bims-bicyki 2022-10-09 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–10–09
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Simultaneous kidney transplantation and ipsilateral native nephrectomy in patients with autosomal dominant polycystic kidney disease.
A single-center analysis of genotype-phenotype characteristics of Chinese patients with autosomal dominant polycystic kidney disease by targeted exome sequencing.
The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD.
[Clinical characteristics and genetic analysis of a child with autosomal recessive polycystic kidney disease].
Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.
The relationship between depression, anxiety, quality of life levels, and the chronic kidney disease stage in the autosomal dominant polycystic kidney disease.
Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease.
Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment.
SPACA9 is a lumenal protein of human ciliary singlet and doublet microtubules.
Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration.
Predicting the number of citations of polycystic kidney disease with 100 top-cited articles since 2010: Bibliometric analysis.
Non-contact optical in-vivo sensing of cilia motion by analyzing speckle patterns.

World J Transplant. 2022 Sep 18. 12(9): 310-312

Simultaneous kidney transplantation and ipsilateral native nephrectomy in patients with autosomal dominant polycystic kidney disease.

Rabea Ahmed Gadelkareem, Amr Mostafa Abdelgawad, Nasreldin Mohammed.

  The simultaneous kidney transplantation and ipsilateral native nephrectomy for autosomal dominant polycystic kidney disease does not seem to be associated with increased rates of comorbidity and complications. This outcome can efficiently be achieved when the indication and surgical approach of native nephrectomy are properly justified.

Keywords:  Autosomal dominant polycystic kidney disease; Kidney transplantation; Native nephrectomy; Retroperitoneal approach; Surgical complications

DOI:  https://doi.org/10.5500/wjt.v12.i9.310
Front Genet. 2022 ;13 934463

A single-center analysis of genotype-phenotype characteristics of Chinese patients with autosomal dominant polycystic kidney disease by targeted exome sequencing.

Ziyan Yan, Yuchen Wang, Wenfeng Deng, Yi Zhou, Yangcheng Hu, Ka Qi, Ding Liu, Renfei Xia, Rumin Liu, Wenli Zeng, Wei Zhang, Jian Xu, Fu Xiong, Yun Miao.

  Background: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by PKD1 and PKD2 mutations. However, only a few studies have investigated the genotype and phenotype characteristics of Asian patients with ADPKD. This study aimed to investigate the relationship between the natural course of ADPKD genotype and phenotype. Methods: Genetic studies of PKD1/2 genes of Chinese patients with ADPKD in a single center were performed using targeted exome sequencing and next-generation sequencing on peripheral blood DNA. Results: Among the 140 patients analyzed, 80.00% (n = 112) harbored PKD1 mutations, 11.43% (n = 16) harbored PKD2 mutations, and 8.57% (n = 12) harbored neither PKD1 nor PKD2 mutations. The average age at dialysis was 52.60 ± 11.36, 60.67 ± 5.64, and 52.11 ± 14.63 years, respectively. The renal survival rate of ADPKD patients with PKD1 mutations (77/112) was significantly lower than that of those with PKD2 mutations (9/16), leading to an earlier onset of end-stage renal disease (ESRD). Renal prognosis was poor for those with nonsense mutations, and they required earlier renal replacement therapy. Conclusions: The genotype and phenotype characteristics of ADPKD patients potentially vary across ethnic groups. Our findings supplement the genetic profiles of Chinese ADPKD patients, could serve as a guide for therapy monitoring and prognosis assessment of ADPKD, and may improve the clinical diagnosis.

Keywords:  PKD1; PKD2; TES using NGS; autosomal dominant polycystic kidney disease; mutation

DOI:  https://doi.org/10.3389/fgene.2022.934463
Kidney Med. 2022 Oct;4(10): 100538

The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD.

Ronald D Perrone, Ali Hariri, Pascal Minini, Curie Ahn, Arlene B Chapman, Shigeo Horie, Bertrand Knebelmann, Michal Mrug, Albert C M Ong, York P C Pei, Vicente E Torres, Vijay Modur, Ronald T Gansevoort.

   Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials.
Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies.
Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively.
Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data.
Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2).
Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects.
Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration.
Funding: This study was funded by Sanofi.
Trial registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.

Keywords:  Autosomal dominant polycystic kidney disease; modeling; study design; total kidney volume; venglustat

DOI:  https://doi.org/10.1016/j.xkme.2022.100538
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Oct 10. 39(10): 1103-1106

[Clinical characteristics and genetic analysis of a child with autosomal recessive polycystic kidney disease].

Shanshan Gao, Qianqian Li, Peng Dai, Ganye Zhao, Xiangdong Kong.

