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Perez SM, Augustineli HS, Marcello MR. Utilizing C. elegans Spermatogenesis and Fertilization Mutants as a Model for Human Disease. J Dev Biol 2025; 13:4. [PMID: 39982357 PMCID: PMC11843878 DOI: 10.3390/jdb13010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/10/2025] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
The nematode C. elegans is a proven model for identifying genes involved in human disease, and the study of C. elegans reproduction, specifically spermatogenesis and fertilization, has led to significant contributions to our understanding of cellular function. Approximately 70 genes have been identified in C. elegans that control spermatogenesis and fertilization (spe and fer mutants). This review focuses on eight genes that have human orthologs with known pathogenic phenotypes. Using C. elegans to study these genes has led to critical developments in our understanding of protein domain function and human disease, including understanding the role of OTOF (the ortholog of C. elegans fer-1) in hearing loss, the contribution of the spe-39 ortholog VIPAS39 in vacuolar protein sorting, and the overlapping functions of spe-26 and KLHL10 in spermatogenesis. We discuss the cellular function of both the C. elegans genes and their human orthologs and the impact that C. elegans mutants and human variants have on cellular function and physiology. Utilizing C. elegans to understand the function of the genes reviewed here, and additional understudied and undiscovered genes, represents a unique opportunity to understand the function of variants that could lead to better disease diagnosis and clinical decision making.
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Andrini O, Eladari D, Picard N. ClC-K Kidney Chloride Channels: From Structure to Pathology. Handb Exp Pharmacol 2024; 283:35-58. [PMID: 36811727 DOI: 10.1007/164_2023_635] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
The molecular basis of chloride transport varies all along the nephron depending on the tubular segments especially in the apical entry of the cell. The major chloride exit pathway during reabsorption is provided by two kidney-specific ClC chloride channels ClC-Ka and ClC-Kb (encoded by CLCNKA and CLCNKB gene, respectively) corresponding to rodent ClC-K1 and ClC-K2 (encoded by Clcnk1 and Clcnk2). These channels function as dimers and their trafficking to the plasma membrane requires the ancillary protein Barttin (encoded by BSND gene). Genetic inactivating variants of the aforementioned genes lead to renal salt-losing nephropathies with or without deafness highlighting the crucial role of ClC-Ka, ClC-Kb, and Barttin in the renal and inner ear chloride handling. The purpose of this chapter is to summarize the latest knowledge on renal chloride structure peculiarity and to provide some insight on the functional expression on the segments of the nephrons and on the related pathological effects.
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Affiliation(s)
- Olga Andrini
- Univ Lyon, University Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U 1314, Melis, Lyon, France.
| | - Dominique Eladari
- CHU Amiens Picardie, Service de Médecine de Précision des maladies Métaboliques et Rénales, Université de Picardie Jules Verne, Amiens, France
| | - Nicolas Picard
- CNRS, LBTI UMR5305, Université Claude Bernard Lyon 1, Lyon, France
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Al-Beltagi M, Saeed NK, Bediwy AS, Elbeltagi R, Hasan S, Hamza MB. Renal calcification in children with renal tubular acidosis: What a paediatrician should know. World J Clin Pediatr 2023; 12:295-309. [PMID: 38178934 PMCID: PMC10762599 DOI: 10.5409/wjcp.v12.i5.295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/15/2023] [Accepted: 10/16/2023] [Indexed: 12/08/2023] Open
Abstract
Renal tubular acidosis (RTA) can lead to renal calcification in children, which can cause various complications and impair renal function. This review provides pediatricians with a comprehensive understanding of the relationship between RTA and renal calcification, highlighting essential aspects for clinical management. The article analyzed relevant studies to explore the prevalence, risk factors, underlying mechanisms, and clinical implications of renal calcification in children with RTA. Results show that distal RTA (type 1) is particularly associated with nephrocalcinosis, which presents a higher risk of renal calcification. However, there are limitations to the existing literature, including a small number of studies, heterogeneity in methodologies, and potential publication bias. Longitudinal data and control groups are also lacking, which limits our understanding of long-term outcomes and optimal management strategies for children with RTA and renal calcification. Pediatricians play a crucial role in the early diagnosis and management of RTA to mitigate the risk of renal calcification and associated complications. In addition, alkaline therapy remains a cornerstone in the treatment of RTA, aimed at correcting the acid-base imbalance and reducing the formation of kidney stones. Therefore, early diagnosis and appropriate therapeutic interventions are paramount in preventing and managing renal calcification to preserve renal function and improve long-term outcomes for affected children. Further research with larger sample sizes and rigorous methodologies is needed to optimize the clinical approach to renal calcification in the context of RTA in the pediatric population.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatrics, University Medical Center, King Abdulla Medical City, Dr. Sulaiman Al Habib Medical Group, Manama, Bahrain, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Manama, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Bahrain, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Chest Disease, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama, Manama 26671, Manama, Bahrain
