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Sas DJ, Bakkaloglu SA, Belostotsky V, Hayes W, Ariceta G, Zhou J, Rawson V. Nedosiran in pediatric patients with PH1 and relatively preserved kidney function, a phase 2 study (PHYOX8). Pediatr Nephrol 2025; 40:1939-1948. [PMID: 39875734 PMCID: PMC12031765 DOI: 10.1007/s00467-025-06675-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/06/2024] [Accepted: 01/05/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder with dysregulated glyoxylate metabolism in the liver. Oxalate over-production leads to renal stones, progressive kidney damage and renal failure, with potentially life-threatening systemic oxalosis. Nedosiran is a synthetic RNA interference therapy, designed to reduce hepatic lactate dehydrogenase (LDH) to decrease oxalate burden in PH. METHODS Currently, in the PHYOX8 study (NCT05001269), pediatric participants (2-11 years) with PH1 (N = 15) and estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m2 received nedosiran once monthly for 6 months. RESULTS Urinary oxalate:creatinine (Uox:Ucr) levels reduced by 64% on average. Mean Uox:Ucr reduction was 52% at day 60 and ˃60% at day 180. At one or more study visits, 93.3% (N = 14) of participants reached Uox:Ucr < 1.5 × upper limit of normal (ULN), and 53.3% (N = 8) reached ≤ 1.0 × ULN. Median percent change in plasma oxalate (12.0 µmol/L at baseline) to day 180 was -39.23% (n = 10). Average number of kidney stones per participant remained stable, whilst a 10.1% average decrease in summed surface area was observed. Median percent change from baseline in eGFR was 2.5%, indicating preservation of renal function. CONCLUSIONS Nedosiran was well tolerated, with only 3 participants experiencing at least one serious adverse event, none considered treatment-related. The incidence of injection site reactions was 6.7% (1/15 participants). In conclusion, nedosiran treatment led to a significant and sustained reduction of Uox levels in children with PH1. These findings support nedosiran treatment in pediatric patients to reduce Uox and shows promise for limiting PH1-related complications.
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Affiliation(s)
- David J Sas
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
| | | | | | - Wesley Hayes
- Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Gema Ariceta
- Pediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Jing Zhou
- Novo Nordisk A/S, Lexington, MA, USA
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Zhang S, Amrite A, Tan B, Jamsen K, Pradhan S, Choy S, Plotkin H. Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1. Br J Clin Pharmacol 2024; 90:3176-3189. [PMID: 39113219 PMCID: PMC11602945 DOI: 10.1111/bcp.16194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/24/2024] [Accepted: 07/02/2024] [Indexed: 11/29/2024] Open
Abstract
AIM To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. METHODS A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. RESULTS Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6 mmol) by week 52. CONCLUSIONS The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.
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Affiliation(s)
- Steven Zhang
- Dicerna Pharmaceuticals, Inc. a Novo Nordisk companyLexingtonMassachusettsUSA
| | - Aniruddha Amrite
- Pyxis OncologyBostonMassachusettsUSA
- Present address:
BioNTech US Inc.CambridgeMassachusettsUSA
| | - Beesan Tan
- Present address:
BioNTech US Inc.CambridgeMassachusettsUSA
- Present address:
Parexel InternationalBrisbaneQueenslandUSA
| | - Kris Jamsen
- Present address:
Parexel InternationalBrisbaneQueenslandUSA
| | - Sudeep Pradhan
- Present address:
Parexel InternationalBrisbaneQueenslandUSA
| | - Steve Choy
- Present address:
Boehringer Ingelheim Pharmaceuticals IncRidgefieldConnecticutUSA
| | - Horacio Plotkin
- Dicerna Pharmaceuticals, Inc. a Novo Nordisk companyLexingtonMassachusettsUSA
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Hassona Y, Hassan S, Atef A, Flaifl Y, AlShammas F, Abdaljaleel M. Primary hyperoxaluria: Description of a new oral finding and review of literature. SPECIAL CARE IN DENTISTRY 2024; 44:1041-1048. [PMID: 38321570 DOI: 10.1111/scd.12968] [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: 12/16/2023] [Revised: 01/04/2024] [Accepted: 01/20/2024] [Indexed: 02/08/2024]
Abstract
OBJECTIVES Oro-dental manifestations of hyperoxaluria and dental management of affected patients are rarely reported in the literature. We describe a new oral presentation of primary hyperoxaluria (PH) and review relevant literature about oro-dental manifestations and management of dental complications of hyperoxaluria. METHODS A case report of a 44-year-old female who presented with symptoms of temporomandibular joint dysfunction due to hyperoxaluria was described according to the CARE guidelines. In addition, an extensive search of biomedical databases (PubMed, Medline, Google Scholar, and Embase) for articles describing oro-dental manifestations and/or dental management in patients with hyperoxaluria was performed using the key words ("oral" and/or "hyperoxaluria" and/or "dental" and/or "oxalosis"). Included articles were reviewed and data about patient demographics, disease type and stage, oral and dental manifestations, and dental treatment outcome were retrieved and analyzed. RESULTS A total of 14 articles describing the oral and dental manifestations in 15 patients with hyperoxaluria were included. Tooth mobility, root resorption, and radiographic alterations were consistently described in all cases. Oral manifestations were described mainly in PH at late stages, and only after the onset of chronic renal disease. Dental management in all reported cases was palliative and aimed to relive pain and treat periodontal infection. Tooth loss due to extraction or uncontrolled mobility was the ultimate outcome in almost all reported cases. CONCLUSION Oral and dental manifestations in hyperoxaluria are rarely reported in the literature. Management of tooth mobility and root resorption in hyperoxaluria is challenging and clinical guidelines and evidence-based recommendations are lacking. Early diagnosis and treatment of hyperoxaluria might be the only effective approach to prevent dental and periodontal complications of the disease.
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Affiliation(s)
- Yazan Hassona
- Faculty of Dentistry, Centre for Oral Diseases Studies (CODS), Al-Ahliyya Amman University, Amman, Jordan
- School of Dentistry, The University of Jordan, Amman, Jordan
| | - Sora Hassan
- School of Dentistry, The University of Jordan, Amman, Jordan
| | - Alaa Atef
- School of Dentistry, The University of Jordan, Amman, Jordan
| | - Yara Flaifl
- School of Dentistry, The University of Jordan, Amman, Jordan
| | - Faris AlShammas
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Maram Abdaljaleel
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
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Liu Y, Zhao Z, Ge Y, He L, Qi S, Wang W. Clinical features and mutational spectrum of Chinese patients with primary hyperoxaluria type 2. Urolithiasis 2024; 52:74. [PMID: 38727838 DOI: 10.1007/s00240-024-01579-y] [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: 02/26/2024] [Accepted: 05/04/2024] [Indexed: 08/29/2024]
Abstract
Primary hyperoxaluria type 2 (PH2) is a rare hereditary disease that causes nephrolithiasis, nephrocalcinosis and kidney failure. This study aimed to investigate the clinical features and mutational spectrum of Chinese patients with PH2. A retrospective cohort study was performed on PH2 patients admitted to our center over seven years. We also systematically reviewed all the articles on Chinese PH2 patients published from January 2000 to May 2023 and conducted a meta-analysis. A total of 25 PH2 patients (10 from our center and 15 from published studies) were included in this study. The median age of onset in patients from our center was 8.50 (1.00, 24.00) years, and 50% were male. Among the full cohort of 25 Chinese patients, the median age of onset was 8.00 (0.40, 26.00) years, and 64% of them were male. Seven patients progressed to end-stage kidney disease, with a median age of 27.50 (12, 31) years. The cumulative renal survival rates were 100%, 91.67%, 45.83% and 30.56% at 10, 20, 30 and 40 years of age, respectively. A total of 18 different variants were identified, and c.864_865del was the dominant variant, accounting for 57.69% of the total alleles. Patients who were heterozygous for c.864_865del were more susceptible to nephrocalcinosis than those who were homozygous for c.864_865del and those harboring other mutations (83.33% versus 33.3% and 0%, respectively) (p = 0.025). The clinical features and mutational spectrum of Chinese PH2 patients were described. This study helps to expand awareness of the phenotypes and genotypes of Chinese PH2 patients and contributes to the improvement of diagnostic and treatment strategies for PH2 patients.
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Affiliation(s)
- Yukun Liu
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China
| | - Zhenqiang Zhao
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China
| | - Yucheng Ge
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China
| | - Longzhi He
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China
| | - Siyu Qi
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China
| | - Wenying Wang
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, 95 YongAn Road, Xicheng District, Beijing, 100050, China.
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Groothoff J, Sellier-Leclerc AL, Deesker L, Bacchetta J, Schalk G, Tönshoff B, Lipkin G, Lemoine S, Bowman T, Zhou J, Hoppe B. Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3. Kidney Int Rep 2024; 9:1387-1396. [PMID: 38707801 PMCID: PMC11068990 DOI: 10.1016/j.ekir.2024.02.1439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH. Methods In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months. Results Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m2) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of ≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to <0.60 mmol/24h; ≥ULN to <1.3 × ULN) 24-hour Uox excretion. All participants experienced ≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs. Conclusion Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing.
