvious discomfort or other special manifestations. Whole exome sequencing suggested a heterozygous deletion in exon 1 (Exon 1) of the SEC63 gene in the proband. Real-time fluorescence quantitative PCR confirmed that the heterozygous deletion variation of the SEC63 gene Exon 1 of the proband came from his father, and the same heterozygous deletion was detected in his grandfather. The gene variant had a pathogenic variation that had been rarely reported before and was in accordance with the the American college of Medical Genetics and Genomics (ACMG) guidelines. Conclusions: The genetic etiology of this autosomal dominant polycystic liver disease has been clarified, and the heterozygous deletion of Exon1 of the SEC63 gene is a newly discovered gene variation that broadens the variation spectrum of the SEC63 gene.

Perioperative and Long-Term Outcomes After Combined Liver and Kidney Transplantation: A Single-Center Experience.

Combined liver-kidney transplantation (CLKT) has evolved as a therapeutic option for patients with concurrent end-stage liver and renal diseases. This study evaluates the perioperative and long-term outcomes of CLKT at a single center in Slovenia, highlighting the challenges and successes of simultaneous organ transplantation. We retrospectively analyzed all patients undergoing simultaneous CLKT at the University Medical Centre Ljubljana from April 2014 to June 2023. Data on demographics, cause of liver and kidney disease, operative details, postoperative complications, patient and graft survival, and follow-up were collected and analyzed. Five patients aged 27 to 60 years underwent CLKT within the study period. All transplants involved deceased donors with whole-liver grafts. Indications for CLKT were polycystic liver disease (n = 3), Caroli's disease (n = 1), and alcoholic cirrhosis (n = 1). The mean follow-up duration was 45.2 months, with a 100% survival rate. The incidence of surgical and postoperative complications was low. This pioneering series of simultaneous CLKTs in Slovenia demonstrates the feasibility and effectiveness of the procedure in smaller transplant centers. Despite challenges, including T cell-mediated kidney rejection and surgical complications, the study emphasizes the importance of comprehensive postoperative care and management in optimizing outcomes for CLKT recipients.

Prevalence and Severity of Polycystic Liver Disease (PLD) in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Prevalence and Severity of Polycystic Liver Disease (PLD) in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Cholangiocyte ciliary defects induce sustained epidermal growth factor receptor signaling.

The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle's dysfunctions have been linked to disorders, including polycystic liver disease (PLD) and Cholangiocarcinoma (CCA). The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions. The study identified aberrant EGFR signaling pathways in cholangiocytes lacking functional primary cilia. Using liver-specific IFT88 knockout mice, a Pkhd1 mutant rat model, and human cell lines that didn't have functional cilia. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts, where EGFR localization to the cilia promotes appropriate signaling. Using HDAC6 inhibitors to restore primary cilia accelerates EGFR degradation, thereby reducing maladaptive signaling. Importantly, experimental intervention with the HDAC6 inhibitor tubastatin A in an orthotopic rat model moved EGFR to cilia and reduced ERK phosphorylation. Concurrent administration of EGFR and HDAC6 inhibitors in cholangiocarcinoma and polycystic liver disease cells demonstrated synergistic anti-proliferative effects, which were associated with the restoration of functioning primary cilia. This study's findings shed light on ciliary function and robust EGFR signaling with slower receptor turnover. We could use therapies that restore the function of primary cilia to treat EGFR-driven diseases in PLD and CCA.

Case series multilocular cystic hemangioma of the liver: Three cases and literature review.

Multilocular cystic hemangioma is a rare benign tumor classified as an atypical hemangioma. Currently, there are limited imaging reports available, and the imaging characteristics can be challenging to distinguish from other malignant multilocular cystic liver diseases such as cystadenocarcinoma, necessitating confirmation through pathological diagnosis. Here, we discuss the imaging features of 3 cases of multilocular cystic hemangiomas. Case 1 was a 24-year-old young female, and Case 2 involved a 60-year-old elderly male. Both patients were asymptomatic and physical examination revealed hepatic space-occupying lesions. Imaging findings revealed multilocular cystic lesions in the left liver with septa, calcification, a high diffusion-weighted magnetic resonance imaging (DWI) signal at the edge of the lesion, and progressive enhancement of the cyst wall and septa. Case 3 involved a 50-year-old male patient with epigastric distending pain for 1 month and sudden severe abdominal pain for 14 hours. Imaging results revealed a multilocular cystic lesion in the left liver with septa and tumor bleeding, a high DWI signal, and an enhanced cyst wall and septa. The pathological diagnosis confirmed a hepatic hemangioma. All 3 patients underwent liver tumor resection. All 3 patients recovered successfully without any intraoperative or postoperative complications during the follow-up periods of 5 years, 6 months, and 5 months. There were no signs of recurrence. Liver imaging revealed multilocular cystic lesions with features, such as compartmentalization, calcification, or bleeding. Multilocular cystic hemangiomas should be considered in imaging diagnosis. Enhancing our understanding of multilocular cystic hemangiomas can aid in improving the differential diagnosis of other malignant multilocular cystic liver diseases, ultimately reducing unnecessary liver resection.

Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History

Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with polycystic kidneys who have a positive family history, >90% have pathogenic variants in PKD1 or PKD2, whereas only 1% have IFT140. However, approximately 40% of patients with polycystic kidneys without a family history do not have any pathogenic variants in PKD1 and PKD2. We conducted a comprehensive genetic analysis of 157 adult patients with polycystic kidneys whose parents did not have evident polycystic kidneys. We sequenced up to 92 genes associated with inherited cystic kidney disease, including IFT140. Of the 157 patients, 7 (4.5%) presented with monoallelic loss-of-function variants in the IFT140 gene, 51 (32.5%) with pathogenic variants in the PKD1 or PKD2 gene, and 7 (4.5%) with pathogenic variants in other genes related to inherited kidney cystic disease. The proportion of monoallelic loss-of-function IFT140 variants in this cohort was higher than that in previously reported cohorts with polycystic kidneys who had a positive family history. None of the patients with monoallelic loss-of-function IFT140 variants had polycystic liver disease (PLD). Furthermore, patients with IFT140 pathogenic variants had a significantly smaller kidney volume and a remarkably higher estimated glomerular filtration rate (eGFR) than those with PKD1 pathogenic variants (P= 0.01 and 0.03, respectively). Because the phenotype of polycystic kidneys caused by the IFT140 gene is mild, parental kidney disease may be overlooked. Therefore, patients without a positive family history are more likely to carry pathogenic variants in IFT140.

NAMPT Overexpression Drives Cell Growth in Polycystic Liver Disease through Mitochondrial Metabolism Regulation

A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes and commonly related to primary cilia defects. The NAD salvage pathway, which sustains cellular bioenergetics and supplies a required substrate for tasks important to rapidly multiplying cells, has a rate-limiting phase that is mediated by nicotinamide phosphoribosyltransferase (NAMPT). In this study, the efficacy and mechanisms of action of FK866, a novel, high-potency NAMPT inhibitor with a good toxicity profile, were assessed. NAMPT-siRNA and FK866 reduced NAD levels and inhibited the proliferation of PLD cells in a dose-dependent manner. Notably, this pharmacologic and siRNA-mediated suppression of NAMPT was less effective in normal cells at the same concentrations. The addition of nicotinamide mononucleotide (NMN), a byproduct of NAMPT that restores NAD concentration, rescued the cellular viability of PLD cells and verified the on-target action of FK866. In FK866-treated PLD cells, mitochondrial respiration and ATP production were impaired and reactive oxygen species production was induced. Importantly, FK866 treatment was associated with improved effects of octreotide, a drug used for PLD treatment. As a result, the use of NAMPT inhibitors, including FK866 therapy, offers the possibility of a further targeted strategy for the therapeutic treatment of PLD.

Liver Transplantation for Benign Massive Hepatomegaly: Results From a Single Center and Contribution of the Left-to-Right Piggyback Approach

IntroductionPolycystic liver disease and giant hepatic hemangioma may present with severe symptom burden and indicate orthotopic liver transplantation. The left-to-right piggyback approach is a useful technique for performing total hepatectomy of enlarged livers. ObjectiveThe purpose of this study is to analyze the results of liver transplantation in patients with benign massive hepatomegaly. MethodsThis is a single-center retrospective study involving all adult patients who underwent liver transplantation due to benign massive hepatomegaly from January 2002 to June 2023. ResultsA total of 22 patients underwent liver transplantation (21 cases of polycystic live disease and 1 case of giant hepatic hemangioma). During the same time, there were 2075 transplants; therefore, benign massive hepatomegaly accounted for 1.06% of cases. Most patients (59.09%) were transplanted using the left-to-right piggyback technique. Seven patients had previous attempted treatment of hepatic cysts. Another patient previously underwent bilateral nephrectomy and living-donor kidney transplantation. Among these patients, in 5 cases there were massive abdominal adhesions with increased bleeding. Four of these 8 patients died in the very early perioperative period. In comparison to patients without previous cysts manipulation, massive adhesions and perioperative death were significantly higher in those cases (62.5 vs 0%, P = .002 and 50% vs 0%, P = .004, respectively). ConclusionLiver transplantation due to polycystic liver disease and giant hemangioma is a rare event. Total hepatectomy is challenging due to the enlarged native liver. The left-to-right piggyback technique is useful, because it avoids vena cava twisting and avulsion of its branches. Massive adhesions due to previous cysts manipulation may lead to increased bleeding, being a risk factor for mortality.

