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Hashmi JA, Afzal S, Balahmar RM, Latif M, Basit S. Biallelic Variant in the AGXT Gene in a Family Segregating Primary Hyperoxaluria; Accurate Genetic Diagnosis and Carrier Detection. Nephrology (Carlton) 2025; 30:e14423. [PMID: 39746862 DOI: 10.1111/nep.14423] [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: 03/17/2024] [Revised: 04/28/2024] [Accepted: 12/16/2024] [Indexed: 01/04/2025]
Abstract
AIM Autosomal recessive primary hyperoxalurias (PH) are genetic disorders characterised by elevated oxalate production. Mutations in genes involved in glycoxylate metabolism are the underlying cause of PH. Type 1 PH (PH1) results in malfunctioning of alanine-glyoxylate aminotransferase enzymes of liver due to a change in the genetic sequence of alanine-glyoxylate aminotransferase (AGXT) gene. We encountered a large family segregating genetic disease of high oxalate kidney stones. A genetic analysis was carried out with the aim to identify underlying genetic defect. METHODS A large family with multiple affected individuals was recruited for this study. An extensive clinical evaluation, followed by genetic analysis, was carried out. Due to the heterogeneous nature of the disease, two members of the family having disease symptoms were subjected to whole exome sequencing (WES). Variants were annotated, filtered, and prioritised using various bioinformatic tools to detect disease associated genetic defects. RESULTS Unbiased and hypothesis-free WES data analysis was performed. Raw reads (fastq files) were mapped to the reference genome and duplicates were removed. Variants were annotated, filtered, and prioritised. A low-frequency missense variant (c. 1049G>A) in the AGXT gene was considered the candidate variant. This variant replaces the highly conserved glycine amino acid with aspartate (p.Gly350Asp). The variant is destabilising for protein-protein interaction based on predicted change in binding free energy (ΔΔG). All members having disease phenotype were found homozygous to the mutation. Both parents and unaffected individuals in a family are heterozygous for the variant. CONCLUSION Identification of pathogenic variant in the AGXT gene, in this family, provides genotype-phenotype correlation and permits accurate clinical diagnosis as well as carrier detection. Moreover, this variant extends the AGXT mutation spectrum in a different population and highlights the clinical significance and diagnostic relevance of the variant.
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Affiliation(s)
- Jamil A Hashmi
- Center for Genetics and Inherited Diseases, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
- Department of Basic Medical Sciences, College of Medicine, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
| | - Sibtan Afzal
- Department of Immunology, College of Medicine, King Saud University Riyadh, Riyadh, Kingdom of Saudi Arabia
| | - Reham M Balahmar
- Center for Genetics and Inherited Diseases, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
| | - Muhammad Latif
- Center for Genetics and Inherited Diseases, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
- Department of Basic Medical Sciences, College of Medicine, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
| | - Sulman Basit
- Center for Genetics and Inherited Diseases, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
- Department of Basic Medical Sciences, College of Medicine, Taibah University Medina, Madinah, Kingdom of Saudi Arabia
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Khan U, Mubariz M, Rezq H, Mahmoud A, Moiz Nasir M, Ul Ain N, Bazai UK, Khan MZ, Abuelazm M. Efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria: A systematic review and meta-analysis of randomized controlled trials. Indian J Urol 2025; 41:11-19. [PMID: 39886625 PMCID: PMC11778695 DOI: 10.4103/iju.iju_359_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/14/2024] [Accepted: 10/25/2024] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Primary hyperoxaluria (PH), a rare autosomal recessive disorder, results in defective metabolism of oxalate, leading to increased oxalate levels. Oxalobacter formigenes (O. formigenes) is a nonpathological anaerobic bacterium that uses oxalate for its survival and thus decreases the plasma oxalate levels. We aimed to use randomized controlled trials (RCTs) to evaluate the efficacy of O. formigenes in treating PH. METHODS A literature review was conducted for synthesizing the evidence from RCTs on Scopus, Web of Science, Embase, PubMed, and CENTRAL until January 2023. The outcomes were pooled using mean difference (MD) for continuous data and odds ratios (OR) for dichotomous data along with confidence interval (CI). The systematic review is registered with Prospero ID CRD42023404421. RESULTS We included five RCTs with 208 patients. The pooled analysis did not favor O. formigenes over placebo in reducing the plasma oxalate levels (MD: -0.00 mmol/day; 95% CI: [ - 0.01-0.00]; P = 0.06). Similar results were observed for urinary oxalate levels (MD: -0.01 mmol/day; 95% CI: [ - 0.12-0.10]; P = 0.86). There were no significant adverse events (OR: 0.44; 95% CI: [0.14-1.39]; P = 0.16) or serious adverse events (OR: 0.80; 95% CI: [0.29-2.25]; P = 0.67). CONCLUSION O. formigenes was ineffective in reducing the serum and urine oxalate levels in patients with PH but has an acceptable safety profile. As PH is a relatively rare disease and few patients consent for the trials, stringent protocols are required in the future to achieve data accuracy pertinent for making conclusive recommendations on the efficacy of O. formigenes in patients with PH.