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Affiliation(s)
- Jaap Groothoff
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Anne-Laure Sellier-Leclerc
- Pediatric Nephrology Rheumatology Dermatology Unit, Reference Center for Rare Renal Diseases, ORKID and ERK-Net networks, Lyon University Hospital, Bron, France
| | - Lisa Deesker
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Justine Bacchetta
- Pediatric Nephrology Rheumatology Dermatology Unit, Reference Center for Rare Renal Diseases, ORKID and ERK-Net networks, Lyon University Hospital, Bron, France
| | - Gesa Schalk
- Pediatric Nephrology Center Bonn, Bonn, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics, University Children’s Hospital, Heidelberg, Germany
| | - Graham Lipkin
- Department of Nephrology, University Hospitals Birmingham, Birmingham, UK
| | - Sandrine Lemoine
- Department of Nephrology, Reference Center for Rare Renal Diseases, ORKID, University of Lyon, Lyon, France
| | - Thomas Bowman
- Dicerna Pharmaceuticals, Inc., a Novo Nordisk Company, Lexington, Massachusetts, USA
| | - Jing Zhou
- Dicerna Pharmaceuticals, Inc., a Novo Nordisk Company, Lexington, Massachusetts, USA
| | - Bernd Hoppe
- Dicerna Pharmaceuticals, Inc., a Novo Nordisk Company, Lexington, Massachusetts, USA
- German Hyperoxaluria Center, Pediatric Nephrology Center Bonn, Bonn, Germany
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Nieto-Romero V, García-Torralba A, Molinos-Vicente A, Moya FJ, Rodríguez-Perales S, García-Escudero R, Salido E, Segovia JC, García-Bravo M. Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts. iScience 2024; 27:109530. [PMID: 38577102 PMCID: PMC10993186 DOI: 10.1016/j.isci.2024.109530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 01/18/2024] [Accepted: 03/16/2024] [Indexed: 04/06/2024] Open
Abstract
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the AGXT gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific AGXT corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of AGXT cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated AGXT-corrected iHeps showed hepatic gene expression profile and exhibited in vitro reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 in vitro disease model.
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Affiliation(s)
- Virginia Nieto-Romero
- Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain
| | - Aida García-Torralba
- Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain
| | - Andrea Molinos-Vicente
- Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain
| | - Francisco José Moya
- Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
| | - Sandra Rodríguez-Perales
- Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
| | - Ramón García-Escudero
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)-ISCIII, Research Institute Hospital 12 de Octubre (imas12)-University Hospital 12 de Octubre, 28040 Madrid, Spain
| | - Eduardo Salido
- Pathology Department, Hospital Universitario de Canarias, Universidad La Laguna, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, 38320 Tenerife, Spain
| | - José-Carlos Segovia
- Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain
| | - María García-Bravo
- Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain
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Linse KP, Enk A, Toberer F. [Primary hyperoxaluria type 1-a rare hereditary metabolic disorder as cause of livedo racemosa]. DERMATOLOGIE (HEIDELBERG, GERMANY) 2024; 75:321-324. [PMID: 38167780 DOI: 10.1007/s00105-023-05276-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 01/05/2024]
Abstract
Livedo racemosa is characterized by a bizarrely configurated lightning figure-like appearance with striated to reticulated, livid erythematous macules and results from a reduced perfusion of the respective skin area, which can have different underlying pathophysiologies. A rare but relevant cause, especially in young patients with end-stage kidney failure, is primary hyperoxaluria type 1 (PH1), a hereditary metabolic disorder in which oxalate accumulates in the body.
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Affiliation(s)
- Kai-Philipp Linse
- Abteilung Dermatologie, Venerologie und Allergologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Deutschland.
| | - Alexander Enk
- Abteilung Dermatologie, Venerologie und Allergologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Deutschland
| | - Ferdinand Toberer
- Abteilung Dermatologie, Venerologie und Allergologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Deutschland
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Pérez-Carrión MD, Posadas I, Ceña V. Nanoparticles and siRNA: A new era in therapeutics? Pharmacol Res 2024; 201:107102. [PMID: 38331236 DOI: 10.1016/j.phrs.2024.107102] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
Since its discovery in 1998, the use of small interfering RNA (siRNA) has been increasing in biomedical studies because of its ability to very selectively inhibit the expression of any target gene. Thus, siRNAs can be used to generate therapeutic compounds for different diseases, including those that are currently 'undruggable'. This has led siRNA-based therapeutic compounds to break into clinical settings, with them holding the promise to potentially revolutionise therapeutic approaches. To date, the United States Food and Drug Administration (FDA) have approved 5 compounds for treating different diseases including hypercholesterolemia, transthyretin-mediated amyloidosis (which leads to polyneuropathy), hepatic porphyria, and hyperoxaluria. This current article presents an overview of the molecular mechanisms involved in the selective pharmacological actions of siRNA-based compounds. It also describes the ongoing clinical trials of siRNA-based therapeutic compounds for hepatic diseases, pulmonary diseases, atherosclerosis, hypertriglyceridemia, transthyretin-mediated amyloidosis, and hyperoxaluria, kidney diseases, and haemophilia, as well as providing a description of FDA-approved siRNA therapies. Because of space constraints and to provide an otherwise comprehensive review, siRNA-based compounds applied to cancer therapies have been excluded. Finally, we discuss how the use of lipid-based nanoparticles to deliver siRNAs holds promise for selectively targeting mRNA-encoding proteins associated with the genesis of different diseases. Thus, siRNAs can help reduce the cellular levels of these proteins, thereby contributing to disease treatment. As consequence, a marked increase in the number of marketed siRNA-based medicines is expected in the next two decades, which will likely open up a new era of therapeutics.
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Affiliation(s)
- María Dolores Pérez-Carrión
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain
| | - Inmaculada Posadas
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain
| | - Valentín Ceña
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain.
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Amrite A, Fuentes E, Marbury TC, Zhang S. Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease. Clin Pharmacol Drug Dev 2023; 12:1164-1177. [PMID: 37605486 DOI: 10.1002/cpdd.1320] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/29/2023] [Indexed: 08/23/2023]
Abstract
Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30 mL/min/1.73 m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10 participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170 mg. Group 1a received nedosiran 8 hours before beginning hemodialysis, Group 1b received nedosiran 2 hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.
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Affiliation(s)
- Aniruddha Amrite
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, MA, USA
| | | | | | - Steven Zhang
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, MA, USA
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Rather JI, Rasheed R, Wani MM, Bhat MA, Wani IA. Primary hyperoxaluria: a case series. J Med Case Rep 2023; 17:421. [PMID: 37803380 PMCID: PMC10559408 DOI: 10.1186/s13256-023-04129-z] [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: 06/21/2023] [Accepted: 08/14/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation. CASE PRESENTATIONS We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents. CONCLUSIONS Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate.
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Affiliation(s)
- Jawad Iqbal Rather
- Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&k, 190011, India.
| | - Rabiya Rasheed
- Department of Pathology, Government Medical College, Srinagar, India
| | | | | | - Imtiyaz Ahmad Wani
- Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&k, 190011, India
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11
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Mittal A, Jain H, Singh A, Yadav T, Vishwajeet V. A Rare Sparkle: A Case of Calcified Kidneys in a Young Infant With Renal Failure. Cureus 2023; 15:e46827. [PMID: 37954792 PMCID: PMC10636571 DOI: 10.7759/cureus.46827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2023] [Indexed: 11/14/2023] Open
Abstract
Primary hyperoxaluria-1 (PH1) is an autosomal recessively inherited rare genetic condition due to the deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase which leads to high systemic levels of oxalate and subsequently, early end-stage renal disease and death. Here, we present a case of a three-month-old male infant who presented with loose stools, reduced oral intake, and decreased activity for 12-13 days along with edema and a peeling rash on cheeks, lips, and genitalia. During the entire duration of the inpatient stay, the child was oligoanuric. Kidney ultrasound (USG) was suggestive of bilateral hyperechoic kidneys with increased cortical echogenicity and a computed tomography scan showed bilateral diffusely calcified renal cortices with well-preserved renal architecture. A diagnosis of "oxalate nephropathy" was made from renal biopsy and genetic testing confirmed it to be "primary hyperoxaluria-1". The child was initially managed conservatively, and then peritoneal dialysis was done, following which the child was shifted to intermittent hemodialysis.
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Affiliation(s)
- Aliza Mittal
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Hritvik Jain
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Amarpal Singh
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Taruna Yadav
- Department of Diagnostic and Interventional Radiology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Vikarn Vishwajeet
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
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12
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Baltazar P, de Melo Junior AF, Fonseca NM, Lança MB, Faria A, Sequeira CO, Teixeira-Santos L, Monteiro EC, Campos Pinheiro L, Calado J, Sousa C, Morello J, Pereira SA. Oxalate (dys)Metabolism: Person-to-Person Variability, Kidney and Cardiometabolic Toxicity. Genes (Basel) 2023; 14:1719. [PMID: 37761859 PMCID: PMC10530622 DOI: 10.3390/genes14091719] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
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Affiliation(s)
- Pedro Baltazar
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Antonio Ferreira de Melo Junior
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Nuno Moreira Fonseca
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Miguel Brito Lança
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
| | - Ana Faria
- CHRC, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal;
| | - Catarina O. Sequeira
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
| | - Luísa Teixeira-Santos
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Emilia C. Monteiro
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Luís Campos Pinheiro
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Joaquim Calado
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
- ToxOmics, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal
| | - Cátia Sousa
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Judit Morello
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
| | - Sofia A. Pereira
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
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Wannous H. Primary hyperoxaluria type 1 in children: clinical and laboratory manifestations and outcome. Pediatr Nephrol 2023; 38:2643-2648. [PMID: 36917293 DOI: 10.1007/s00467-023-05917-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 03/16/2023]
Abstract
BACKGROUND Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the liver. This study aimed to report clinical and laboratory manifestations and outcome of PH type 1 in children in our center. METHODS A single-center observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients admitted from 2018 to 2020, with a diagnosis of hyperoxaluria (urinary oxalate excretion > 45 mg/1.73 m2/day, or > 0.5 mmol/1.73 m2/day). PH type 1 (PH1) diagnosis was established by identification of biallelic pathogenic variants (compound heterozygous or homozygous mutations) in AGXT gene on molecular genetic testing. RESULTS The study included 100 patients with hyperoxaluria, with slight male dominance (57%), and median age 1.75 years (range, 1 month-14 years). Initial complaint was urolithiasis or nephrocalcinosis in 47%, kidney failure manifestations in 29%, and recurrent urinary tract infection in 24%. AGXT mutations were detected in 40 patients, and 72.5% of PH1 patients had kidney failure at presentation. Neither gender, age nor urinary oxalate excretion in 24 h had statistical significance in distinguishing PH1 from other forms of hyperoxaluria (P-Value > 0.05). Parental consanguinity, family history of kidney stones, bilateral nephrocalcinosis, presence of oxalate crystals in random urine sample, kidney failure and mortality were statistically significantly higher in PH1 (P-values < 0.05). Mortality was 32.5% among PH1 patients, with 4 PH1 patients (10%) on hemodialysis awaiting combined liver-kidney transplantation. CONCLUSION PH1 is still a grave disease with wide variety of clinical presentations which frequent results in delays in diagnosis, thus kidney failure is still a common presentation. In Syria, we face many challenges in diagnosis of PH, especially PH2 and PH3, and in management, with hopes that diagnosis tools and modern therapies will become available in our country. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Hala Wannous
- Faculty Member of Pediatric Nephrology in Faculty of Medicine, Damascus University, Damascus, Syria.