FRI-158-YI The cyst microenvironment is spatially patterned to promote polycystic liver disease

FRI-158-YI The cyst microenvironment is spatially patterned to promote polycystic liver disease

Deep learning-based liver cyst segmentation in MRI for autosomal dominant polycystic kidney disease

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) can lead to polycystic liver disease (PLD), characterized by liver cysts. Although majority of the patients are asymptomatic, massively enlarged liver secondary to PLD can cause discomfort, and compression on adjacent structures requiring cyst aspiration/fenestration, partial liver resection, or liver transplantation. Monitoring PLD by measuring liver volume fails to track the early stages when liver cyst volume is too small to affect liver volume. Purpose To improve PLD assessment in the early stages by automating detection and segmentation of liver cysts using deep learning (DL) models. Materials and Methods A self-configured UNet-based platform (nnU-Net) was trained with 40 ADPKD subjects with liver cysts annotated by a radiologist. Internal (n = 7), External (n = 10), and test-retest reproducibility (n = 17) validations included macro- and micro-level performance metrics: patient-level Dice scores (PDice), along with voxel-level true positive rates (VTPR), as well as analysis of time saved in a model-assisted scenario. Additionally, we assessed human-level reliability in liver cyst segmentation and evaluated the model’s test-retest reproducibility. We further compared liver volume vs cyst volume for tracking disease in a subject with 16+ years follow-up. Results The model achieved an 82% ± 11% PDice and a 75% ± 15% VTPR on the internal test sets (n = 7 patients), and 80% ± 12% Dice score and a 91% ± 7% VTPR on the external test sets (n = 10 patients). It excelled particularly in detecting small liver cysts, a challenging task for manual annotation. This efficiency translated to a median of 91% (IQR: 14%) reduction in annotation time compared to manual labeling. Test-retest assessment demonstrated excellent reproducibility, with coefficients of variation of 94% for liver cyst fraction and 92% for cyst count. Conclusion DL automation of liver cyst segmentations demonstrates potential to improve tracking of liver cyst volume in polycystic liver disease.

Liver transplantation for polycystic liver disease: How feasible is this option?

BackgroundPolycystic liver disease is a rare hereditary disease that can occur as an isolated disease. Because of its benign nature, polycystic liver disease rarely needs treatment. If treatment is needed, there are no standard guidelines, but usually, a liver resection or medical therapy is performed. A liver transplant is the last resort when all other possibilities have been exhausted, or complications arise. However, the risks and benefits must be carefully weighed. Methods and materialsA retrospective registry analysis of the SRTR database was done for liver transplants performed in the United States from January 2001 to May 2023. ResultsThe analysis of the data indicated a notable improvement in 5-year graft survival rates between the 2001–2010 group (mean of 92 %) and the 2011–2023 group (mean of 97 %) (P < .001). The 2011–2023 group had a higher proportion of simultaneous kidney and liver transplants, more than 3 times, from 106 cases to 374 cases (57.7 % vs. 42.3 %, P = .001). The type of transplant was also considered when analyzing the 5-year survival of grafts. Patients who underwent both kidney and liver transplants simultaneously had a slightly better outcome. It was found that the only hazard affecting LT graft survival in the cohort was the cold ischemic time (HR: 2.80, P = .03). ConclusionWith all the surgical techniques and post-operation improvements, a liver transplant can be a feasible option for polycystic liver disease when the medical treatments are not sufficient to eliminate the symptoms.