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Affiliation(s)
- Ubaid Khan
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Muhammad Mubariz
- Department of Medicine Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - Hazem Rezq
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | | | - Noor Ul Ain
- Department of Medicine King Edward Medical University, Lahore, Pakistan
| | - Umar Khan Bazai
- Department of Medicine King Edward Medical University, Lahore, Pakistan
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Rosenberg N, Manders E, van den Berg S, Deesker LJ, Garrelfs SF, de Visser SJ, Groothoff JW, Hollak CEM. Application of four pricing models for orphan medicines: a case study for lumasiran. Orphanet J Rare Dis 2024; 19:485. [PMID: 39716306 DOI: 10.1186/s13023-024-03446-w] [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: 06/17/2024] [Accepted: 11/11/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND The combination of high prices and uncertain effectiveness is a growing challenge in the field of orphan medicines, hampering health technology assessments. Hence, new methods for establishing price benchmarks might be necessary to support reimbursement negotiations. In this study, we applied several pricing models containing cost-based elements to the case of lumasiran for treating primary hyperoxaluria type 1. METHODS Price ranges were calculated by estimating minimum and maximum scenarios for four pricing models: Novel Cancer Pricing Model (NCP-model), AIM Model for Innovative Medicines (AIM-model), Discounted Cash Flow model (DCF-model), and the Real-Option Rate Of Return model (ROROR-model). Data was gathered from disease registries, scientific literature, Security and Exchange Committee filings, and expert opinion. A sensitivity analysis was performed to assess the parameters with the largest influence. RESULTS Outcomes resulting from the NCP-model ranged between €87,000 and €224,000 per patient per year, between €33,000 and €340,000 for the AIM-model, between €182,000 and €748,000 for the DCF-model, and between €81,000 and €273,000 for the ROROR-model. CONCLUSION Outcomes of the four pricing models show wide and heterogeneous price ranges. The DCF-model might be most compatible with the case of lumasiran, due to inclusion of parameters for prevalence, incidence, prescription restrictions and cost of capital. The minimum DCF price could serve as a starting point for pricing and reimbursement negotiations. Uncertainties can be solved by more transparency on input variables.
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Affiliation(s)
- Noa Rosenberg
- Medicine for Society, Platform at Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Meibergdreef 9, Amsterdam, The Netherlands
| | - Evert Manders
- Medicine for Society, Platform at Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Meibergdreef 9, Amsterdam, The Netherlands
| | - Sibren van den Berg
- Medicine for Society, Platform at Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Meibergdreef 9, Amsterdam, The Netherlands
| | - Lisa J Deesker
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
| | - Sander F Garrelfs
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
| | - Saco J de Visser
- Medicine for Society, Platform at Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
- Centre for Future Affordable and Sustainable Therapy Development (FAST), The Hague, The Netherlands
| | - Jaap W Groothoff
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands
| | - Carla E M Hollak
- Medicine for Society, Platform at Amsterdam University Medical Center - University of Amsterdam, Amsterdam, The Netherlands.
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Meibergdreef 9, Amsterdam, The Netherlands.
