bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–04–30
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Nonpharmacological Management of Autosomal Dominant Polycystic Kidney Disease.
  2. Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon.
  3. Recent updates in therapeutic approach using tolvaptan for autosomal dominant polycystic kidney disease.
  4. Drug Development in Autosomal Dominant Polycystic Kidney Disease: Opportunities and Challenges.
  5. Pharmacologic Management of Autosomal Dominant Polycystic Kidney Disease.
  6. Rediscovering Primary Cilia in Pancreatic Islets.
  7. Autosomal Dominant Polycystic Kidney Disease in Children and Adolescents: Assessing and Managing Risk of Progression.
  8. Mechanisms of Cyst Development in Polycystic Kidney Disease.
  9. Patient Perspectives on ADPKD.
  10. Biomarkers in Polycystic Kidney Disease: Are We There?
  11. Severity of polycystic kidney disease revealed by multiparametric MRI.
  12. The MIR34B/C genomic region contains multiple potential regulators of multiciliogenesis.
  13. Higher Incidence of Unruptured Intracranial Aneurysms among Black and Hispanic Women on Screening MRA in Large Urban Populations.
  14. The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes.
  1. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(22)00033-7. [Epub ahead of print]30(3): 220-227
    Nonpharmacological Management of Autosomal Dominant Polycystic Kidney Disease.
    Cortney N Steele, Kristen L Nowak.
      Autosomal dominant polycystic kidney disease is a slowly progressive, lifelong disease characterized by continuous development and enlargement of kidney cysts. Thus, nonpharmacological interventions are crucial in disease management and have the potential for a large clinical impact as standalone interventions or in conjunction with pharmacological therapies. Current potential strategies regarding nonpharmacological management of autosomal dominant polycystic kidney disease include nonpharmacological management of blood pressure, calorie restriction, weight loss or weight management, enhanced hydration, limiting caffeine, dietary sodium restriction, protein restriction or altering the type of protein intake, phosphorus restriction, and reducing net acid load. This brief review discusses the available evidence, including cell culture, animal, epidemiological, and clinical studies, regarding the utility of such strategies in the nonpharmacological management of autosomal dominant polycystic kidney disease. We assert that lifestyle modification strategies should be a critical aspect of the treatment of autosomal dominant polycystic kidney disease, while further trial and mechanistic evidence continue to become available.
    Keywords:  Diet; Hydration; Obesity; Polycystic kidney disease; Sodium
    DOI:  https://doi.org/10.1053/j.akdh.2022.12.008
  2. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00003-4. [Epub ahead of print]30(3): 245-260
    Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon.
    Julie Xia Zhou, Vicente E Torres.
      Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.
    Keywords:  ADPKD therapies; Cell proliferation; Cyst fluid secretion; Cyst growth
    DOI:  https://doi.org/10.1053/j.akdh.2023.01.003
  3. Korean J Intern Med. 2023 Apr 25.
    Recent updates in therapeutic approach using tolvaptan for autosomal dominant polycystic kidney disease.
    Yaerim Kim, Seungyeup Han.
      As a genetic disease, there has been a long-standing effort to identify therapeutic options for autosomal dominant polycystic kidney disease (ADPKD). Following the development of tolvaptan, a vasopressin 2 receptor antagonist, the treatment strategy for ADPKD patients with rapid disease progression has been changed with a disease-targeted approach. Tolvaptan showed significant efficacy in preserving kidney function and reducing the total kidney volume (TKV) growth rate. These effects were especially pronounced in patients with more severe clinical phenotypes, such as higher TKV and rapidly declining kidney function. Despite the therapeutic effects of tolvaptan, aquaretic symptoms are unavoidable side effects related to the mechanism of the drug and are also directly related to the quality of life. A shared decision-making process could be a valuable strategy for reducing the incidence of side effects and improving medication adherence. Herein, we aimed to review overall clinical trials for applying tolvaptan and suggest important factors during the shared decision-making process.