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland - Bahrain, Busiateen 15503, Muharraq, Bahrain
| | - Samir Hasan
- Department of Pediatrics, Faculty of Medicine, Tanta University Hospital, Tanta 31511, Algharbia, Egypt
| | - Mohamed Basiony Hamza
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Algharbia, Egypt
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Bertholet-Thomas A, Manso-Silván MA, Navas-Serrano V, Guittet C, Joukoff S, Bacchetta J, Boyer O, Rodriguez Portillo M, Granier LA. Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103). Nefrologia 2023; 43:458-466. [PMID: 36529656 DOI: 10.1016/j.nefroe.2022.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 02/27/2022] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND AND OBJECTIVES ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated. PATIENTS AND METHODS Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well. RESULTS After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p=0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005). There was an increase>0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69-86% and 93-96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients. CONCLUSIONS Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters.
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Affiliation(s)
- Aurélia Bertholet-Thomas
- Centre de Référence des Maladies Rénales Rares - Néphrogones - Hôpital Femme Mère Enfant, Hospices Civils de Lyon - Filière ORKiD, Bron, France
| | | | | | | | | | - Justine Bacchetta
- Centre de Référence des Maladies Rénales Rares - Néphrogones - Hôpital Femme Mère Enfant, Hospices Civils de Lyon - Filière ORKiD, Bron, France
| | - Olivia Boyer
- Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Institut Imagine, Hôpital Necker-Enfants Malades, Université de Paris, France
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Acquadro M, Marrel A, Manso-Silván MA, Guittet C, Joukoff S, Bertholet-Thomas A. Lived experiences of patients with distal renal tubular acidosis treated with ADV7103 and of their caregivers: a qualitative study. Orphanet J Rare Dis 2022; 17:141. [PMID: 35346296 PMCID: PMC8962487 DOI: 10.1186/s13023-022-02294-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/27/2022] [Indexed: 12/30/2022] Open
Abstract
Background Consequences of distal renal tubular acidosis (dRTA) on growth, bone and kidney, sometimes associated with hearing loss, may significantly affect quality of life (QoL). This descriptive qualitative study explores QoL linked to dRTA and gathers the impressions of patients with this rare disease (and caregivers) 5 years after enrolment in a clinical study, during which patients were treated with ADV7103, a prolonged-release granule formulation combining potassium citrate and potassium bicarbonate. Semi-structured, one-hour interviews with 6 adult and 13 paediatric patients with a confirmed diagnosis of dRTA and with parents of paediatric patients were performed using an interview guide. Qualitative analysis of anonymized interview transcripts based on grounded theory was conducted. Results The main QoL domains impacted by dRTA and its treatment were education/work, social/family life, and emotional and physical well-being. ADV7103 (administered twice daily) was compared with the standard of care (SoC) taken before study entry (more than twice daily). Patients/parents reported that switching from previous SoC to ADV7103 had changed their lives:
Difficulties at school due to burdensome administrative issues and need to explain disease and treatment affecting all families of paediatric patients (n = 13) disappeared, facilitating parents who had stopped working (to deal with their child’s treatment) to return to work, Family functioning was improved (n = 18), as travel and holidays became easier to organise and patients/parents stopped thinking about managing treatment daily/nightly, reducing tension in the family or couple, The emotional burden of disease perceived was relieved (n = 12) in the absence of treatment-related invasive questions from others, Gastro-intestinal adverse events and taste problems improved with ADV7103 (n = 18) and better compliance led to milder physical impacts and less need to be hospitalised. The mean satisfaction score with ADV7103 compared to SoC was 9 out of 10 (10 = very satisfied). ADV7103 exceeded or met the expectations of 14 out of 17 patients that commented on that. Conclusions Qualitative interviews show that dRTA and its treatment have a significant impact on QoL of patients and parents and that ADV7103 helps improve daily-life and reduces treatment burden, resulting in greater overall satisfaction of the patients and their families. Trial registration EU Clinical Trials Register, EudraCT 2013-003828-36 on the 3rd of September 2013.