- Pediatric Nephrology, Hemodialysis, and Kidney Transplantation Department at Children's University Hospital, Damascus University, Damascus, Syria.
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14
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Boussetta A, Fatnassi R, Jellouli M, Maamouri R, Mrad R, Gargah T, Omezzine A. Hyperoxalurie primitive de type 1: Particularités cliniques, génétiques
et évolutive chez l’enfant Tunisien. LA TUNISIE MEDICALE 2023; 101:626-630. [PMID: 38445424 PMCID: PMC11217970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/09/2023] [Indexed: 07/05/2024]
Abstract
INTRODUCTION There are three types of primary hyperoxaluria, with type 1 considered the most severe. AIM To analyze the clinical, genetic, and evolutionary characteristics of type 1 primary hyperoxaluria with pediatric onset. METHODS This was a retrospective, descriptive study that included Tunisian children under the age of 18 at the time of diagnosis over a period of 25 years (January 1, 1996, to December 31, 2022). RESULTS Thirty-five patients were included, with a mean age of 4.1 years. The most common presenting circumstances of the disease were nephrolithiasis and end-stage renal failure. The average serum creatinine level was 225.42 µmol/l. Five mutations were identified, with the p.Ile244Thr mutation being the most prevalent. Nephrocalcinosis, surgical intervention, and a creatinine level ≥57 µmol/l were predictive of progression to end-stage renal failure. The infantile form was predictive of mortality. CONCLUSIONS Screening for the disease would improve the prognosis of this condition.
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Affiliation(s)
- Abir Boussetta
- Department of Pediatric Nephrology, Charles Nicolle Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Rihab Fatnassi
- Department of Pediatric Nephrology, Charles Nicolle Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Manel Jellouli
- Department of Pediatric Nephrology, Charles Nicolle Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Rym Maamouri
- Department of Ophthalmology, Habib Thameur Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Ridha Mrad
- Department of Hereditary and Congenital Diseases, Charles Nicolle Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Tahar Gargah
- Department of Pediatric Nephrology, Charles Nicolle Hospital
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
| | - Asma Omezzine
- Department of Biochemistry, Sahloul Hospital, Tunisia
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15
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Zijlstra HW, Stegeman CA. Oxalate nephropathy in an elderly patient with newly diagnosed celiac disease - a case report. BMC Nephrol 2023; 24:189. [PMID: 37370009 DOI: 10.1186/s12882-023-03241-y] [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: 01/20/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023] Open
Abstract
Oxalate nephropathy, due to secondary hyperoxaluria has widely been described in gastrointestinal diseases. However, reports of oxalate nephropathy in newly diagnosed celiac disease are rare. A 72-year-old Caucasian male presented to the hospital with abdominal discomfort and acute renal insufficiency with a creatinine of 290 µmol/L. The clinical course, laboratory results and urinalysis were suspect for tubular injury. Renal biopsy showed calcium oxalate depositions. Elevated plasma and urine oxalate levels established the diagnosis oxalate nephropathy. The abdominal complaints with steatorrhea and positive anti-tissue transglutaminase antibodies were diagnosed as celiac disease, which was confirmed after duodenal biopsies. Treatment with prednisone, and gluten-free, low oxalate and normal calcium diet, lowered the plasma oxalate levels and improved his renal function. Decreased absorption of free fatty acids can lead to increased free oxalate in the colon due to the binding of free fatty acids to calcium, preventing the formation of the less absorbable calcium oxalate in the colon. Oxalate dispositions in the kidney can lead to acute tubular injury and chronic renal insufficiency. Celiac disease is therefore one of the intestinal diseases that can lead to hyperoxaluria and oxalate nephropathy.
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Affiliation(s)
- Hendrik W Zijlstra
- Department of critical care, University Medical Center Groningen, Groningen, The Netherlands.
| | - Coen A Stegeman
- Department of nephrology, University Medical Center Groningen, Groningen, The Netherlands
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16
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Goldfarb DS, Modersitzki F, Karafilidis J, Li-McLeod J. Healthcare utilization, quality of life, and work productivity associated with primary hyperoxaluria: a cross-sectional web-based US survey. Urolithiasis 2023; 51:72. [PMID: 37067624 PMCID: PMC10110695 DOI: 10.1007/s00240-023-01436-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/25/2023] [Indexed: 04/18/2023]
Abstract
Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney failure, and serious complications due to systemic oxalosis, resulting in significant morbidity. We investigated the burden of PH among affected patients and caregivers. This cross-sectional, web-based survey was used to quantify the burden of PH, in terms of healthcare resource utilization, health-related quality of life, and work productivity and activity impairment among adults (≥ 18 years) with PH and caregivers of children (≤ 17 years) with PH in the US. Among the 20 respondents, there were 7 adults with PH and 13 caregivers of children with PH. Adherence to hyperhydration was noted as the most, or one of the most, difficult aspects of PH by 56% of respondents. Most patients (95%) had experienced painful kidney stone events, one-third had visited the emergency room, and 29% were hospitalized for complications due to PH. Of the 24% of patients on dialysis, all found the procedure burdensome. Adult patients' quality of life was negatively affected across several domains. Most respondents (81%) reported that PH had a negative effect on their finances. Employed adult patients and caregivers, and children with PH, had moderate impairment in work productivity, school attendance, and activity. Anxiety about future PH-related sequelae was moderate to high. These findings highlight the need for improvements in PH medical management. A plain language summary is available in the supplementary information.
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Affiliation(s)
- David S Goldfarb
- New York University Grossman School of Medicine, New York, NY, 10016, USA.
| | - Frank Modersitzki
- New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - John Karafilidis
- Dicerna Pharmaceuticals, Inc., a Novo Nordisk Company, Lexington, MA, USA
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17
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Wang XY, Zeng ZG, Zhu ZJ, Wei L, Qu W, Liu Y, Tan YL, Wang J, Zhang HM, Shi W, Sun LY. Effect of liver transplantation with primary hyperoxaluria type 1: Five case reports and review of literature. World J Clin Cases 2023; 11:1068-1076. [PMID: 36874433 PMCID: PMC9979304 DOI: 10.12998/wjcc.v11.i5.1068] [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: 10/09/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease stemming from a deficiency in liver-specific alanine-glyoxylate aminotransferase, resulting in increased endogenous oxalate deposition and end-stage renal disease. Organ transplantation is the only effective treatment. However, its approach and timing remain controversial.
CASE SUMMARY We retrospectively analyzed 5 patients diagnosed with PH1 from the Liver Transplant Center of the Beijing Friendship Hospital from March 2017 to December 2020. Our cohort included 4 males and 1 female. The median age at onset was 4.0 years (range: 1.0-5.0), age at diagnosis was 12.2 years (range: 6.7-23.5), age at liver transplantation (LT) was 12.2 years (range: 7.0-25.1), and the follow-up time was 26.3 mo (range: 12.8-40.1). All patients had delayed diagnosis, and 3 patients had progressed to end-stage renal disease by the time they were diagnosed. Two patients received preemptive LT; their estimated glomerular filtration rate was maintained at > 120 mL/min/1.73 m2, indicating a better prognosis. Three patients received sequential liver and kidney transplantation. After transplantation, serum and urinary oxalate decreased, and liver function recovered. At the last follow-up, the estimated glomerular filtration rates of the latter 3 patients were 179, 52 and 21 mL/min/1.73 m2.
CONCLUSION Different transplantation strategies should be adopted for patients based on their renal function stage. Preemptive-LT offers a good therapeutic approach for PH1.
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Affiliation(s)
- Xin-Yue Wang
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Zhi-Gui Zeng
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Lin Wei
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Wei Qu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Ying Liu
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Yu-Le Tan
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Jun Wang
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Hai-Ming Zhang
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
| | - Wen Shi
- Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Li-Ying Sun
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China
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18
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Nóbrega DF, Marutani VHB, Alcala MM, de Lima Cesar de Albuquerque IG, Goldberg DW, Del Rio do Valle CM, Del Rio do Valle R. Systemic oxalosis in a free-ranging green turtle (Chelonia mydas). J Comp Pathol 2023; 201:13-15. [PMID: 36646034 DOI: 10.1016/j.jcpa.2022.12.004] [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: 07/23/2022] [Revised: 08/29/2022] [Accepted: 12/01/2022] [Indexed: 01/15/2023]
Abstract
A female juvenile green turtle (Chelonia mydas), found alive in Guanabara Bay, Rio de Janeiro, Brazil, was weak, dehydrated and cachectic, with a healed fracture in the caudal portion of the carapace. Despite supportive treatment, the animal died after 9 days. At necropsy the main lesions were pallor of visceral organs, arthritis and deposits of whitish granular material in the wall of large arteries and the trachea. Histopathological analysis revealed mild to severe deposition of crystals, consistent with calcium oxalate, in both kidneys and the spleen, heart, small intestine, pancreas, thymus and salt gland, as well as bacterial meningitis, septic arthritis, spirorchidiasis and a fibropapilloma on the nictitating membrane. The main pathological findings were suggestive of septic shock, mainly due to the bacterial meningitis and septic arthritis, with systemic oxalosis and spirorchidiasis as contributing lesions. Although renal oxalosis has been described in green turtles as an incidental finding, presumably due to ingestion of oxalate-containing plants, this turtle had an unusual systemic deposition of oxalate crystals.