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Pearce RJ, Sui W, Yang H, Chi T, Stoller M. The Yield of Genetic Testing in Management of Nephrolithiasis. Urology 2024; 193:27-34. [PMID: 38992507 DOI: 10.1016/j.urology.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/13/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024]
Abstract
OBJECTIVE To describe the yield and indications for performing genetic testing in patients with nephrolithiasis. Genetic testing for nephrolithiasis is becoming more accessible and rapid due to technologic advances. This study aimed to determine the diagnostic yield of genetic testing in a cohort of high-risk stone formers and to identify 24-hour urine characteristics to prompt genetic screening. MATERIALS AND METHODS We retrospectively identified patients who underwent genetic testing for nephrolithiasis from 2020 to 22 at a single institution using a custom PerkinElmer genomics panel for nephrolithiasis. We compared characteristics of patients with and without genetic abnormalities. We used receiver operator characteristic (ROC) analysis to identify candidate thresholds for genetic testing. RESULTS Fourteen of 36 patients (39%) who underwent genetic testing had identifiable mutations. Five patients (14%) had known pathogenic mutations, including genes for primary hyperoxaluria (PH2 and PH3), cystinuria, and enamel-renal syndrome. The remaining mutations were variants of uncertain significance. Of the 14 patients with identified mutations, only 6 had concordant 24-hour urine abnormalities, including 3/5 with known pathogenic mutations. In patients with urine oxalate ≥ 40 mg/day, 3/29 (10.3%) had PH2 or PH3. ROC analysis showed that an oxalate threshold of ≥ 80 mg/day may have promising screening characteristics. CONCLUSION Genetic testing for nephrolithiasis remains controversial due to unknown yield and the time and energy required to discuss results with patients. This preliminary report describes the yield and identifies clinical factors and a potential cut-off that may assist clinicians in deciding when genetic profiling should be pursued.
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Affiliation(s)
- Robert J Pearce
- Department of Urology, University of California San Francisco, San Francisco, CA
| | - Wilson Sui
- Department of Urology, University of California San Francisco, San Francisco, CA
| | - Heiko Yang
- Department of Urology, University of California San Francisco, San Francisco, CA
| | - Thomas Chi
- Department of Urology, University of California San Francisco, San Francisco, CA
| | - Marshall Stoller
- Department of Urology, University of California San Francisco, San Francisco, CA.
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Habash NW, Jaoudeh RARA, Hentz RC, Sas DJ, Ibrahim SH, Hassan S. Primary hyperoxaluria: Long-term outcomes of isolated kidney versus simultaneous liver/kidney transplant. J Pediatr Gastroenterol Nutr 2024; 79:826-834. [PMID: 39005225 DOI: 10.1002/jpn3.12315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 04/03/2024] [Accepted: 06/05/2024] [Indexed: 07/16/2024]
Abstract
OBJECTIVES To compare long-term transplant outcomes (organ rejection and retransplant) of simultaneous liver/kidney transplant (SLK) versus isolated kidney transplant (IK) for patients with primary hyperoxaluria (PH). METHODS The Rare Kidney Stone Consortium PH registry was queried to identify patients with PH who underwent SLK or IK from 1999 to 2021. Patient characteristics and long-term transplant outcomes were abstracted and analyzed. Statistical comparisons were performed with Kaplan-Meier plots and Cox proportional hazards models. RESULTS We identified 250 patients with PH, of whom 35 received care at Mayo Clinic and underwent SLK or IK. Patients who underwent SLK as their index transplant had lower odds of kidney rejection than did those who underwent IK (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.08-0.99; p = .048). The immunoprotective effect of concomitant liver and kidney transplant appeared to enhance outcomes for patients with PH. Additionally, the odds of retransplant were significantly lower for patients who underwent SLK as their index transplant than for those who underwent IK (HR, 0.08; 95% CI, 0.02-0.42; p = .003). Of five patients who underwent IK and had maintained graft function for at least 5 years after transplant, three (60%) had documented vitamin B6 responsiveness. CONCLUSIONS Patients with PH who underwent SLK had a lower risk of kidney rejection and retransplant than those who underwent IK. Accurate genetic assessment for vitamin B6 responsiveness may optimize IK allocation. Novel therapeutics, such as lumasiran, have been introduced as promising agents for the management of PH.