OBJECTIVE: To explore the clinical characteristics and molecular pathogenesis of a child with autosomal dominant polycystic kidney disease (ARPKD).
METHODS: Prenatal ultrasound, clinical feature and family history of the child were analyzed. Whole exome sequencing was carried out for the child. Candidate variants were verified by Sanger sequencing.
RESULTS: The child has featured premature birth with very low weight, neonatal respiratory distress, metabolic acidosis, and congenital nephrotic syndrome. Gene sequencing revealed that he has harbored compound heterozygous variants of the PKHD1 gene (NM_138694), including c.3885T>A (p.Tyr1295*) in exon 32 and c.7812_7816dupTGATA (p.Thr2606Metfs*63) in exon 49, which were respectively inherited from his mother and father.
CONCLUSION: The compound heterozygous variants of the PKHD1 gene probably underlay the disease in this child.

DOI: https://doi.org/10.3760/cma.j.cn511374-20211022-00840
Am J Kidney Dis. 2022 Sep 30. pii: S0272-6386(22)00921-0. [Epub ahead of print]

Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

David H Alpers, James H Lewis, Christine M Hunt, James W Freston, Vicente E Torres, Hui Li, Wenchyi Wang, Molly E Hoke, Sharin E Roth, Lucas Westcott-Baker, Alvin Estilo.

   RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury (DILI) when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE Study and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted.
STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan.
SETTING & PARTICIPANTS: Multicenter clinical trials including >2900 tolvaptan-treated subjects, >2300 with ≥18 months of drug exposure.
INTERVENTION(S): Tolvaptan administered twice daily in split-dose regimens.
OUTCOMES: Frequency of liver enzyme elevations detected by regular laboratory monitoring.
RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38/681 [5.6%] vs 8/685 [1.2%]) experienced alanine aminotransferase (ALT) elevations >3x upper limit of normal (ULN), similar to TEMPO 3:4 (40/957 [4.4%] vs 5/484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent ALT >3x ULN and total bilirubin >2x ULN (Hy's Law laboratory criteria). Based on the expanded dataset, liver enzyme elevations most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Elevations returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial DILI episode, with return of liver enzyme elevations in 30; 1 additional participant adapted after the initial episode, with resolution of the enzyme elevations despite continuation of tolvaptan.
LIMITATIONS: Retrospective analysis.
CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme elevations as is recommended on the drug label.

Keywords:  Hy’s Law; alanine aminotransferase; autosomal dominant polycystic kidney disease (ADPKD); clinical trial; drug-induced liver injury (DILI); liver safety; tolvaptan

DOI:  https://doi.org/10.1053/j.ajkd.2022.08.012
Int Urol Nephrol. 2022 Oct 02.

The relationship between depression, anxiety, quality of life levels, and the chronic kidney disease stage in the autosomal dominant polycystic kidney disease.

Aysenur Miray Yarlioglu, Ebru Gok Oguz, Ayse Gokcen Gundogmus, Kadir Gokhan Atilgan, Hatice Sahin, Mehmet Deniz Ayli.

   PURPOSE: Decreased quality of life, anxiety, depression, and other negative psychosocial factors in autosomal dominant polycystic kidney disease (ADPKD) may lead to the patient's attitudes that reduce treatment effectiveness. We aimed to evaluate the relationship between the depression, anxiety, perceived social support, genetic psychosocial risk and quality of life levels, and chronic kidney disease (CKD) stage in ADPKD and to investigate the relationship between these variables/parameters and the dietary compliance that is an essential factor in the course of the disease.
METHODS: 100 ADPKD patients were enrolled in this cross-sectional study. EuroQol-5D-3L (EQ-5D-3L) health-related quality of life ındex, EuroQol-5D-3L visual analog scale (EQ-5D-3L VAS), multidimensional scale of perceived social support (MSPSS), patient health questionnaire (PHQ)-9, and genetic psychosocial risk ınstrument (GPRI) were applied to the patients.
RESULTS: There is a relationship with negative regression coefficient between the CKD stage and the total scores of the EQ-5D-3L and EQ-5D-3L VAS scales (p < 0.000 and β = - 5.355, p < 0.000, and β = - 8.394, respectively). There is a relationship with positive regression coefficient between the CKD stage and MSPSS total score and level (p < 0.000 and β = 0.364, p < 0.000 and β = 0.331, respectively). There is no relationship between the CKD stage and GPRI total score (p = 0.800). In addition, there is a relationship with positive regression coefficient between the dietary compliance and EQ-5D and EQ-5D VAS total scores (p = 0.006 and β = 2.687, p = 0.004 and β = 3.148, respectively). There is a relationship with negative regression coefficient between the dietary adherence and PHQ-9 total score and CKD stage (p = 0.003, p = 0.006, and β = - 0.692, respectively).
CONCLUSION: As the CKD stage increases in the ADPKD patients, the quality of life decreases, whereas the level of anxiety and depression increases. It has been seen that the ADPKD patients with more depressive complaints have less dietary compliance. In this particular patient group, the early detection and treatment of psychosocial difficulties and the work to improve the quality of life that affect the course of the ADPKD may be as important as the medical treatment. To determine the needs of ADPKD patients with multiple physical and psychosocial difficulties and to perform appropriate interventions, we think that there is a necessity for a specific scale that evaluates these effective components together in the ADPKD process.