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Affiliation(s)
| | | | | | | | - Sophie Joukoff
- Advicenne S.A., 21 Allée Boissy d'Anglas, 30000, Nîmes, France
| | - Aurélia Bertholet-Thomas
- Centre de Référence des Maladies Rénales Rares-Néphrogones-Hôpital Femme Mère Enfant, Hospices Civils de Lyon-Filière ORKiD, Bron, France
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Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103). Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Organs-on-chip technology: a tool to tackle genetic kidney diseases. Pediatr Nephrol 2022; 37:2985-2996. [PMID: 35286457 PMCID: PMC9587109 DOI: 10.1007/s00467-022-05508-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/01/2022] [Accepted: 02/10/2022] [Indexed: 01/10/2023]
Abstract
Chronic kidney disease (CKD) is a major healthcare burden that takes a toll on the quality of life of many patients. Emerging evidence indicates that a substantial proportion of these patients carry a genetic defect that contributes to their disease. Any effort to reduce the percentage of patients with a diagnosis of nephropathy heading towards kidney replacement therapies should therefore be encouraged. Besides early genetic screenings and registries, in vitro systems that mimic the complexity and pathophysiological aspects of the disease could advance the screening for targeted and personalized therapies. In this regard, the use of patient-derived cell lines, as well as the generation of disease-specific cell lines via gene editing and stem cell technologies, have significantly improved our understanding of the molecular mechanisms underlying inherited kidney diseases. Furthermore, organs-on-chip technology holds great potential as it can emulate tissue and organ functions that are not found in other, more simple, in vitro models. The personalized nature of the chips, together with physiologically relevant read-outs, provide new opportunities for patient-specific assessment, as well as personalized strategies for treatment. In this review, we summarize the major kidney-on-chip (KOC) configurations and present the most recent studies on the in vitro representation of genetic kidney diseases using KOC-driven strategies.
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Gómez-Conde S, García-Castaño A, Aguirre M, Herrero M, Gondra L, Castaño L, Madariaga L. Hereditary distal renal tubular acidosis: Genotypic correlation, evolution to long term, and new therapeutic perspectives. Nefrologia 2021; 41:383-390. [PMID: 36165107 DOI: 10.1016/j.nefroe.2021.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 08/14/2020] [Indexed: 06/16/2023] Open
Abstract
Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3 groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA.
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Affiliation(s)
- Sara Gómez-Conde
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain
| | - Alejandro García-Castaño
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; CIBERDEM, CIBERER, Endo-ERN
| | - Mireia Aguirre
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; Sección de Nefrología Pediátrica, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain
| | - María Herrero
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; Sección de Nefrología Pediátrica, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain
| | - Leire Gondra
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; Sección de Nefrología Pediátrica, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain; Departamento de Pediatría, Universidad del País Vasco UPV/EHU, Barakaldo, Bizkaia, Spain
| | - Luis Castaño
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; CIBERDEM, CIBERER, Endo-ERN; Sección de Endocrinología Pediátrica, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain; Departamento de Pediatría, Universidad del País Vasco UPV/EHU, Barakaldo, Bizkaia, Spain
| | - Leire Madariaga
- Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Bizkaia, Spain; CIBERDEM, CIBERER, Endo-ERN; Sección de Nefrología Pediátrica, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain; Departamento de Pediatría, Universidad del País Vasco UPV/EHU, Barakaldo, Bizkaia, Spain.