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Affiliation(s)
- Daniela F Nóbrega
- Pat Animal Laboratory, São José do Rio Preto, São Paulo, SP, Brazil.
| | | | | | | | | | | | - Rodrigo Del Rio do Valle
- Instituto Biopesca, Praia Grande, São Paulo, SP, Brazil; Health Science Institute, Paulista University, São Paulo, SP, Brazil
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PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2. Kidney Int 2023; 103:207-217. [PMID: 36007597 DOI: 10.1016/j.kint.2022.07.025] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/21/2022] [Accepted: 07/11/2022] [Indexed: 01/12/2023]
Abstract
Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.
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Abid A, Raza A, Khan AR, Firasat S, Shahid S, Hashmi S, Zafar MN, Sultan S, Khaliq S, Rizvi SAUH. Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease-associated pathogenic variants. Clin Genet 2023; 103:53-66. [PMID: 36185032 DOI: 10.1111/cge.14240] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/13/2022] [Accepted: 09/27/2022] [Indexed: 12/13/2022]
Abstract
The primary hyperoxalurias are rare disorders of glyoxylate metabolism. Accurate diagnosis is essential for therapeutic and management strategies. We conducted a molecular study on patients suffering from recurrent calcium-oxalate stones and nephrocalcinosis and screened primary hyperoxaluria causing genes in a large cohort of early-onset cases. Disease-associated pathogenic-variants were defined as missense, nonsense, frameshift-indels, and splice-site variants with a reported minor allele frequency <1% in controls. We found pathogenic-variants in 34% of the cases. Variants in the AGXT gene causing PH-I were identified in 81% of the mutation positive cases. PH-II-associated variants in the GRHPR gene are found in 15% of the pediatric PH-positive population. Only 3% of the PH-positive cases have pathogenic-variants in the HOGA1 gene, responsible to cause PH-III. A population-specific AGXT gene variant c.1049G>A; p.Gly350Asp accounts for 22% of the PH-I-positive patients. Pathogenicity of the identified variants was evaluated by in-silico tools and ACMG guidelines. We have devised a rapid and low-cost approach for the screening of PH by using targeted-NGS highlighting the importance of an accurate and cost-effective screening platform. This is the largest study in Pakistani pediatric patients from South-Asian region that also expands the mutation spectrum of the three known genes.
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Affiliation(s)
- Aiysha Abid
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ali Raza
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Abdul Rafay Khan
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Sadaf Firasat
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Saba Shahid
- Molecular Diagnostic Laboratory, Al Qassimi Hospital, Sharjah, UAE
| | - Seema Hashmi
- Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Mirza Naqi Zafar
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Sajid Sultan
- Department of Pediatric Urology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Shagufta Khaliq
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore, Pakistan
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21
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Cutaneous Oxalosis Due to Primary Hyperoxaluria. Am J Dermatopathol 2022; 44:981-983. [DOI: 10.1097/dad.0000000000002307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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22
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Soliman NA, Mabrouk S. Primary hyperoxaluria type 1 in developing countries: novel challenges in a new therapeutic era. Clin Kidney J 2022; 15:i33-i36. [PMID: 35592622 PMCID: PMC9113489 DOI: 10.1093/ckj/sfab203] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Indexed: 11/20/2022] Open
Abstract
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate due to deficiency of hepatic peroxisomal alanine-glyoxylate aminotransferase caused by AGXT gene mutation. One major hallmark of PH1 in developed as well as developing countries (DC) is the diagnostic delay. Notably in DC, where the disease is most prevalent and probably underdiagnosed, there are many challenges in PH1 diagnosis and management, with economic constrains and ethical concerns. This has led to the existing gap in the management of PH1 between developed and DC, which is expected to further deepen with the advent of novel therapeutic agents unless appropriate actions are taken. Until recently, treatment possibilities were limited to supportive measures. Thanks to a better understanding of the molecular basis of the disease a number of new therapies are developed, or being developed, leading to profound changes in management strategies. In this review we discuss the current situation of PH1 in DC as well as the accessibility challenges and the advantages of using promising novel therapeutics to bridge the currently existing gap. We also provide an overview of an integrated approach to ensure equitable access of sustainable therapeutics to PH1 patients in DC. This is expected to reduce global PH1 healthcare disparities, improve its standard of care and reduce disability linked to extrarenal complications of PH1 by implementing personalized medicine.
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Affiliation(s)
- Neveen A Soliman
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
| | - Sameh Mabrouk
- Biochemistry Department, University Hospital of Sahloul, Sousse, Tunisia
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23
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Ye L, Park JJ, Peng L, Yang Q, Chow RD, Dong MB, Lam SZ, Guo J, Tang E, Zhang Y, Wang G, Dai X, Du Y, Kim HR, Cao H, Errami Y, Clark P, Bersenev A, Montgomery RR, Chen S. A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy. Cell Metab 2022; 34:595-614.e14. [PMID: 35276062 PMCID: PMC8986623 DOI: 10.1016/j.cmet.2022.02.009] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 09/15/2021] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knockin or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression reshaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic, and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together, these findings provide a system for identification of GOF immune boosters and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
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Affiliation(s)
- Lupeng Ye
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Jonathan J Park
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA; Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA; MCGD Program, Yale University, New Haven, CT 06510, USA
| | - Lei Peng
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Quanjun Yang
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Ryan D Chow
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA; Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA; MCGD Program, Yale University, New Haven, CT 06510, USA
| | - Matthew B Dong
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA; Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA; MCGD Program, Yale University, New Haven, CT 06510, USA; Immunobiology Program, Yale University, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Stanley Z Lam
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; The College, Yale University, New Haven, CT 06520, USA
| | - Jianjian Guo
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA; Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA; MCGD Program, Yale University, New Haven, CT 06510, USA
| | - Erting Tang
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Yueqi Zhang
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Guangchuan Wang
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Xiaoyun Dai
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Yaying Du
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Hyunu R Kim
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Hanbing Cao
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Youssef Errami
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Paul Clark
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA
| | - Alexey Bersenev
- Advanced Cell Therapy Laboratory, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Ruth R Montgomery
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Epidemiology of Microbial Diseases, Yale University School of Public Health, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA; Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA; Comprehensive Cancer Center, Yale University, New Haven, CT 06510, USA
| | - Sidi Chen
- System Biology Institute, Integrated Science & Technology Center, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, West Haven, CT 06516, USA; Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA; MCGD Program, Yale University, New Haven, CT 06510, USA; Immunobiology Program, Yale University, New Haven, CT 06520, USA; Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA; Comprehensive Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA; Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA; Center for RNA Science and Medicine, Yale University, New Haven, CT 06510, USA.
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25
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Lee O, Park K, Sun K, O'Shea JP, Gordon S. Cashew-Induced Oxalate Nephropathy: A Rare Cause of Acute Renal Failure. Mil Med 2021; 188:usab453. [PMID: 34741455 DOI: 10.1093/milmed/usab453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/19/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022] Open
Abstract
We present a rare case of cashew-induced oxalate nephropathy in a 69 year old veteran male with history of type 2 diabetes mellitus, nephrolithiasis, and undiagnosed chronic kidney disease (CKD). Oxalate nephropathy is a rare cause of acute renal failure with poor prognosis. The various causes of oxalate nephropathy are categorized as primary or secondary hyperoxaluria. Primary hyperoxaluria is caused by genetic mutation in genes involved in the metabolism of glyoxylate. Secondary hyperoxaluria is caused by mal-absorptive state, excessive intake of oxalate-rich diet, inflammatory diseases, and medications such as orlistat and antibiotics. Diet-induced oxalate nephropathy is often identified after unexplained acute kidney injury in patients with underlying CKD. Definitive diagnosis requires renal biopsy as laboratory tests are non-specific. A simple dietary history in CKD patients during routine primary care visit may lead to early diagnosis and lead to prevention of acute renal failure and progression of renal disease.
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Affiliation(s)
- Oliver Lee
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Katherine Park
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Kelly Sun
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - John-Paul O'Shea
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Sarah Gordon
- Department of Nephrology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
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26
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Hoppe B, Koch A, Cochat P, Garrelfs SF, Baum MA, Groothoff JW, Lipkin G, Coenen M, Schalk G, Amrite A, McDougall D, Barrios K, Langman CB. Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria. Kidney Int 2021; 101:626-634. [PMID: 34481803 DOI: 10.1016/j.kint.2021.08.015] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/27/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022]
Abstract
Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.