    Keywords:  Decision making, shared; Polycystic kidney, autosomal dominant; Tolvaptan
    DOI:  https://doi.org/10.3904/kjim.2022.376
  4. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00004-6. [Epub ahead of print]30(3): 261-284
    Drug Development in Autosomal Dominant Polycystic Kidney Disease: Opportunities and Challenges.
    Fouad T Chebib, Ronald D Perrone.
      Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by relentless growth of innumerable renal cysts bilaterally, associated with decline in glomerular filtration rate over the course of decades. The burden of ADPKD and its treatment is associated with a significant economic and societal cost. Despite several clinical studies conducted over the past decade, only one treatment has been approved by regulatory agencies to slow disease progression in ADPKD. Elucidating feasible endpoints and clear regulatory pathway may stimulate interest in developing and translating novel therapeutics. This review summarizes the recent progress, challenges, and opportunities in drug development for ADPKD. We discuss the traditional and accelerated regulatory approval pathways, the various clinical trials endpoints, and biomarkers in ADPKD. Furthermore, we propose strategies that could optimize the clinical trial design in ADPKD. Finally, we owe it to our ADPKD patient community to strive for international collaborative studies geared toward discovery and validation of surrogate endpoints and to rally for funded infrastructure that would allow phase 3 master protocols in ADPKD. These advances will serve to derisk and potentially accelerate the development of therapies and eventually bring hope to patients and families who endure through this devastating disease.
    Keywords:  ADPKD; Clinical trial; Drug development; Drug registration; End point; Glomerular filtration rate; Kidney failure; PKD; Polycystic; Polycystic kidney disease; TKV; Total kidney volume
    DOI:  https://doi.org/10.1053/j.akdh.2023.01.004
  5. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00030-7. [Epub ahead of print]30(3): 228-235
    Pharmacologic Management of Autosomal Dominant Polycystic Kidney Disease.
    William Ackley, Neera K Dahl, Meyeon Park.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder and the fourth leading cause of end-stage kidney disease. ADPKD encompasses a wide range of morbidity in addition to chronic kidney disease and end-stage kidney disease, and its pathogenesis remains incompletely understood. Progress in the management of this condition includes the 2018 FDA approval of tolvaptan as the only mechanism-specific treatment available for individuals at risk of rapid progression. Assessing the risk of rapid progression is discussed at greater length in a separate article in this special issue. This section will address use and prescription of tolvaptan in more detail and address other therapies that may be considered in the treatment of patients with ADPKD.
    Keywords:  ADPKD; Aquaresis; Genetic kidney diseases; Liver cysts; Tolvaptan
    DOI:  https://doi.org/10.1053/j.akdh.2023.02.002
  6. Diabetes Metab J. 2023 Apr 28.
    Rediscovering Primary Cilia in Pancreatic Islets.
    Eun Young Lee, Jing W Hughes.
      Primary cilia are microtubule-based sensory and signaling organelles on the surfaces of most eukaryotic cells. Despite their early description by microscopy studies, islet cilia had not been examined in the functional context until recent decades. In pancreatic islets as in other tissues, primary cilia facilitate crucial developmental and signaling pathways in response to extracellular stimuli. Many human developmental and genetic disorders are associated with ciliary dysfunction, some manifesting as obesity and diabetes. Understanding the basis for metabolic diseases in human ciliopathies has been aided by close examination of cilia action in pancreatic islets at cellular and molecular levels. In this article, we review the evidence for ciliary expression on islet cells, known roles of cilia in pancreas development and islet hormone secretion, and summarize metabolic manifestations of human ciliopathy syndromes. We discuss emerging data on primary cilia regulation of islet cell signaling and the structural basis of cilia-mediated cell crosstalk, and offer our interpretation on the role of cilia in glucose homeostasis and human diseases.
    Keywords:  Cilia; Ciliopathies; Insulin; Insulin-secreting cells; Islets of Langerhans
    DOI:  https://doi.org/10.4093/dmj.2022.0442
  7. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00014-9. [Epub ahead of print]30(3): 236-244
    Autosomal Dominant Polycystic Kidney Disease in Children and Adolescents: Assessing and Managing Risk of Progression.