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D'Ambrosio V, Azzarà A, Sangiorgi E, Gurrieri F, Hess B, Gambaro G, Ferraro PM. Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis. Kidney Blood Press Res 2021; 46:469-474. [PMID: 34107482 DOI: 10.1159/000516389] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/07/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. METHODS In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72. RESULTS Two unrelated individuals were found to have two different variants in SLC4A1 that had never been described before. CONCLUSIONS Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.
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Affiliation(s)
- Viola D'Ambrosio
- U.O.S. Terapia Conservativa della Malattia Renale Cronica, U.O.C. Nefrologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessia Azzarà
- Istituto di Medicina Genomica, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy
| | - Eugenio Sangiorgi
- Università Cattolica del Sacro Cuore, Rome, Italy.,Istituto di Medicina Genomica, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy
| | - Fiorella Gurrieri
- Unità di genetica Medica e Funzionale, Università Campus Bio-Medico, Rome, Italy
| | - Bernhard Hess
- Internal Medicine and Nephrology, Klinik Im Park, Zurich, and University of Zurich, Zurich, Switzerland
| | - Giovanni Gambaro
- Renal Unit, Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy
| | - Pietro Manuel Ferraro
- U.O.S. Terapia Conservativa della Malattia Renale Cronica, U.O.C. Nefrologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
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Li X, Cordat E, Schmitt MJ, Becker B. Boosting endoplasmic reticulum folding capacity reduces unfolded protein response activation and intracellular accumulation of human kidney anion exchanger 1 in Saccharomyces cerevisiae. Yeast 2021; 38:521-534. [PMID: 34033682 DOI: 10.1002/yea.3652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/20/2021] [Accepted: 05/21/2021] [Indexed: 11/09/2022] Open
Abstract
Human kidney anion exchanger 1 (kAE1) facilitates simultaneous efflux of bicarbonate and absorption of chloride at the basolateral membrane of α-intercalated cells. In these cells, kAE1 contributes to systemic acid-base balance along with the proton pump v-H+ -ATPase and the cytosolic carbonic anhydrase II. Recent electron microscopy analyses in yeast demonstrate that heterologous expression of several kAE1 variants causes a massive accumulation of the anion transporter in intracellular membrane structures. Here, we examined the origin of these kAE1 aggregations in more detail. Using various biochemical techniques and advanced light and electron microscopy, we showed that accumulation of kAE1 mainly occurs in endoplasmic reticulum (ER) membranes which eventually leads to strong unfolded protein response (UPR) activation and severe growth defect in kAE1 expressing yeast cells. Furthermore, our data indicate that UPR activation is dose dependent and uncoupled from the bicarbonate transport activity. By using truncated kAE1 variants, we identified the C-terminal region of kAE1 as crucial factor for the increased ER stress level. Finally, a redistribution of ER-localized kAE1 to the cell periphery was achieved by boosting the ER folding capacity. Our findings not only demonstrate a promising strategy for preventing intracellular kAE1 accumulation and improving kAE1 plasma membrane targeting but also highlight the versatility of yeast as model to investigate kAE1-related research questions including the analysis of structural features, protein degradation and trafficking. Furthermore, our approach might be a promising strategy for future analyses to further optimize the cell surface targeting of other disease-related PM proteins, not only in yeast but also in mammalian cells.