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Affiliation(s)
- Bernd Hoppe
- Department of Pediatrics, Division of Pediatric Nephrology, University Hospital Bonn, Bonn, Germany; Dicerna Pharmaceuticals, Inc., Lexington, Massachusetts, USA
| | - Annelize Koch
- Clinical Pharmacology Unit, Simbec Research Ltd., Merthyr Tydfil, UK
| | - Pierre Cochat
- Center for Rare Renal Diseases and Inserm Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon, France
| | - Sander F Garrelfs
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands
| | - Michelle A Baum
- Division of Pediatric Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Jaap W Groothoff
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands
| | - Graham Lipkin
- Department of Nephrology, Queen Elizabeth Hospital, Birmingham, UK
| | - Martin Coenen
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Gesa Schalk
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | | | - David McDougall
- Model Answers, a Parexel Company, Brisbane, Queensland, Australia
| | - Kelly Barrios
- Dicerna Pharmaceuticals, Inc., Lexington, Massachusetts, USA
| | - Craig B Langman
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Division of Kidney Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
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27
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Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol 2021; 189:114432. [PMID: 33513339 PMCID: PMC8187268 DOI: 10.1016/j.bcp.2021.114432] [Citation(s) in RCA: 321] [Impact Index Per Article: 80.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/14/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022]
Abstract
More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.
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Affiliation(s)
- M May Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
| | - Theodore P Rasmussen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
| | - José E Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
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28
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Murad H, Alhalabi MB, Dabboul A, Alfakseh N, Nweder MS, Zghib Y, Wannous H. Molecular analysis of the AGXT gene in Syrian patients suspected with primary hyperoxaluria type 1. BMC Med Genomics 2021; 14:146. [PMID: 34082749 PMCID: PMC8176596 DOI: 10.1186/s12920-021-00996-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/27/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Characterization of the molecular basis of primary hyperoxaluria type 1 (PH-1) in Syria has been accomplished through the analysis of 90 unrelated chromosomes from 45 Syrians patients with PH-1 from different regions. METHODS Alanine glyoxylate aminotransferase (AGXT) gene mutations have been analyzed by using molecular detection methods based on the direct DNA sequencing for all exons of the AGXT gene. RESULTS Seventeen pathogenic mutations were detected in our patients. Six mutations were novels. The three most frequent mutations were c.33_34insC (p.Lys12fs) in Exon 1, c.584 T < G; p.Met195Arg in exon 5 and c.1007 T > A (p.Val336Asp) in exon 10, with a frequency of 33.3%, 12.2%, and 11.1%, respectively. CONCLUSION DNA sequencing used in this study can offer a useful method to investigate the mutations in Syrian PH-1 patients, and could offer an accurate tool for prenatal diagnosis and genetic counseling.
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Affiliation(s)
- Hossam Murad
- Human Genetics Division, Molecular Biology and Biotechnology Department, Human Genetics Division, Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria.
| | - Mohamad Baseel Alhalabi
- Human Genetics Division, Molecular Biology and Biotechnology Department, Human Genetics Division, Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria
| | - Amir Dabboul
- Human Genetics Division, Molecular Biology and Biotechnology Department, Human Genetics Division, Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria
| | - Nour Alfakseh
- Human Genetics Division, Molecular Biology and Biotechnology Department, Human Genetics Division, Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria
| | - Mohamad Sayah Nweder
- Human Genetics Division, Molecular Biology and Biotechnology Department, Human Genetics Division, Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria
| | | | - Hala Wannous
- Chlidien's Hospital of Damascus, Damascus, Syria
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29
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Xu CB, Zhou XD, Xu HE, Zhao YL, Zhao XH, Liu DH, Tian YA, Hu XX, Guan JY, Guo JC, Tang WX, Xue X. A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome. BMC Nephrol 2021; 22:83. [PMID: 33691640 PMCID: PMC7945658 DOI: 10.1186/s12882-021-02276-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 02/19/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. CASE PRESENTATION In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband's mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. CONCLUSIONS Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.
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Affiliation(s)
- Chang Bao Xu
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xu Dong Zhou
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hong En Xu
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, ZhengZhou University, Zhengzhou, China.,Precision Medicine Center of ZhengZhou University, Zhengzhou, China
| | - Yong Li Zhao
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xing Hua Zhao
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Dan Hua Liu
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yong An Tian
- BGI College, ZhengZhou University, Zhengzhou, China
| | - Xin Xin Hu
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Precision Medicine Center of ZhengZhou University, Zhengzhou, China
| | - Jing Yuan Guan
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Precision Medicine Center of ZhengZhou University, Zhengzhou, China
| | - Jian Cheng Guo
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, ZhengZhou University, Zhengzhou, China.,Precision Medicine Center of ZhengZhou University, Zhengzhou, China.,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wen Xue Tang
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, ZhengZhou University, Zhengzhou, China.,Precision Medicine Center of ZhengZhou University, Zhengzhou, China.,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xia Xue
- Academy of Medical Sciences, ZhengZhou University, Zhengzhou, China. .,Precision Medicine Center of ZhengZhou University, Zhengzhou, China.
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Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies. Pediatr Nephrol 2021; 36:1785-1793. [PMID: 33515281 PMCID: PMC8172484 DOI: 10.1007/s00467-020-04894-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 11/06/2020] [Accepted: 12/03/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01). METHODS Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman's rank and Pearson's correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used. RESULTS A total of 106 patients were analyzed. A statistically significant inverse Spearman's correlation between eGFR and Pox was observed across all analyses; correlation coefficients were - 0.44 in study OC3-DB-01, - 0.55 in study OC3-DB-02, - 0.51 in study OC5-DB-01, and - 0.49 in the pooled studies (p < 0.0064). CONCLUSIONS Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1-3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.
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Angelico R, Guzzo I, Pellicciaro M, Saffioti MC, Grimaldi C, Mourani C, Smedile F, Pariante R, Semprini A, Monti L, Candusso M, Dello Strologo L, Spada M. Same Donor Laparoscopic Liver and Kidney Procurement for Sequential Living Donor Liver-Kidney Transplantation in Primary Hyperoxaluria Type I. J Laparoendosc Adv Surg Tech A 2019; 29:1616-1622. [PMID: 31687885 DOI: 10.1089/lap.2019.0483] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor.
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Affiliation(s)
- Roberta Angelico
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Isabella Guzzo
- Department of Nephrology and Dyalisis, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Marco Pellicciaro
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Maria Cristina Saffioti
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Chiara Grimaldi
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Chebl Mourani
- Department of Pediatrics, Hôtel-Dieu de France Hospital (HDF), Beirut, Lebanon
| | - Francesco Smedile
- Department of Anesthesiology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Rosanna Pariante
- Department of Anesthesiology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Alessia Semprini
- Department of Radiology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Lidia Monti
- Department of Radiology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Manila Candusso
- Division of Hepatology and Gastroenterology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Luca Dello Strologo
- Department of Nephrology and Dyalisis, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Marco Spada
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
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Fang X, He L, Xu G, Lin H, Xu M, Geng H. Nine novel HOGA1 gene mutations identified in primary hyperoxaluria type 3 and distinct clinical and biochemical characteristics in Chinese children. Pediatr Nephrol 2019; 34:1785-1790. [PMID: 31123811 DOI: 10.1007/s00467-019-04279-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 04/08/2019] [Accepted: 05/14/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are thought to present with a less severe phenotype than PH1 and PH2 patients. However, the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aims of this study were to report HOGA1 mutations of PH3 in Chinese children, and to analyze the genotype and clinical characteristics of these PH3 patients. METHODS Genetic analysis (targeted gene panel-based and/or whole-exome sequencing) of HOGA1 was performed in 52 patients with a high suspicion of PH3, and DNA was obtained from the patient and both the parents. The clinical, biochemical, and genetic data of these 12 patients identified with HOGA1 mutations were subsequently retrospectively reviewed. RESULTS These 12 patients were identified with HOGA1 mutation. The median onset of clinical symptoms was 18.25 (range 5-38) months. In total, 14 different mutations were identified including 9 novel mutations in these 12 patients with PH3. All of these 12 patients initially presented with urolithiasis, and 3 patients among them comorbid urinary tract infection (UTI) as another initial symptom. Ten patients experienced hyperoxaluria (average oxalate 0.77 mmol/1.73 m2/24h). In contrast, urine calcium excretion was normal in 8 patients and 2 patients with hypercalciuria (urine calcium > 4 mg/kg/24 h). At the time of diagnosis, estimated GFR was 155.6 ml/min per 1.73 m2, and at last follow-up time (17.3 months later from diagnosis on average), estimated GFR was 157.5 ml/min per 1.73 m2. To date, none of the patients has impaired renal function based on and progressed to ESRD. CONCLUSIONS We found that PH3 was significantly diagnosed in our urolithiasis patients during childhood. Nine novel HOGA1 mutations were identified in association with PH3, which provide a first-line investigation in Chinese PH3 patients. The eGFR was normal in all children with PH3. This finding is in contrast to the early impairment of renal function in PH1 and PH2.
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Affiliation(s)
- Xiaoliang Fang
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China
| | - Lei He
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China
| | - Guofeng Xu
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China
| | - Houwei Lin
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China
| | - Maosheng Xu
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China
| | - Hongquan Geng
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China. .,Children's Stone Treatment Center of National Health and Family Planning Commission of the People's Republic of China, 1665 KongJiang Road, Shanghai, 200092, China.