    Angélique Dachy, Liselotte Van Loo, Djalila Mekahli.
      The clinical management of autosomal dominant polycystic kidney disease (ADPKD) in adults has shifted from managing complications to delaying disease progression through newly emerging therapies. Regarding pediatric management of the disease, there are still specific hurdles related to the management of children and adolescents with ADPKD and, unlike adults, there are no specific therapies for pediatric ADPKD or stratification models to identify children and young adults at risk of rapid decline in kidney function. Therefore, early identification and management of factors that may modify disease progression, such as hypertension and obesity, are of most importance for young children with ADPKD. Many of these risk factors could promote disease progression in both ADPKD and chronic kidney disease. Hence, nephroprotective measures applied early in life can represent a window of opportunity to prevent the decline of the glomerular filtration rate especially in young patients with ADPKD. In this review, we highlight current challenges in the management of patients with pediatric ADPKD, the importance of early modifying factors in disease progression as well as the gaps and future perspectives in the pediatric ADPKD research field.
    Keywords:  ADPKD; Clinical management; Pediatric; Progression marker; Therapy
    DOI:  https://doi.org/10.1053/j.akdh.2023.01.007
  8. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00034-4. [Epub ahead of print]30(3): 209-219
    Mechanisms of Cyst Development in Polycystic Kidney Disease.
    Jiahe Qiu, Gregory G Germino, Luis F Menezes.
      Autosomal dominant polycystic kidney disease is the most common inherited cause of end-stage kidney disease worldwide. Most cases result from mutation of either of 2 genes, PKD1 and PKD2, which encode proteins that form a probable receptor/channel complex. Studies suggest that a loss of function of the complex below an indeterminate threshold triggers cyst initiation, which ultimately results in dysregulation of multiple metabolic processes and downstream pathways and subsequent cyst growth. Noncell autonomous factors may also promote cyst growth. In this report, we focus primarily on the process of early cyst formation and factors that contribute to its variability with brief consideration of how new studies suggest this process may be reversible.
    Keywords:  "Two-hit" disease; ADPKD; Disease mechanism; PKD1 and PKD2; Threshold model
    DOI:  https://doi.org/10.1053/j.akdh.2023.03.001
  9. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(23)00002-2. [Epub ahead of print]30(3): 294-302
    Patient Perspectives on ADPKD.
    Matthew Gittus, Tess Harris, Albert Cm Ong.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. It has been associated with a significant physical and psychological burden, leading to a reduced quality of life. The purpose of this literature review is to summarize the patient perspective on ADPKD based on the current published literature. A systematic literature review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Publications reporting a patient or caregiver/relative perspective of ADPKD were included. Sources searched included Medline (PubMed), Embase (Ovid), Cochrane Library, and Web of Science from inception to April 2022. This was followed by a subsequent reference and citation search. A total of 1011 articles were identified by the search process, with 28 studies included in the review. An inductive thematic analysis identified six key themes: diagnosis, monitoring, and screening; symptoms; lifestyle and dietary interventions; psychological, physical, and social impact; future planning; and interaction with the health care system. The findings of this review highlight the burden and uncertainty associated with ADPKD from a patient's perspective. This impacts patients and their caregivers/relatives at each stage of the patient's journey from screening to initiation of renal replacement therapy and future planning.
    Keywords:  Autosomal dominant; Health knowledge; Patient-centered care; Polycystic kidney; Qualitative research
    DOI:  https://doi.org/10.1053/j.akdh.2023.01.002
  10. Adv Kidney Dis Health. 2023 May;pii: S2949-8139(22)00034-9. [Epub ahead of print]30(3): 285-293
    Biomarkers in Polycystic Kidney Disease: Are We There?
    Alan S L Yu, Douglas P Landsittel.