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Affiliation(s)
- Xiaobing Li
- Molecular and Cell Biology, Department of Biosciences and Centre of Human and Molecular Biology (ZHMB), Saarland University, Saarbrücken, Germany
| | - Emmanuelle Cordat
- Department of Physiology and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada
| | - Manfred J Schmitt
- Molecular and Cell Biology, Department of Biosciences and Centre of Human and Molecular Biology (ZHMB), Saarland University, Saarbrücken, Germany
| | - Björn Becker
- Molecular and Cell Biology, Department of Biosciences and Centre of Human and Molecular Biology (ZHMB), Saarland University, Saarbrücken, Germany
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Palmer BF, Kelepouris E, Clegg DJ. Renal Tubular Acidosis and Management Strategies: A Narrative Review. Adv Ther 2021; 38:949-968. [PMID: 33367987 PMCID: PMC7889554 DOI: 10.1007/s12325-020-01587-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 11/26/2020] [Indexed: 12/29/2022]
Abstract
Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid−base homeostasis because of tubular defects in acid excretion or bicarbonate ion reabsorption. Using illustrative clinical cases, this review describes the main types of RTA observed in clinical practice and provides an overview of their diagnosis and treatment. The three major forms of RTA are distal RTA (type 1; characterized by impaired acid excretion), proximal RTA (type 2; caused by defects in reabsorption of filtered bicarbonate), and hyperkalemic RTA (type 4; caused by abnormal excretion of acid and potassium in the collecting duct). Type 3 RTA is a rare form of the disease with features of both distal and proximal RTA. Accurate diagnosis of RTA plays an important role in optimal patient management. The diagnosis of distal versus proximal RTA involves assessment of urinary acid and bicarbonate secretion, while in hyperkalemic RTA, selective aldosterone deficiency or resistance to its effects is confirmed after exclusion of other causes of hyperkalemia. Treatment options include alkali therapy in patients with distal or proximal RTA and lowering of serum potassium concentrations through dietary modification and potential new pharmacotherapies in patients with hyperkalemic RTA including newer potassium binders.
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Bertholet-Thomas A, Guittet C, Manso-Silván MA, Castang A, Baudouin V, Cailliez M, Di Maio M, Gillion-Boyer O, Golubovic E, Harambat J, Klein A, Knebelmann B, Nobili F, Novo R, Podracka L, Roussey-Kesler G, Stylianou C, Granier LA. Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments. Pediatr Nephrol 2021; 36:83-91. [PMID: 32712761 PMCID: PMC7701073 DOI: 10.1007/s00467-020-04693-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/16/2020] [Accepted: 06/25/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.
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Affiliation(s)
- Aurélia Bertholet-Thomas
- Centre de Référence des Maladies Rénales Rares - Néphrogones - Hôpital Femme Mère Enfant - Filière ORKiD, Hospices Civils de Lyon, Bron, France.
| | | | | | | | | | - Mathilde Cailliez
- Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone, AP-HM, Marseille, France
| | - Massimo Di Maio
- Service de Réanimation Néonatale et Néonatologie, CHU de Nîmes, Nîmes, France
| | - Olivia Gillion-Boyer
- Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Institut Imagine, Hôpital Necker-Enfants Malades, Université de Paris, Paris, France
| | - Emilija Golubovic
- Klinički Centar Niš, Klinika za dečije interne bolesti - Odeljenje za nefrologiju, Niš, Serbia
| | - Jérôme Harambat
- Service de Pédiatrie, CHU de Bordeaux, Hôpital Pellegrin-Enfants, Bordeaux, France
| | - Alexandre Klein
- Service de Néphrologie, Pôle DIACOR, Hôpitaux Civils de Colmar, Colmar, France
| | | | - François Nobili
- Service de Pédiatrie 2, Hôpital Jean Minjoz, CHU de Besançon, Besançon, France
| | - Robert Novo
- Service de Néphrologie Pédiatrique, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France
| | - Ludmila Podracka
- Department of Pediatrics, National Institute of Children's Health, Bratislava, Slovakia
| | - Gwenaëlle Roussey-Kesler
- Unité de Néphrologie et Hémodialyse Pédiatrique, Clinique Médicale Pédiatrique Hôpital Mère-Enfant, CHU de Nantes, Nantes, France
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Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis. Pediatr Nephrol 2021; 36:1765-1774. [PMID: 33635379 PMCID: PMC8172410 DOI: 10.1007/s00467-020-04873-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/21/2020] [Accepted: 11/23/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months. METHODS Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored. RESULTS There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study. CONCLUSIONS Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable. TRIAL REGISTRATION NUMBER Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.