Keywords:  ADPKD; Anxiety; Depression; Polycystic kidney; Psychosocial risk; Quality of life

DOI:  https://doi.org/10.1007/s11255-022-03375-2
Front Physiol. 2022 ;13 1006427

Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease.

Qi Zheng, Glen Reid, Michael R Eccles, Cherie Stayner.

  Polycystic kidney disease (PKD) is a significant cause of end-stage kidney failure and there are few effective drugs for treating this inherited condition. Numerous aberrantly expressed non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), may contribute to PKD pathogenesis by participating in multiple intracellular and intercellular functions through post-transcriptional regulation of protein-encoding genes. Insights into the mechanisms of miRNAs and other ncRNAs in the development of PKD may provide novel therapeutic strategies. In this review, we discuss the current knowledge about the roles of dysregulated miRNAs and other ncRNAs in PKD. These roles involve multiple aspects of cellular function including mitochondrial metabolism, proliferation, cell death, fibrosis and cell-to-cell communication. We also summarize the potential application of miRNAs as biomarkers or therapeutic targets in PKD, and briefly describe strategies to overcome the challenges of delivering RNA to the kidney, providing a better understanding of the fundamental advances in utilizing miRNAs and other non-coding RNAs to treat PKD.

Keywords:  autosomal dominant polycystic kidney disease; long non-coding RNAs; miRNAs; non-coding RNAs; polycystic kidney disease

DOI:  https://doi.org/10.3389/fphys.2022.1006427
Hepat Med. 2022 ;14 135-161

Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment.

Luiz Fernando Norcia, Erika Mayumi Watanabe, Pedro Tadao Hamamoto Filho, Claudia Nishida Hasimoto, Leonardo Pelafsky, Walmar Kerche de Oliveira, Ligia Yukie Sassaki.

  Polycystic liver disease (PLD) is a clinical condition characterized by the presence of more than 10 cysts in the liver. It is a rare disease Of genetic etiology that presents as an isolated disease or assoc\iated with polycystic kidney disease. Ductal plate malformation, ciliary dysfunction, and changes in cell signaling are the main factors involved in its pathogenesis. Most patients with PLD are asymptomatic, but in 2-5% of cases the disease has disabling symptoms and a significant reduction in quality of life. The diagnosis is based on family history of hepatic and/or renal polycystic disease, clinical manifestations, patient age, and polycystic liver phenotype shown on imaging examinations. PLD treatment has evolved considerably in the last decades. Somatostatin analogues hold promise in controlling disease progression, but liver transplantation remains a unique curative treatment modality.

Keywords:  hepatomegaly; liver; liver cysts; polycystic liver disease; therapeutics

DOI:  https://doi.org/10.2147/HMER.S377530
Proc Natl Acad Sci U S A. 2022 Oct 11. 119(41): e2207605119

SPACA9 is a lumenal protein of human ciliary singlet and doublet microtubules.

Miao Gui, Jacob T Croft, Davide Zabeo, Vajradhar Acharya, Justin M Kollman, Thomas Burgoyne, Johanna L Höög, Alan Brown.

  The cilium-centrosome complex contains triplet, doublet, and singlet microtubules. The lumenal surfaces of each microtubule within this diverse array are decorated by microtubule inner proteins (MIPs). Here, we used single-particle cryo-electron microscopy methods to build atomic models of two types of human ciliary microtubule: the doublet microtubules of multiciliated respiratory cells and the distal singlet microtubules of monoflagellated human spermatozoa. We discover that SPACA9 is a polyspecific MIP capable of binding both microtubule types. SPACA9 forms intralumenal striations in the B tubule of respiratory doublet microtubules and noncontinuous spirals in sperm singlet microtubules. By acquiring new and reanalyzing previous cryo-electron tomography data, we show that SPACA9-like intralumenal striations are common features of different microtubule types in animal cilia. Our structures provide detailed references to help rationalize ciliopathy-causing mutations and position cryo-EM as a tool for the analysis of samples obtained directly from ciliopathy patients.