      This article describes the use of prognostic, predictive, and response biomarkers that have been developed for autosomal dominant polycystic kidney disease and their use in clinical care or drug development. We focus on biochemical markers that can be assayed in patients' blood and urine and their association with the outcome of decreased glomerular filtration rate. There have been several studies on prognostic biomarkers. The most promising ones have been markers of tubular injury, inflammation, metabolism, or the vasopressin-urinary concentration axis. So far, none have been shown to be superior to kidney volume-based biomarkers. Several biomarkers are additive to kidney volume and genotype in prognostic models, but there have been few direct comparisons between the biochemical markers to identify the best ones. Moreover, there is a lack of uniformity in the statistical tools used to assess and compare biomarkers. There have been few reports of predictive and response biomarkers, and none are suitable surrogate endpoints. The U.S. Food and Drug Administration's Biomarker Qualification Program provides a regulatory pathway to approve biomarkers for use across multiple drug-development programs.
    Keywords:  Biomarker; Clinical trial; Polycystic kidney disease; Prognosis; Surrogate endpoint
    DOI:  https://doi.org/10.1053/j.akdh.2022.12.009
  11. Magn Reson Med. 2023 Apr 24.
    Severity of polycystic kidney disease revealed by multiparametric MRI.
    Feng Wang, Seo Yeon Lee, Fatemeh Adelnia, Keiko Takahashi, Kevin D Harkins, Lilly He, Zhongliang Zu, Philipp Ellinger, Manuel Grundmann, Raymond C Harris, Takamune Takahashi, John C Gore.
       PURPOSE: We aimed to compare multiple MRI parameters, including relaxation rates ( R1$$ {R}_1 $$ , R2$$ {R}_2 $$ , and R1ρ$$ {R}_{1\rho } $$ ), ADC from diffusion weighted imaging, pool size ratio (PSR) from quantitative magnetization transfer, and measures of exchange from spin-lock imaging ( Sρ$$ {S}_{\rho } $$ ), for assessing and predicting the severity of polycystic kidney disease (PKD) over time.
    METHODS: Pcy/Pcy mice with CD1 strain, a mouse model of autosomal dominant PKD, were imaged at 5, 9, and 26 wk of age using a 7T MRI system. Twelve-week normal CD1 mice were used as controls. Post-mortem paraffin tissue sections were stained using hematoxylin and eosin and picrosirius red to identify histological changes.
    RESULTS: Histology detected segmental cyst formation in the early stage (week 5) and progression of PKD over time in Pcy kidneys. In T2$$ {T}_2 $$ -weighted images, small cysts appeared locally in cystic kidneys in week 5 and gradually extended to the whole cortex and outer stripe of outer medulla region from week 5 to week 26. Regional PSR, R1$$ {R}_1 $$ , R2$$ {R}_2 $$ , and R1ρ$$ {R}_{1\rho } $$ decreased consistently over time compared to normal kidneys, with significant changes detected in week 5. Among all the MRI measures, R2$$ {R}_2 $$ and R1ρ$$ {R}_{1\rho } $$ allow highest detectability to PKD, while PSR and R1$$ {R}_1 $$ have highest correlation with pathological indices of PKD. Using optimum MRI parameters as regressors, multiple linear regression provides reliable prediction of PKD progression.
    CONCLUSION: R2$$ {R}_2 $$ , R1$$ {R}_1 $$ , and PSR are sensitive indicators of the presence of PKD. Multiparametric MRI allows a comprehensive analysis of renal changes caused by cyst formation and expansion.
    Keywords:  MRI; diffusion weighted imaging; magnetization transfer; polycystic kidney disease (PKD); relaxation; spin-lock
    DOI:  https://doi.org/10.1002/mrm.29679
  12. FEBS Lett. 2023 Apr 27.
    The MIR34B/C genomic region contains multiple potential regulators of multiciliogenesis.
    Amélie Cavard, Elisa Redman, Olivier Mercey, Sophie Abelanet, Magali Plaisant, Marie-Jeanne Arguel, Virginie Magnone, Sandra Ruiz García, Géraldine Rios, Marie Deprez, Kévin Lebrigand, Gilles Ponzio, Ignacio Caballero, Pascal Barbry, Laure-Emmanuelle Zaragosi, Brice Marcet.