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Hereditary distal renal tubular acidosis: Genotypic correlation, evolution to long term, and new therapeutic perspectives. Nefrologia 2020. [PMID: 33386195 DOI: 10.1016/j.nefro.2020.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA.
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Hypercalcemia in distal renal tubular acidosis: A case report. JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY CASE REPORTS 2020. [DOI: 10.1016/j.jecr.2020.100069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Abstract
Renal tubular acidosis (RTA) comprises a group of disorders characterized by low capacity for net acid excretion and persistent hyperchloremic metabolic acidosis, despite preserved glomerular filtration rate. RTA are classified into chiefly three types (1, 2 and 4) based on pathophysiology and clinical and laboratory characteristics. Most patients have primary RTA that presents in infancy with polyuria, growth retardation, rickets and/or hypotonia. Diagnosis requires careful evaluation, including exclusion of other entities that can cause acidosis. A variety of tests, administered stepwise, are useful for the diagnosis and characterization of RTA. A genetic or acquired basis can be determined in majority of patients through focused evaluation. Management involves correction of acidosis and dyselectrolytemia; patients with proximal RTA with Fanconi syndrome and rickets require additional supplements of phosphate and vitamin D.
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Affiliation(s)
- Arvind Bagga
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Aditi Sinha
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
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Screening and function discussion of a hereditary renal tubular acidosis family pathogenic gene. Cell Death Dis 2020; 11:159. [PMID: 32123165 PMCID: PMC7052238 DOI: 10.1038/s41419-020-2354-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/11/2020] [Accepted: 02/11/2020] [Indexed: 12/18/2022]
Abstract
Hereditary distal renal tubular acidosis (dRTA) is a rare disease of H+ excretion defect of α-intercalated cells in renal collecting duct, caused by decreased V-ATPase function due to mutations in the ATP6V1B1 or ATP6V0A4 genes. In the present study, a genetic family with 5 members of the complete dRTA phenotype were found with distal tubule H+ secretion disorder, hypokalemia, osteoporosis, and kidney stones. A variant NM_020632.2:c.1631C > T (p.Ser544Leu) in exon 16 on an ATP6V0A4 gene associated with dRTA was detected by next generation sequencing target region capture technique and verified by Sanger sequencing, which suggested that except for one of the patients who did not receive the test, the other four patients all carried the p.S544L heterozygote. In transfected HEK293T cells, cells carrying p.S544L-mut showed early weaker ATPase activity and a slower Phi recovery rate after rapid acidification. By immunofluorescence localization, it was observed that the expression level of p.S544L-mut on the cell membrane increased and the distribution was uneven. Co-immunoprecipitation showed the a4 subunit of ATP6V0A4/p.S544L-mut could not bind to the B1 subunit, which might affect the correct assembly of V-ATPase. The present study of dRTA family suggests that the p.S544L variant may be inherited in a dominant manner.