Keywords:  axoneme; cilia; cryo-EM; cryo-ET; microtubules

DOI:  https://doi.org/10.1073/pnas.2207605119
Stem Cells Int. 2022 ;2022 2560441

Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration.

Haiqi Zhou, Sha Wu, Huixian Ling, Changjie Zhang, Ying Kong.

Osteoarthritis (OA) is the most common joint disease that can cause pain and disability in adults. The main pathological characteristic of OA is cartilage degeneration, which is caused by chondrocyte apoptosis, cartilage matrix degradation, and inflammatory factor destruction. The current treatment for patients with OA focuses on delaying its progression, such as oral anti-inflammatory analgesics or injection of sodium gluconate into the joint cavity. Primary cilia are an important structure involved in cellular signal transduction. Thus, they are very sensitive to mechanical and physicochemical stimuli. It is reported that the primary cilia may play an important role in the development of OA. Here, we review the correlation between the morphology (location, length, incidence, and orientation) of chondrocyte primary cilia and OA and summarize the relevant signaling pathways in chondrocytes that could regulate the OA process through primary cilia, including Hedgehog, Wnt, and inflammation-related signaling pathways. These data provide new ideas for OA treatment.

DOI: https://doi.org/10.1155/2022/2560441
Medicine (Baltimore). 2022 Sep 23. 101(38): e30632

Predicting the number of citations of polycystic kidney disease with 100 top-cited articles since 2010: Bibliometric analysis.

Chen-Yu Wang, Tsair-Wei Chien, Willy Chou, Hsien-Yi Wang.

BACKGROUND: Polycystic kidney disease (PKD) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidneys. Numerous studies on PKD have been published in the literature. However, no such articles used medical subject headings (MeSH terms) to predict the number of article citations. This study aimed to predict the number of article citations using 100 top-cited PKD articles (T100PKDs) and dissect the characteristics of influential authors and affiliated counties since 2010.
METHODS: We searched the PubMed Central® (PMC) database and downloaded 100PKDs from 2010. Citation analysis was performed to compare the dominant countries and authors using social network analysis (SNA). MeSh terms were analyzed by referring to their citations in articles and used to predict the number of article citations using its correlation coefficients (CC) to examine the prediction effect.
RESULTS: We observed that the top 3 countries and journals in 100PKDs were the US (65%), Netherlands (7%), France (5%), J Am Soc Nephrol (21%), Clin J Am Soc Nephrol (8%), and N Engl J Med (6%); the most cited article (PMID = 23121377 with 473 citations) was authored by Vicente Torres from the US in 2012; and the most influential MeSH terms were drug therapy (3087.2), genetics (2997.83), and therapeutic use (2760.7). MeSH terms were evident in the prediction power of the number of article citations (CC = 0.37; t = 3.92; P < .01, n = 100).
CONCLUSIONS: A breakthrough was made by developing a method using MeSH terms to predict the number of article citations based on 100PKDs. MeSH terms are evident in predicting article citations that can be applied to future research, not limited to PKD, as we did in this study.

DOI: https://doi.org/10.1097/MD.0000000000030632
Sci Rep. 2022 Oct 05. 12(1): 16614

Non-contact optical in-vivo sensing of cilia motion by analyzing speckle patterns.

Doron Duadi, Nadav Shabairou, Adi Primov-Fever, Zeev Zalevsky.

Cilia motion is an indicator of pathological-ciliary function, however current diagnosis relies on biopsies. In this paper, we propose an innovative approach for sensing cilia motility. We present an endoscopic configuration for measuring the motion frequency of cilia in the nasal cavity. The technique is based on temporal tracking of the reflected spatial distribution of defocused speckle patterns while illuminating the cilia with a laser. The setup splits the optical signal into two channels; One imaging channel is for the visualization of the physician and another is, defocusing channel, to capture the speckles. We present in-vivo measurements from healthy subjects undergoing endoscopic examination. We found an average motion frequency of around 7.3 Hz and 9.8 Hz in the antero-posterior nasal mucus (an area rich in cilia), which matches the normal cilia range of 7-16 Hz. Quantitative and precise measurements of cilia vibration will optimize the diagnosis and treatment of pathological-ciliary function. This method is simple, minimally invasive, inexpensive, and promising to distinguish between normal and ciliary dysfunction.

DOI: https://doi.org/10.1038/s41598-022-20557-1