      The MIR449 genomic locus encompasses several regulators of multiciliated cell formation (multiciliogenesis). The miR-449 homologues miR-34b/c represent additional regulators of multiciliogenesis that are transcribed from another locus. Here, we characterized the expression of BTG4, LAYN and HOATZ, located in the MIR34B/C locus using single-cell RNA-seq and super-resolution microscopy from human, mouse or pig multiciliogenesis models. BTG4, LAYN and HOATZ transcripts were expressed in both precursors and mature multiciliated cells. The Layilin/LAYN protein was absent from primary cilia, but it was expressed in apical membrane regions or throughout motile cilia. LAYN silencing altered apical actin cap formation and multiciliogenesis. HOATZ protein was detected in primary cilia or throughout motile cilia. Altogether, our data suggest that the MIR34B/C locus may gather potential actors of multiciliogenesis.
    Keywords:  BTG4; HOATZ; LAYN; airway epithelium; miR-34b/c; motile cilia; multiciliated cells; single-cell RNA sequencing
    DOI:  https://doi.org/10.1002/1873-3468.14630
  13. AJNR Am J Neuroradiol. 2023 Apr 27.
    Higher Incidence of Unruptured Intracranial Aneurysms among Black and Hispanic Women on Screening MRA in Large Urban Populations.
    K Javed, S Ahmad, J Qin, W Mowrey, D Kadaba, G Liriano, A Fortunel, R Holland, D Khatri, N Haranhalli, D Altschul.
       BACKGROUND AND PURPOSE: Intracranial aneurysms have a reported prevalence of 1%-2% in the general population. Currently, only patients with a strong family history or autosomal dominant polycystic kidney disease are screened for intracranial aneurysms using MRA. The purpose of this study was to determine whether there are other specific patient populations at risk that should be offered screening for intracranial aneurysms.
    MATERIALS AND METHODS: This is a retrospective case-control study of adult patients who underwent a screening MRA of their brain at our comprehensive stroke center from 2011 to 2020. Patients with a history of a known brain aneurysm were excluded. Data were extracted on patient demographics and medical comorbidities. Bivariate analyses were performed, followed by multivariable logistic regression, to identify factors associated with a positive MRA screen for incidental aneurysms.
    RESULTS: Of 24,397 patients eligible for this study, 2084 screened positive for a possible intracranial aneurysm. On bivariate analysis, significant differences were present in the following categories: age, sex, race and ethnicity, chronic constipation, and hyperlipidemia. On logistic regression analysis, older age (+10 years: OR = 10.01; 95% CI, 10.01-10.02; P = .001), female sex (OR = 1.37; 95% CI, 1.24-1.51; P = .001), non-Hispanic Black (OR = 1.19; 95% CI, 1.02-1.40; P = .031), and Hispanic ethnicity (OR = 1.35; 95% CI, 1.16-1.58; P = .001) versus non-Hispanic White remained significant when adjusted for other factors.
    CONCLUSIONS: Targeted screening for high-risk elderly women of Black or Hispanic descent will yield higher positive findings for brain aneurysms, which may mitigate the risk of rupture. Whether this is a cost-effective approach has yet to be determined.
    DOI:  https://doi.org/10.3174/ajnr.A7856
  14. JCI Insight. 2023 Apr 27. pii: e168836. [Epub ahead of print]
    The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes.
    Amjad Horani, Deepesh Gupta, Jian Xu, Huihui Xu, Lis Del C Puga Molina, Celia M Santi, Sruthi Ramagiri, Steven K Brennan, Jiehong Pan, Jeffrey R Koenitzer, Tao Huang, Rachael M Hyland, Sean P Gunsten, Shin-Cheng Tzeng, Jennifer M Strahle, Pleasantine Mill, Moe R Mahjoub, Susan K Dutcher, Steven L Brody.
      DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift null deletion in Dnaaf5. Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partial preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. While transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. Together, these findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies.
    Keywords:  Genetic diseases; Genetics; Mouse models; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.168836
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