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Saccharomyces cerevisiae: First Steps to a Suitable Model System To Study the Function and Intracellular Transport of Human Kidney Anion Exchanger 1. mSphere 2020; 5:5/1/e00802-19. [PMID: 31996424 PMCID: PMC6992373 DOI: 10.1128/msphere.00802-19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Distal renal tubular acidosis (dRTA) is a common kidney dysfunction characterized by impaired acid secretion via urine. Previous studies revealed that α-intercalated cells of dRTA patients express mutated forms of human kidney anion exchanger 1 (kAE1) which result in inefficient plasma membrane targeting or diminished expression levels of kAE1. However, the precise dRTA-causing processes are inadequately understood, and alternative model systems are helpful tools to address kAE1-related questions in a fast and inexpensive way. In contrast to a previous study, we successfully expressed full-length kAE1 in Saccharomyces cerevisiae. Using advanced microscopy techniques as well as different biochemical and functionality assays, plasma membrane localization and biological activity were confirmed for the heterologously expressed anion transporter. These findings represent first important steps to use the potential of yeast as a model organism for studying trafficking, activity, and degradation of kAE1 and its mutant variants in the future. Saccharomyces cerevisiae has been frequently used to study biogenesis, functionality, and intracellular transport of various renal proteins, including ion channels, solute transporters, and aquaporins. Specific mutations in genes encoding most of these renal proteins affect kidney function in such a way that various disease phenotypes ultimately occur. In this context, human kidney anion exchanger 1 (kAE1) represents an important bicarbonate/chloride exchanger which maintains the acid-base homeostasis in the human body. Malfunctions in kAE1 lead to a pathological phenotype known as distal renal tubular acidosis (dRTA). Here, we evaluated the potential of baker's yeast as a model system to investigate different cellular aspects of kAE1 physiology. For the first time, we successfully expressed yeast codon-optimized full-length versions of tagged and untagged wild-type kAE1 and demonstrated their partial localization at the yeast plasma membrane (PM). Finally, pH and chloride measurements further suggest biological activity of full-length kAE1, emphasizing the potential of S. cerevisiae as a model system for studying trafficking, activity, and/or degradation of mammalian ion channels and transporters such as kAE1 in the future. IMPORTANCE Distal renal tubular acidosis (dRTA) is a common kidney dysfunction characterized by impaired acid secretion via urine. Previous studies revealed that α-intercalated cells of dRTA patients express mutated forms of human kidney anion exchanger 1 (kAE1) which result in inefficient plasma membrane targeting or diminished expression levels of kAE1. However, the precise dRTA-causing processes are inadequately understood, and alternative model systems are helpful tools to address kAE1-related questions in a fast and inexpensive way. In contrast to a previous study, we successfully expressed full-length kAE1 in Saccharomyces cerevisiae. Using advanced microscopy techniques as well as different biochemical and functionality assays, plasma membrane localization and biological activity were confirmed for the heterologously expressed anion transporter. These findings represent first important steps to use the potential of yeast as a model organism for studying trafficking, activity, and degradation of kAE1 and its mutant variants in the future.
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19
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Soares SBM, de Menezes Silva LAW, de Carvalho Mrad FC, Simões E Silva AC. Distal renal tubular acidosis: genetic causes and management. World J Pediatr 2019; 15:422-431. [PMID: 31079338 DOI: 10.1007/s12519-019-00260-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Distal renal tubular acidosis (dRTA) is a kidney tubulopathy that causes a state of normal anion gap metabolic acidosis due to impairment of urine acidification. This review aims to summarize the etiology, pathophysiology, clinical findings, diagnosis and therapeutic approach of dRTA, with emphasis on genetic causes of dRTA. DATA SOURCES Literature reviews and original research articles from databases, including PubMed and Google Scholar. Manual searching was performed to identify additional studies about dRTA. RESULTS dRTA is characterized as the dysfunction of the distal urinary acidification, leading to metabolic acidosis. In pediatric patients, the most frequent etiology of dRTA is the genetic alteration of genes responsible for the codification of distal tubule channels, whereas, in adult patients, dRTA is more commonly secondary to autoimmune diseases, use of medications and uropathies. Patients with dRTA exhibit failure to thrive and important laboratory alterations, which are used to define the diagnosis. The oral alkali and potassium supplementation can correct the biochemical defects, improve clinical manifestations and avoid nephrolithiasis and nephrocalcinosis. CONCLUSIONS dRTA is a multifactorial disease leading to several clinical manifestations. Clinical and laboratory alterations can be corrected by alkali replacement therapy.
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Affiliation(s)
- Sílvia Bouissou Morais Soares
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Luiz Alberto Wanderley de Menezes Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Flávia Cristina de Carvalho Mrad
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
- Pediatric Nephrology Unit, Faculty of Medicine, UFMG, Belo Horizonte, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room # 281, Belo Horizonte, MG, 30130-100, Brazil.