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33
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Estève J, Blouin JM, Lalanne M, Azzi-Martin L, Dubus P, Bidet A, Harambat J, Llanas B, Moranvillier I, Bedel A, Moreau-Gaudry F, Richard E. Generation of induced pluripotent stem cells-derived hepatocyte-like cells for ex vivo gene therapy of primary hyperoxaluria type 1. Stem Cell Res 2019; 38:101467. [PMID: 31151050 DOI: 10.1016/j.scr.2019.101467] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 03/30/2019] [Accepted: 05/19/2019] [Indexed: 12/17/2022] Open
Abstract
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of the liver metabolism due to functional deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in overproduction of oxalate which complexes with calcium to form insoluble calcium-oxalate salts in urinary tracts, ultimately leading to end-stage renal disease. Currently, the only curative treatment for PH1 is combined liver-kidney transplantation, which is limited by donor organ shortage and lifelong requirement for immunosuppression. Transplantation of genetically modified autologous hepatocytes is an attractive therapeutic option for PH1. However, the use of fresh primary hepatocytes suffers from limitations such as organ availability, insufficient cell proliferation, loss of function, and the risk of immune rejection. We developed patient-specific induced pluripotent stem cells (PH1-iPSCs) free of reprogramming factors as a source of renewable and genetically defined autologous PH1-hepatocytes. We then investigated additive gene therapy using a lentiviral vector encoding wild-type AGT under the control of the liver-specific transthyretin promoter. Genetically modified PH1-iPSCs successfully provided hepatocyte-like cells (HLCs) that exhibited significant AGT expression at both RNA and protein levels after liver-specific differentiation process. These results pave the way for cell-based therapy of PH1 by transplantation of genetically modified autologous HLCs derived from patient-specific iPSCs.
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Affiliation(s)
- Julie Estève
- Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France
| | - Jean-Marc Blouin
- Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France
| | - Magalie Lalanne
- Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France
| | | | - Pierre Dubus
- Univ.Bordeaux, INSERM, BARITON, U1053, CHU Bordeaux, 33076, France
| | - Audrey Bidet
- Laboratoire d'hématologie, CHU Bordeaux, Bordeaux, France
| | - Jérôme Harambat
- Service de Néphrologie pédiatrique, Centre de Référence Maladies Rénales Rares du Sud-Ouest, CHU Bordeaux, 33000 Bordeaux, France
| | - Brigitte Llanas
- Service de Néphrologie pédiatrique, Centre de Référence Maladies Rénales Rares du Sud-Ouest, CHU Bordeaux, 33000 Bordeaux, France
| | | | - Aurélie Bedel
- Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France
| | | | - Emmanuel Richard
- Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France.
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Bruel A, Bacchetta J, Ginhoux T, Rodier-Bonifas C, Sellier-Leclerc AL, Fromy B, Cochat P, Sigaudo-Roussel D, Dubourg L. Skin microvascular dysfunction as an early cardiovascular marker in primary hyperoxaluria type I. Pediatr Nephrol 2019; 34:319-327. [PMID: 30276532 DOI: 10.1007/s00467-018-4081-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/03/2018] [Accepted: 09/03/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an orphan inborn error of oxalate metabolism leading to hyperoxaluria, progressive renal failure, oxalate deposition, and increased cardiovascular complications. As endothelial dysfunction and arterial stiffness are early markers of cardiovascular risk, we investigated early endothelial and vascular dysfunction in young PH1 patients either under conservative treatment (PH1-Cons) or after combined kidney liver transplantation (PH1-T) in comparison to healthy controls (Cont-H) and patients with a past of renal transplantation (Cont-T). METHODS Skin microvascular function was non-invasively assessed by laser Doppler flowmetry before and after stimulation by current, thermal, or pharmacological (nitroprussiate (SNP) or acetylcholine (Ach)) stimuli in young PH1 patients and controls. RESULTS Seven PH1-Cons (6 F, median age 18.2) and 6 PH1-T (2 F, median age 13.3) were compared to 96 Cont-H (51 F, median age 14.2) and 6 Cont-T (4 F, median age 14.5). The endothelium-independent vasodilatation (SNP) was severely decreased in PH1-T compared to Cont-H. Ach, current-induced vasodilatation (CIV), and thermal response was increased in PH1-Cons and Cont-T compared to controls. CONCLUSIONS PH1-T patients displayed severely decreased smooth muscle capacity to vasodilate. An exacerbated endothelial-dependent vasodilation suggests a role for silent inflammation in the early dysfunction of microcirculation observed in PH1-Cons and Cont-T.
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Affiliation(s)
- Alexandra Bruel
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France.,Service de Pédiatrie, Hôpital Mère et Enfants, Centre hospitalo-universitaire de Nantes, Nantes, France
| | - Justine Bacchetta
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Tiphanie Ginhoux
- EPICIME-CIC 1407 de Lyon, Inserm, Service de Pharmacologie Clinique, CHU-Lyon, Lyon, France
| | - Christelle Rodier-Bonifas
- Service d'ophtalmologie, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Anne-Laure Sellier-Leclerc
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France
| | - Bérengère Fromy
- Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Claude Bernard Lyon 1, Villeurbanne, France
| | - Pierre Cochat
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France.,Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Claude Bernard Lyon 1, Villeurbanne, France
| | - Dominique Sigaudo-Roussel
- Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Claude Bernard Lyon 1, Villeurbanne, France
| | - Laurence Dubourg
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France. .,Université Claude Bernard Lyon 1, Lyon, France. .,Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Claude Bernard Lyon 1, Villeurbanne, France. .,Néphrologie, Dialyse, Hypertension et Exploration Fonctionnelle Rénale, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
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Dindo M, Conter C, Oppici E, Ceccarelli V, Marinucci L, Cellini B. Molecular basis of primary hyperoxaluria: clues to innovative treatments. Urolithiasis 2018; 47:67-78. [PMID: 30430197 DOI: 10.1007/s00240-018-1089-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 11/08/2018] [Indexed: 12/21/2022]
Abstract
Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic end-product that is eliminated by urine. The main symptoms are related to the precipitation of calcium oxalate crystals in the urinary tract with progressive renal damage and, in the most severe form named Primary Hyperoxaluria Type I (PH1), to systemic oxalosis. The therapies currently available for PH are either poorly effective, because they address the symptoms and not the causes of the disease, or highly invasive. In the last years, advances in our understanding of the molecular bases of PH have paved the way for the development of new therapeutic strategies. They include (i) substrate-reduction therapies based on small-molecule inhibitors or the RNA interference technology, (ii) gene therapy, (iii) enzyme administration approaches, (iv) colonization with oxalate-degrading intestinal microorganisms, and, in PH1, (v) design of pharmacological chaperones. This paper reviews the basic principles of these new therapeutic strategies and what is currently known about their application to PH.
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Affiliation(s)
- Mirco Dindo
- Department of Experimental Medicine, University of Perugia, P.le Gambuli 1, 06132, Perugia, Italy
| | - Carolina Conter
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, 37134, Verona, VR, Italy
| | - Elisa Oppici
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, 37134, Verona, VR, Italy
| | - Veronica Ceccarelli
- Department of Experimental Medicine, University of Perugia, P.le Gambuli 1, 06132, Perugia, Italy
| | - Lorella Marinucci
- Department of Experimental Medicine, University of Perugia, P.le Gambuli 1, 06132, Perugia, Italy
| | - Barbara Cellini
- Department of Experimental Medicine, University of Perugia, P.le Gambuli 1, 06132, Perugia, Italy.
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36
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An Unusual Presentation of a Child with Hyperoxaluria. ARCHIVES OF PEDIATRIC INFECTIOUS DISEASES 2018. [DOI: 10.5812/pedinfect.67357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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37
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Yang H, Male M, Li Y, Wang N, Zhao C, Jin S, Hu J, Chen Z, Ye Z, Xu H. Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary hyperoxaluria in Drosophila Melanogaster. BMC Nephrol 2018; 19:167. [PMID: 29980178 PMCID: PMC6035412 DOI: 10.1186/s12882-018-0980-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 06/28/2018] [Indexed: 12/11/2022] Open
Abstract
Background Substrate reduction therapy with analogs reduces the accumulation of substrates by inhibiting the metabolic pathways involved in their biosynthesis, providing new treatment options for patients with primary hyperoxalurias (PHs) that often progress to end-stage renal disease (ESRD). This research aims to evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster (D. Melanogaster) by comparing them with Pyridoxine (Vitamin B6). Methods Three stocks of Drosophila Melanogaster (W118, CG3926 RNAi, and Act5C-GAL4/CyO) were utilized. Two stocks (CG3926 RNAi and Act5C-GAL4 /CyO) were crossed to generate the Act5C > dAGXT RNAi recombinant line (F1 generation) of D. Melanogaster which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs inhibiting CaOx crystal formation with Vitamin B6 as the traditional therapy for primary hyperoxaluria. Results Nephrolithiasis model was successfully constructed by downregulating the function of the dAGXT gene in D. Melanogaster (P-Value = 0.0045). Furthermore, the efficacy of Hydroxy-L-proline (HYP) analogs against CaOx crystal formation was demonstrated in vivo using D. Melanogaster model; the results showed that these L-Proline analogs were better in inhibiting stone formation at very low concentrations than Vitamin B6 (IC50 = 0.6 and 1.8% for standard and dietary salt growth medium respectively) compared to N-acetyl-L-Hydroxyproline (IC50 = 0.1% for both standard and dietary salt growth medium) and Baclofen (IC50 = 0.06 and 0.1% for standard and dietary salt growth medium respectively). Analysis of variance (ANOVA) also showed that Hydroxy-L-proline (HYP) analogs were better alternatives for CaOx inhibition at very low concentration especially when both genetics and environmental factors are intertwined (p < 0.0008) for the dietary salt growth medium and (P < 0.063) for standard growth medium. Conclusion Addition of Hydroxy-L-Proline analogs to growth medium resulted in the reduction of CaOx crystals formation. These analogs show promise as potential inhibitors for oxalate reduction in Primary Hyperoxaluria.