#1936 Investigating genetic and environmental modifiers of autosomal dominant polycystic kidney disease through a distinct PKD2-founder variant (p.Arg803*)

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary diseases that lead to kidney failure [1]. Apart from progressive, cystic enlargement of the kidneys, classic ADPKD is inevitably associated with polycystic liver disease (PLD) and arterial hypertension [2] due to mutated PKD1 (78%) or PKD2 (15%) [3]. Despite knowledge of the diagnostic PKD1 or PKD2 variant, there is great intrafamilial variability in terms of disease progression and organ involvement. Therefore, there is an unmet medical need to establish better genotype-phenotype correlations. In 2022, Taiwanese colleagues identified a PKD2 founder variant (NM_000297.4 (PKD2): c.2407C&amp;gt;T (p.Arg803*)) which accounts for 17.8% of all ADPKD cases in Taiwan [4]. As we also detected patients with PKD2-Arg803* in our European center, we hypothesize that p.Arg803* constitutes a recurrent mutation. The established Taiwanese cohort provides the unique opportunity to build up a sister cohort of patients with this specific mutation. This novel approach can aid in identifying genetic and environmental modifiers of ADPKD, which in turn is essential in elucidating the pathogenesis, as well as the adequate classification, prognosis and treatment of ADPKD patients. Method For patient recruitment, the search was carried out simultaneously in a multi-pronged approach. First, the European Rare Kidney Disease Network (ERKNet), relevant registries and biobanks were searched to identify patients. In addition, authors of ClinVar entries and published literature with specific mentions of the variant were contacted. Lastly, clinical and genetic ADPKD specialists were reached out to directly. Deep phenotyping was performed by a specific clinical questionnaire that was sent to the respective treating physicians via Microsoft Forms. This included baseline information about patients as well as clinical parameters. Specifically, a detailed analysis of kidney, liver, CNS and further manifestations of ADPKD was performed. In addition to the main mutation, additional findings in relevant ADPKD genes were documented. Environmental factors such as smoking, estrogen use, diets and exercise were also been explicitly recorded. Results Through systematic search, 545 institutions or clinicians were contacted in 47 countries. Thus far, about 170 patients with PKD2-p.Arg803* have been identified in 25 centers from 15 countries outside of Taiwan. The process of deep phenotyping is ongoing (completed on 20 patients as of 01/2024). A preliminary analysis of this smaller cohort showed a mean age of 62 (range: 38–90) years and a sex distribution (F:M) of 11: 9. The median total kidney volume was 1437 ml (IQR 2525.5) mL and three patients had reached kidney failure at age 70, 72 and 69. Eighteen out of the 20 patients had three or more liver cysts with a median total liver volume of 1849 (IQR 822.5) mL. Conclusion We are continuing to expand the cohort, aiming to reach full datasets in about 80 international patients for joint analysis with the Taiwanese founder cohort. Detailed statistical analysis of the joint cohort will allow us to better characterize modifiers on the genetic and environmental level. We hope our project can contribute to further understanding disease variability in ADPKD.

#2810 Exploring non-renal vasculature: therapeutic implications of proton pump inhibitor and anthelmintic treatment in PCK rat model

Abstract Background and Aims Cystic kidney diseases represent ciliopathies that can cause vascular damage through renal hypertension. Additionally, there is growing experimental evidence of endothelial cell abnormalities associated with ciliary protein deficiencies. PCK rats, a strain derived from Sprague-Dawley (SD) rats that develops both polycystic kidney disease (PKD) and liver disease, serve as a model for recessive PKD. The PCK rat model also presents abnormalities in non-renal vascular function. Another study from our group suggests a potential therapeutic benefit of repurposed therapy with a proton pump inhibitor (PPi) and an anthelmintic agent in attenuating the progression of PKD in a PCK rat model. Here, we investigated whether these drugs can also improve endothelial function. Method The compounds were administered to 3-week-old male and female PCK rats (n = 5-6) for a total of 10 weeks. Untreated PCK rats and age-matched SD rats (n = 5-6) served as controls. After perfusion fixation, the aorta was harvested and its thoracic rings were used to evaluate the contraction/relaxation responses ex vivo by organ bath experiments. Additional rings were preserved for histological and molecular biological analyses. Results Male PCK rats exhibited impaired endothelial function compared to healthy controls. Endothelium-dependent relaxation to acetylcholine was improved by 10% after treatment with PPi, while the anthelmintic administration had no protective effect. PKD also impaired endothelial function in female PCK rats compared to healthy SD controls. There was an improvement in endothelium-dependent relaxation to acetylcholine after treatment with PPi by 5.5%, while administration of the anthelmintic agent further impaired endothelial function. Conclusion 13-week-old PCK rats show endothelial dysfunction in non-renal vasculature. Treatment with a proton pump inhibitor improved endothelial function in male PCK rats to the level of healthy SD controls. By contrast, in a parallel study, the anthelmintic had a positive effect on renal function but a detrimental impact on endothelial function. These intricate relationships underscore the need for further exploration to understand the underlying mechanisms and broader implications of our findings, illustrating the challenges and potential avenues for the development of effective treatments for PKD.