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20
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Lashhab R, Ullah AS, Cordat E. Renal collecting duct physiology and pathophysiology. Biochem Cell Biol 2019; 97:234-242. [DOI: 10.1139/bcb-2018-0192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Rawad Lashhab
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - A.K.M. Shahid Ullah
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Emmanuelle Cordat
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Department of Physiology and Membrane Protein and Disease Research Group, University of Alberta, Edmonton, AB T6G 2H7, Canada
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Katuri A, Bryant JL, Patel D, Patel V, Andhavarapu S, Asemu G, Davis H, Makar TK. HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy. Exp Mol Pathol 2018; 106:139-148. [PMID: 30605635 DOI: 10.1016/j.yexmp.2018.12.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/25/2018] [Accepted: 12/29/2018] [Indexed: 12/31/2022]
Abstract
Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.
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Affiliation(s)
- Akhil Katuri
- Department of Neurology, University of Maryland, Baltimore, MD 21201, United States
| | - Joseph L Bryant
- Animal Model Division, Institute of Human Virology, Baltimore, MD 21201, United States
| | - Dhruvil Patel
- Department of Neurology, University of Maryland, Baltimore, MD 21201, United States
| | - Vivek Patel
- Department of Neurology, University of Maryland, Baltimore, MD 21201, United States
| | - Sanketh Andhavarapu
- Department of Neurology, University of Maryland, Baltimore, MD 21201, United States
| | - Girma Asemu
- Animal Model Division, Institute of Human Virology, Baltimore, MD 21201, United States
| | - Harry Davis
- Animal Model Division, Institute of Human Virology, Baltimore, MD 21201, United States
| | - Tapas K Makar
- Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; VA Medical Center, Baltimore, MD 21201, United States.
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22
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Watanabe T. Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead. Pediatric Health Med Ther 2018; 9:181-190. [PMID: 30588151 PMCID: PMC6296208 DOI: 10.2147/phmt.s174459] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal acidification due to a failure of type A intercalated cells (A-ICs) in the collecting tubule. dRTA is characterized by persistent hyperchloremia, a normal plasma anion gap, and the inability to maximally lower urinary pH in the presence of systemic metabolic acidosis. Common clinical features of dRTA include vomiting, failure to thrive, polyuria, hypercalciuria, hypocitraturia, nephrocalcinosis, nephrolithiasis, growth delay, and rickets. Mutations in genes encoding three distinct transport proteins in A-ICs have been identified as causes of dRTA, including the B1/ATP6V1B1 and a4/ATP6V0A4 subunits of the vacuolar-type H+-ATPase (H+-ATPase) and the chloride-bicarbonate exchanger AE1/SLC4A1. Homozygous or compound heterozygous mutations in ATP6V1B1 and ATP6V0A4 lead to autosomal recessive (AR) dRTA. dRTA caused by SLC4A1 mutations can occur with either autosomal dominant or AR transmission. Red blood cell abnormalities have been associated with AR dRTA due to SLC4A1 mutations, including hereditary spherocytosis, Southeast Asia ovalocytosis, and others. Some patients with dRTA exhibit atypical clinical features, including transient and reversible proximal tubular dysfunction and hyperammonemia. Incomplete dRTA presents with inadequate urinary acidification, but without spontaneous metabolic acidosis and recurrent urinary stones. Heterozygous mutations in the AE1 or H+-ATPase genes have recently been reported in patients with incomplete dRTA. Early and sufficient doses of alkali treatment are needed for patients with dRTA. Normalized serum bicarbonate, urinary calcium excretion, urinary low-molecular-weight protein levels, and growth rate are good markers of adherence to and/or efficacy of treatment. The prognosis of dRTA is generally good in patients with appropriate treatment. However, recent studies showed an increased frequency of chronic kidney disease (CKD) in patients with dRTA during long-term follow-up. The precise pathogenic mechanisms of CKD in patients with dRTA are unknown.
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Affiliation(s)
- Toru Watanabe
- Department of Pediatrics, Niigata City General Hospital, Niigata City 950-1197, Japan,
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Park E, Cho M, Hyun H, Shin J, Lee J, Park Y, Choi H, Kang H, Cheong H. Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis. Kidney Blood Press Res 2018; 43:513-521. [DOI: 10.1159/000488698] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/23/2018] [Indexed: 11/19/2022] Open
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