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Affiliation(s)
- Huan Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Musa Male
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Li
- College of Life Sciences, Hubei University, Wuhan, China
| | - Ning Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenming Zhao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shan Jin
- College of Life Sciences, Hubei University, Wuhan, China
| | - Juncheng Hu
- College of Life Sciences, Hubei University, Wuhan, China
| | - Zhiqiang Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangqun Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China. .,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Cazzolla AP, Zhurakivska K, Ciavarella D, Lacaita MG, Favia G, Testa NF, Marzo G, La Carbonara V, Troiano G, Lo Muzio L. Primary hyperoxaluria: Orthodontic management in a pediatric patient: A case report. SPECIAL CARE IN DENTISTRY 2018; 38:259-265. [DOI: 10.1111/scd.12302] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/16/2018] [Accepted: 05/25/2018] [Indexed: 12/15/2022]
Affiliation(s)
- A. P. Cazzolla
- Department of Odontostomatology and Surgery; University of Bari; Bari Italy
| | - K. Zhurakivska
- Department of Clinical and Experimental Medicine; University of Foggia; Foggia Italy
| | - D. Ciavarella
- Department of Odontostomatology and Surgery; University of Bari; Bari Italy
| | - M. G. Lacaita
- Department of Odontostomatology and Surgery; University of Bari; Bari Italy
| | - G. Favia
- Department of Odontostomatology and Surgery; University of Bari; Bari Italy
| | - N. F. Testa
- Department of Clinical and Experimental Medicine; University of Foggia; Foggia Italy
| | - G. Marzo
- Department of Life; Health and Environmental Sciences; Dental Clinic; University of L'Aquila; L'Aquila Italy
| | - V. La Carbonara
- Department of Odontostomatology and Surgery; University of Bari; Bari Italy
| | - G. Troiano
- Department of Clinical and Experimental Medicine; University of Foggia; Foggia Italy
| | - L. Lo Muzio
- Department of Clinical and Experimental Medicine; University of Foggia; Foggia Italy
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Hyperoxalurie primaire de type 1 : de l’enfance à l’âge adulte, comment gérer adéquatement l’adhésion au traitement médical ? Nephrol Ther 2018; 14:148-152. [DOI: 10.1016/j.nephro.2017.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 06/21/2017] [Accepted: 06/25/2017] [Indexed: 11/22/2022]
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Liu S, Gao B, Wang G, Wang W, Lian X, Wu S, Yu J, Fu Y, Zhou H. Recurrent primary hyperoxaluria type 2 leads to early post-transplant renal function loss: A case report. Exp Ther Med 2018; 15:3169-3172. [PMID: 29545831 PMCID: PMC5840950 DOI: 10.3892/etm.2018.5841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 03/10/2017] [Indexed: 01/29/2023] Open
Abstract
Primary hyperoxaluria type 2 is a rare autosomal recessive disorder caused by glyoxylate reductase/hydroxypyruvate reductase deficiency and characterized by recurrent episodes of nephrolithiasis and nephrocalcinosis. Herein, we describe a case of primary hyperoxaluria type 2 in a 33-year-old man who failed to respond to conventional therapies; thus renal transplantation was performed. This case demonstrated that, although primary hyperoxaluria type 2 is rare, hyperoxaluria should be suspected and blood oxalate and stone component be examined in patients with recurrent episodes of nephrolithiasis, particularly in those who are unresponsive to conventional therapies. Combined liver-kidney transplant may be required as kidney transplant alone is not likely to be successful.
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Affiliation(s)
- Si Liu
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Baoshan Gao
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Gang Wang
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Weigang Wang
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xin Lian
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shan Wu
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jinyu Yu
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yaowen Fu
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Honglan Zhou
- Department of Urology, Transplant Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Kanoun H, Jarraya F, Maalej B, Lahiani A, Mahfoudh H, Makni F, Hachicha J, Fakhfakh F. Identification of compound heterozygous patients with primary hyperoxaluria type 1: clinical evaluations and in silico investigations. BMC Nephrol 2017; 18:303. [PMID: 28969594 PMCID: PMC5625645 DOI: 10.1186/s12882-017-0719-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 09/20/2017] [Indexed: 01/04/2023] Open
Abstract
Background Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder of glyoxylate metabolism in which excessive oxalates are formed by the liver and excreted by the kidneys. Calcium oxalate crystallizes in the urine, leading to urolithiasis, nephrocalcinosis, and consequent renal failure if treatment is not initiated promptly. Mutations in the AGXT gene which encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase are responsible of PH1. In the present work, we aimed to analyze AGXT gene and in silico investigations performed in four patients with PH1 among two non consanguineous families. Methods Exhaustive gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools were used to predict the impact of AGXT variants on gene expression as well as on the protein structure and function. Results Direct sequencing of all exons of AGXT gene revealed the emergence of multiple mutations in compound heterozygous state in the two studied families. Two patients were compound heterozygous for the c.731 T > C, c.32C > T, c.1020A > G and c.33_34insC and presented clinically with recurrent urinary tract infection, multiple urolithiasis and nephrocalcinosis under the age of 1 year and a persistent hyperoxaluria at the age of diagnosis. The two other patients presenting a less severe phenotypes were heterozygous for c.731 T > C and homozygous for the c.32C > T and c.1020A > G or compound heterozygous for c.26C > A and c.65A > G variants. Conclusion In Summary, we provided relevance regarding the compound heterozygous mutations in non consanguineous PH1 families with variable severity.
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Affiliation(s)
- Houda Kanoun
- Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Sfax, Tunisie. .,Unité de Recherche Pathologie rénale UR12ES14 et Service de Néphrologie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia.
| | - Faiçal Jarraya
- Unité de Recherche Pathologie rénale UR12ES14 et Service de Néphrologie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia
| | - Bayen Maalej
- Unité de Recherche Pathologie rénale UR12ES14 et Service de Néphrologie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia.,Service de Pédiatrie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia
| | - Amina Lahiani
- Laboratoire de Biochimie, Hôpital Habib Bourguiba Sfax, Sfax, Tunisia
| | - Hichem Mahfoudh
- Unité de Recherche Pathologie rénale UR12ES14 et Service de Néphrologie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia
| | - Fatma Makni
- Laboratoire de Biochimie, Hôpital Habib Bourguiba Sfax, Sfax, Tunisia
| | - Jamil Hachicha
- Unité de Recherche Pathologie rénale UR12ES14 et Service de Néphrologie, Hôpital Hédi Chaker Sfax, Sfax, Tunisia
| | - Faiza Fakhfakh
- Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Sfax, Tunisie. .,Département des Sciences de la vie, Faculté des Sciences de Sfax, Université des Sfax, Sfax, Tunisia.
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Martin-Higueras C, Torres A, Salido E. Molecular therapy of primary hyperoxaluria. J Inherit Metab Dis 2017; 40:481-489. [PMID: 28425073 DOI: 10.1007/s10545-017-0045-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/20/2017] [Accepted: 04/03/2017] [Indexed: 12/19/2022]
Abstract
During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches. The availability of PH mouse models has facilitated preclinical studies testing innovative treatments. PHs are autosomal recessive diseases where the enzymatic deficit plays a central pathogenic role. Thus, molecular therapies aimed at restoring such deficit or limiting the consequences of the metabolic derangement could be envisioned, keeping in mind the specific challenges posed by the cell-autonomous nature of the deficiency. Various molecular approaches like enzyme replacement, substrate reduction, pharmacologic chaperones, and gene and cell therapies have been explored in cells and mouse models of disease. Some of these proof-of-concept studies have paved the way to current clinical trials on PH type 1, raising hopes that much needed treatments will become available for this severe inborn error of metabolism.
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Affiliation(s)
- Cristina Martin-Higueras
- Department of Pathology & Nephrology, Centre for Biomedical Research on Rare Diseases (CIBERER) Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain
| | - Armando Torres
- Department of Pathology & Nephrology, Centre for Biomedical Research on Rare Diseases (CIBERER) Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain
| | - Eduardo Salido
- Department of Pathology & Nephrology, Centre for Biomedical Research on Rare Diseases (CIBERER) Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain.
- Department of Pathology, ULL School Medicine, 38320, Tenerife, Spain.
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Abstract
Numerous metabolic anomalies, which often have no direct pathological relevance when considered individually, are found in all people. In most patients with urinary tract stones, it can be assumed that a specific combination or interaction of these anomalies occurs, thus, resulting in stone formation, but only after individual exogenous risk factors are triggered. Lithogenesis is the result of a cascade of different "events" that are temporally close to one another, but sometimes these events interact strong enough that significant stone growth occurs. Chronic metabolic disorders usually lead to permanently altered urine compositions. The occurrence of physiological urine constituents in nonnormal concentration ratios and/or the nonphysiological excretion of metabolic products can significantly increase the lithogenicity of urine, so that urolithiasis can manifest itself as a clinical symptom. In cases of urolithiasis of unknown origin, a potentially hidden rare metabolic anomaly should always be considered. In addition, if a patient has a known metabolic disease, then this should always be taken into account as a risk factor for stone formation and attempts should be taken to clarify its influence on urine composition. This also applies to the efficacy of a therapy. A distinct link between a metabolic disease and stone formation is generally rare and will likely remain so despite significant advances regarding differential diagnosis and etiopathology. This article focuses on very rare metabolic causes and/or genetic syndromes which may be associated with urolithiasis. Patients receiving symptomatic stone treatment should receive life-long follow-up care from a urologist because reducing the recurrence rate helps to improve the quality of life of the patients.