#2613 Clinical spectrum and prognosis of the atypical polycystic kidney disease caused by monoallelic loss-of-function IFT140 variants

Abstract Background and Aims Monoallelic loss-of-function (LoF) variants in IFT140, which protein product is involved in retrograde ciliary trafficking and ciliary entry of membrane protein, have been recently linked to ADPKD spectrum, with 44 pedigrees reported so far [1]. The aim of this study was to characterize the disease presentation and renal outcome of individuals with monoallelic LoF variants of IFT140. Method Clinical information, family history and imaging data were collected for individuals with LoF IFT140-variants identified amongst 2800 individuals recruited in the Genkyst and Cystic ADPKD patients cohorts, and in different French, Spanish, and German centers. Targeted massive parallel sequencing of cystic genes or whole exome sequencing was performed. Newly identified and recently reported cases were combined to evaluate the influence of sex on eGFR using linear regression taking age into account. In addition, data of the Genome Aggregation (GnomAD) v4.0 and of the 100k Genomes project were respectively used to explore genetic prevalence and disease penetrance and expressivity. Results A total of 75 individuals from 61 pedigrees were identified (median age at last follow-up 56 years, 52% females). Forty-one different LoF IFT140-variants were identified: 14 nonsense, 7 splice-site, 14 frameshifting deletions or insertions and 6 large deletions, and no additional pathogenic variant was identified in any other gene. A majority of the individuals presented with large, exophytic cysts, median total kidney volume 688 (n = 35, range 201-4139) ml, and 90.9% were classified in Mayo Class 2A. Although 70.4% of the individuals had stage 1 or 2 chronic kidney disease (CKD) at the last follow up, proportion of CKD stage 3-5 was significantly higher (56.3% vs 7.7%, p &amp;lt; 0.00001) after 60 years of age. Adjusted for age, males exhibited lower eGFR (linear regression, p = 0.038, Fig. 1). Median age at diagnosis of hypertension was 63 years. Liver cysts were present in 12% of affected individuals with no case of symptomatic polycystic liver disease, and intracranial aneurysms in three of 10 screened patients. The genetic prevalence of monoallelic LoF IFT140 variants was estimated to be 19.56 (0.95 CI 18.60-20.53) per 10,000 in the entire GnomAD population (n = 280 in 807,162) and 29.4 (0.95 CI 25.4-33.8) per 10,000 in the 100kG (n = 190 in 64,185). Amongst the latter, kidney cysts were reported in 26.8% and diagnosis cystic kidney disease (Q61) was established in 18.4%. No obvious extra renal manifestations were identified, and out of total of 730 phenotype association tests conducted, only Q61 was associated with pLOF IFT140 variants (p = 2.9 × 10−9, OR = 5.6 (3.3-9.2)). Conclusion Individuals with monoallelic LoF variants of IFT140 are likely to develop kidney cysts and/or atypical forms of ADPKD. However, a large proportion may remain asymptomatic or undiagnosed. There is no evidence to recommend cascade screening using genetic testing in young at risk relatives. Follow-up of blood pressure and eGFR after 50 years of age should be advised.

Outcomes of Combined Liver-Kidney Transplantation – Single Center Experience

There is continuous growth of combined liver-kidney transplantation (CLKTx) numbers with remarkable outcomes, especially among patient with liver cirrhosis and end-stage renal disease. The aim was to present a single center experience. Twenty patients (9 males) with a mean age of 48 (range: 20-62) years underwent CLKTx from 2005 to 2022. Indications were polycystic liver and kidney diseases (ADPKD) in 12 cases, cirrhosis due to hepatitis (4 patients), and 1 case of amyloidosis, alcoholic liver disease, nonalcoholic steatosis, and congenital hepatic fibrosis with concomitant glomerulonephritis. After hepatectomy, half of the patients had orthotopic liver transplantation with piggy-back technique, and the other had conventional technique. All but 1 recipient had biliary end-to-end anastomosis. 3 patients had preemptive kidney graft transplantation. 4 underwent simultaneous right-side nephrectomy due to volume of the right kidney. Kidney was transplanted from the separate incision after abdominal closure with typical anastomoses. Tacrolimus, mycophenolate mofetile, basiliximab, and steroids were applied for all recipients. Mean follow-up was 57.7 ± 54 months. No primary non-function of the grafts occurred. Delayed kidney graft function (DGF) occurred in 8 patients. Three-month, 1-year, and 5-year cumulative survival rates were: 90%, 80%, and 72% respectively. None of the patients required retransplantation, and 1 recipient returned to hemodialysis 19 months after transplantation. Preemptive kidney transplantation and simultaneous right-side nephrectomy were not significant for DGF and recipient survival. No deaths within the first year occurred in piggy-back technique. CLKTx is safe and effective in the treatment of both liver and kidney failure.

Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms

SEC61A1 encodes a central protein of the mammalian translocon and dysfunction results in severe disease. Recently, mutation R236C was identified in patients having autosomal dominant polycystic liver disease (ADPLD). The molecular phenotype of R236C was assessed in two cellular platforms. Cells were immortalized by retroviral transduction of an oncogene (UCi) or reprogrammed to induced pluripotent stem cells (iPSC) that were differentiated to cholangiocyte progenitor-like cells (CPLC). UCi and CPLC were subjected to analyses of molecular pathways that were associated with development of disease. UCi displayed markers of epithelial cells, while CPLCs expressed typical markers of both cholangiocytes and hepatocytes. Cells encoding R236C showed a stable, continuous proliferation in both platforms, however growth rates were reduced as compared to wildtype control. Autophagy, cAMP synthesis, and secretion of important marker proteins were reduced in R236C-expressing cells. In addition, R236C induced increased calcium leakiness from the ER to the cytoplasm. Upon oxidative stress, R236C led to a high induction of apoptosis and necrosis. Although the grade of aberrant cellular functions differed between the two platforms, the molecular phenotype of R236C was shared suggesting that the mutation, regardless of the cell type, has a dominant impact on disease-associated pathways.

The pathophysiology of polycystic liver disease

The pathophysiology of polycystic liver disease

A Classification-Based Adaptive Segmentation Pipeline: Feasibility Study Using Polycystic Liver Disease and Metastases from Colorectal Cancer CT Images.

Automated segmentation tools often encounter accuracy and adaptability issues when applied to images of different pathology. The purpose of this study is to explore the feasibility of building a workflow to efficiently route images to specifically trained segmentation models. By implementing a deep learning classifier to automatically classify the images and route them to appropriate segmentation models, we hope that our workflow can segment the images with different pathology accurately. The data we used in this study are 350 CT images from patients affected by polycystic liver disease and 350 CT images from patients presenting with liver metastases from colorectal cancer. All images had the liver manually segmented by trained imaging analysts. Our proposed adaptive segmentation workflow achieved a statistically significant improvement for the task of total liver segmentation compared to the generic single-segmentation model (non-parametric Wilcoxon signed rank test, n = 100, p-value << 0.001). This approach is applicable in a wide range of scenarios and should prove useful in clinical implementations of segmentation pipelines.

Navigating PRKCSH's impact on cancer: from N-linked glycosylation to death pathway and anti-tumor immunity.

PRKCSH, also known as Glucosidase II beta subunit (GluIIβ), is a crucial component of the endoplasmic reticulum (ER) quality control system for N-linked glycosylation, essential for identifying and eliminating misfolded proteins. Glucosidase II consists of the catalytic alpha subunit (GluIIα) and the regulatory beta subunit (GluIIβ), ensuring proper protein folding and release from the ER. The induction of PRKCSH in cancer and its interaction with various cellular components suggest broader roles beyond its previously known functions. Mutations in the PRKCSH gene are linked to autosomal dominant polycystic liver disease (ADPLD). Alternative splicing generates distinct PRKCSH isoforms, which can influence processes like epithelial-mesenchymal transition (EMT) and the proliferation of lung cancer cells. PRKCSH's involvement in cancer is multifaceted, impacting cell growth, metastasis, and response to growth factors. Additionally, PRKCSH orchestrates cell death programs, affecting both autophagy and apoptosis. Its role in facilitating N-linked glycoprotein release from the ER is hypothesized to assist cancer cells in managing increased demand and ER stress. Moreover, PRKCSH modulates anti-tumor immunity, with its suppression augmenting NK cell and T cell activity, promising enhanced cancer therapy. PRKCSH's diverse functions, including regulation of IGF1R and IRE1α, implicate it as a therapeutic target and biomarker in cancer immunotherapy. However, targeting its glucosidase II activity alone may not fully counteract its effects, suggesting broader mechanisms in cancer development. Further investigations are needed to elucidate PRKCSH's precise role and validate its therapeutic potential in cancer treatment.