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Affiliation(s)
- C Fisang
- Harnsteinzentrum Rhein-Ahr, Marienhausklinikum im Kreis Ahrweiler, Dahlienweg 3, 53474, Bad Neuenahr-Ahrweiler, Deutschland.
| | - N Laube
- Harnsteinzentrum Rhein-Ahr, Marienhausklinikum im Kreis Ahrweiler, Dahlienweg 3, 53474, Bad Neuenahr-Ahrweiler, Deutschland
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Villani V, Gupta N, Elias N, Vagefi PA, Markmann JF, Paul E, Traum AZ, Yeh H. Bilateral native nephrectomy reduces systemic oxalate level after combined liver-kidney transplant: A case report. Pediatr Transplant 2017; 21. [PMID: 28261895 DOI: 10.1111/petr.12901] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2017] [Indexed: 12/11/2022]
Abstract
Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of plasma oxalate. Accumulation of oxalate in the kidney and subsequent renal failure are fatal to PH1 patients often in pediatric age. Combined liver and kidney transplantation is the therapy of choice for end-stage renal disease due to PH1. Levels of plasma oxalate remain elevated for several months after liver transplantation, as the residual body oxalate is slowly excreted. Patients with persistent hyperoxaluria after transplant often require hemodialysis, and accumulation of residual oxalate in the kidney can induce graft dysfunction. As the native kidneys are the main target of calcium oxalate accumulation, we postulated that removal of native kidneys could drastically decrease total body oxalate levels after transplantation. Here, we report a case of bilateral nephrectomy at the time of combined liver-kidney transplantation in a pediatric PH1 patient. Bilateral nephrectomy induced a rapid decrease in plasma oxalate to normal levels in less than 20 days, compared to the several months reported in the literature. Our results suggest that removal of native kidneys could be an effective strategy to decrease the need for hemodialysis and the risk of renal dysfunction after combined liver-kidney transplantation in patients with PH1.
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Affiliation(s)
- Vincenzo Villani
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Neena Gupta
- Division of Nephrology, Department of Pediatrics, University of Massachusetts Medical School, Worchester, MA, USA
| | - Nahel Elias
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Parsia A Vagefi
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - James F Markmann
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Elahna Paul
- Division of Pediatric Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Avram Z Traum
- Division of Pediatric Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Heidi Yeh
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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45
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Affiliation(s)
- Barbara Cellini
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Verona (VR), Italy
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46
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Leal R, Costa J, Santos T, Galvão A, Santos L, Romãzinho C, Macário F, Alves R, Campos M, Furtado E, Mota A. Combined liver and kidney transplantation in two women with primary hyperoxaluria: Different roads led to different outcomes. Nefrologia 2017; 37:433-434. [PMID: 28209444 DOI: 10.1016/j.nefro.2016.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 07/25/2016] [Accepted: 10/16/2016] [Indexed: 12/25/2022] Open
Affiliation(s)
- Rita Leal
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - Joana Costa
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Telma Santos
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Ana Galvão
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Lidia Santos
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Catarina Romãzinho
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Fernando Macário
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Rui Alves
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Mario Campos
- Serviço de Nefrologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Emanuel Furtado
- Unidade de Transplantação Hepática, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Alfredo Mota
- Serviço de Urologia e Transplantação Renal, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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Roncador A, Oppici E, Talelli M, Pariente AN, Donini M, Dusi S, Voltattorni CB, Vicent MJ, Cellini B. Use of polymer conjugates for the intraperoxisomal delivery of engineered human alanine:glyoxylate aminotransferase as a protein therapy for primary hyperoxaluria type I. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 13:897-907. [PMID: 27993722 DOI: 10.1016/j.nano.2016.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/25/2016] [Accepted: 12/07/2016] [Indexed: 01/22/2023]
Abstract
Alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme whose deficit causes the rare disorder Primary Hyperoxaluria Type I (PH1). We now describe the conjugation of poly(ethylene glycol)-co-poly(L-glutamic acid) (PEG-PGA) block-co-polymer to AGT via the formation of disulfide bonds between the polymer and solvent-exposed cysteine residues of the enzyme. PEG-PGA conjugation did not affect AGT structural/functional properties and allowed the enzyme to be internalized in a cellular model of PH1 and to restore glyoxylate-detoxification. The insertion of the C387S/K390S amino acid substitutions, known to favor interaction with the peroxisomal import machinery, reduced conjugation efficiency, but endowed conjugates with the ability to reach the peroxisomal compartment. These results, along with the finding that conjugates are hemocompatible, stable in plasma, and non-immunogenic, hold promise for the development of polypeptide-based AGT conjugates as a therapeutic option for PH1 patients and represent the base for applications to other diseases related to deficits in peroxisomal proteins.
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Affiliation(s)
- Alessandro Roncador
- Neuroscience, Biomedicine and Movement Sciences Department, Section of Biological Chemistry, University of Verona, Verona (VR), Italy
| | - Elisa Oppici
- Neuroscience, Biomedicine and Movement Sciences Department, Section of Biological Chemistry, University of Verona, Verona (VR), Italy
| | - Marina Talelli
- Polymer Therapeutics Lab, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Amaya Niño Pariente
- Polymer Therapeutics Lab, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Marta Donini
- Department of Medicine, Section of General Pathology, University of Verona, Verona (VR), Italy
| | - Stefano Dusi
- Department of Medicine, Section of General Pathology, University of Verona, Verona (VR), Italy
| | - Carla Borri Voltattorni
- Neuroscience, Biomedicine and Movement Sciences Department, Section of Biological Chemistry, University of Verona, Verona (VR), Italy
| | - María J Vicent
- Polymer Therapeutics Lab, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
| | - Barbara Cellini
- Neuroscience, Biomedicine and Movement Sciences Department, Section of Biological Chemistry, University of Verona, Verona (VR), Italy.
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M'dimegh S, Omezzine A, M'barek I, Moussa A, Mabrouk S, Kaarout H, Souche G, Chemli J, Aloui S, Aquaviva-Bourdain C, Achour A, Abroug S, Bouslama A. Mutational Analysis of Agxt in Tunisian Population with Primary Hyperoxaluria Type 1. Ann Hum Genet 2016; 81:1-10. [PMID: 27935012 DOI: 10.1111/ahg.12178] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 11/10/2016] [Indexed: 01/25/2023]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine:glyoxylate aminotransferase (AGT). PH1 is a clinically and genetically heterogeneous disorder. The aim of our study was to analyze and characterize the mutational spectrum of PH1 in Tunisian patients. MATERIALS AND METHODS Molecular studies of 146 Tunisian patients suspected with PH were performed by PCR/Restriction fragment length polymorphism (RFLP) to detect seven mutations described as the most common. Direct sequencing for the 11 exons was performed in patients in whom any mutation was not identified. RESULTS The genetic diagnosis of PH1 was confirmed in 62.3% of patients. The first molecular approach based on PCR/restriction enzyme test was positive in 37.6% of patients, whereas the second molecular approach based on whole gene sequencing was successful in 24% of cases. Twelve pathogenic mutations were detected in our cohort. Two mutations were novel, and five were detected for the first time in Tunisians. The three most frequent mutations were p.Ile244Thr, p.Gly190Arg, and c.33dupC, with a frequency of 43.4%, 21.4%, and 13.1%, respectively. CONCLUSION The two novel mutations detected in our study extend the spectrum of known AGXT gene mutations. The screen for the mutations identified in this study can provide a useful, cost-effective, and first-line investigation in Tunisian PH1 patients.
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Affiliation(s)
- Saoussen M'dimegh
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Asma Omezzine
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Ibtihel M'barek
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Amira Moussa
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Sameh Mabrouk
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Hayet Kaarout
- Internal Medicine A Department, Charles Nicolle University Hospital, Tunis, Tunisia
| | - Geneviéve Souche
- Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, France
| | - Jalel Chemli
- Pediatric Department, Sahloul University Hospital, Sousse, Tunisia
| | - Sabra Aloui
- Nephrology Department, Fatouma Bourguiba University Hospital, Monastir, Tunisia
| | - Cécile Aquaviva-Bourdain
- Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, France
| | | | - Saoussen Abroug
- Pediatric Department, Sahloul University Hospital, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
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Shedding light on the morphology of calcium oxalate monohydrate crystallites present in kidney biopsies in the case of hyperoxaluria. CR CHIM 2016. [DOI: 10.1016/j.crci.2016.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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50
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M'dimegh S, Aquaviva-Bourdain C, Omezzine A, Souche G, M'barek I, Abidi K, Gargah T, Abroug S, Bouslama A. HOGA1 Gene Mutations of Primary Hyperoxaluria Type 3 in Tunisian Patients. J Clin Lab Anal 2016; 31. [PMID: 27561601 DOI: 10.1002/jcla.22053] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 07/13/2016] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Primary hyperoxaluria type 3 (PH3) is due to mutations in the recently identified 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 might be the least severe form with a milder phenotype with good preservation of kidney function in most patients. The aim of this study was to report three PH3 cases carrying mutations in HOGA1. MATERIALS AND METHODS Genetic analysis of HOGA1 was performed in patients with a high clinical suspicion of PH after sequencing of AGXT and GRHPR genes, which was negative. Also, a complete AGXT/GRHPR MLPA was performed in these patients in order to detect large deletions/insertions. RESULTS AND DISCUSSION Two different HOGA1 gene mutations were identified: the p.Pro190Leu in a homozygous state and the p.Gly287Val in two patients in homozygous and heterozygous carriers. The median age at onset of clinical symptoms was 3.93 years. Most of the patients had a positive family history for recurrent urolithiasis. The p.Pro190Leu mutation was reported with impaired renal function at follow-up; however, the p.Gly287Val was presented with normal renal function. All patients were presented with urolithiasis, but only one had a nephrocalcinosis. CONCLUSION This study expanded the number of PH3 patients from 63 to 66 cases. The p.Pro190Leu and the p.Gly287Val mutations found in this study can provide a first-line investigation in Tunisian PH1 patients.
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Affiliation(s)
- Saoussen M'dimegh
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
| | - Cécile Aquaviva-Bourdain
- Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, Bron Cedex, France
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
| | - Geneviéve Souche
- Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, Bron Cedex, France
| | - Ibtihel M'barek
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
| | - Kamel Abidi
- Pediatric Department, Charles Nicolle University Hospital, Tunis, Tunisia
| | - Tahar Gargah
- Pediatric Department, Charles Nicolle University Hospital, Tunis, Tunisia
| | - Saoussen Abroug
- Pediatric Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
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