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Affiliation(s)
- Nawras W Habash
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rasha A R A Jaoudeh
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Roland C Hentz
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
| | - David J Sas
- Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H Ibrahim
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara Hassan
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Aaboudech TY, Znati K, Jahid A, Sassi S, Driouich S, Zouaidia F, Bernoussi Z. Unveiling primary Hyperoxaluria type 1: a fortuitous discovery through bone marrow biopsy. Oxf Med Case Reports 2024; 2024:omae128. [PMID: 39464227 PMCID: PMC11512696 DOI: 10.1093/omcr/omae128] [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: 06/05/2024] [Revised: 07/16/2024] [Accepted: 08/19/2024] [Indexed: 10/29/2024] Open
Abstract
This paper details a rare case of primary hyperoxaluria type 1 (PH1) identified through a bone marrow biopsy in a 46-year-old female patient with a history of nephrolithiasis and chronic renal failure. Genetic analysis identified the p.Ile244Thr mutation in the AGXT gene, confirming the diagnosis of PH1. The paper aims to highlight this case, focusing on the genetic basis of the disorder, including the identified mutation. It underscores the importance of early diagnosis of infantile and childhood nephrolithiasis, particularly in cases with familial history, to prevent renal loss and systemic oxalosis.
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Affiliation(s)
- Taha Yassine Aaboudech
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
| | - Kaoutar Znati
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
| | - Ahmed Jahid
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
| | - Samia Sassi
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
| | - Salima Driouich
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Department of Internal Medicine Hematology and Geriatrics, Ibn Sina Hospital, Rabat, Morocco
| | - Fouad Zouaidia
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
| | - Zakia Bernoussi
- Pathology Department, Ibn Sina Hospital, Rabat, Morocco
- Mohammed V University in Rabat, Rabat, Morocco
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Polinyk A, Suffo S, Aljundi W, Seitz B, Abdin AD. Unilateral Crystalline Ischemic Retinopathy Secondary to Primary Hyperoxaluria with Renal Failure and Oxalosis. Klin Monbl Augenheilkd 2024. [PMID: 39047761 DOI: 10.1055/a-2327-8530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Affiliation(s)
- Anna Polinyk
- Department of Ophthalmology, Saarland University Medical Center UKS, Homburg/Saar, Germany
| | - Shady Suffo
- Department of Ophthalmology, Saarland University Medical Center UKS, Homburg/Saar, Germany
| | - Wissam Aljundi
- Department of Ophthalmology, Saarland University Medical Center UKS, Homburg/Saar, Germany
| | - Berthold Seitz
- Department of Ophthalmology, Saarland University Medical Center UKS, Homburg/Saar, Germany
| | - Alaa Din Abdin
- Department of Ophthalmology, Saarland University Medical Center UKS, Homburg/Saar, Germany
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Papatsoris A, Alba AB, Galán Llopis JA, Musafer MA, Alameedee M, Ather H, Caballero-Romeu JP, Costa-Bauzá A, Dellis A, El Howairis M, Gambaro G, Geavlete B, Halinski A, Hess B, Jaffry S, Kok D, Kouicem H, Llanes L, Lopez Martinez JM, Popov E, Rodgers A, Soria F, Stamatelou K, Trinchieri A, Tuerk C. Management of urinary stones: state of the art and future perspectives by experts in stone disease. Arch Ital Urol Androl 2024; 96:12703. [PMID: 38934520 DOI: 10.4081/aiua.2024.12703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
AIM To present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the Experts in Stone Disease Congress in Valencia in January 2024. Options of treatment: The surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. For 1.5 cm renal stones, both m-PCNL and RIRS have proven to be valid treatment alternatives with comparable stone-free rates. The m-PCNL has proven to be more cost effective and requires a shorter operative time, while the RIRS has demonstrated lower morbidity in terms of blood loss and shorter recovery times. SWL has proven to be less effective at least for lower calyceal stones but has the highest safety profile. For a 6mm obstructing stone of the pelviureteric junction (PUJ) stone, SWL should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. RIRS has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. Technical issues of the surgical procedures for stone removal: In patients receiving antithrombotic therapy, SWL, PCN and open surgery are at elevated risk of hemorrhage or perinephric hematoma. URS, is associated with less morbidity in these cases. An individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. Pre-interventional urine culture and antibiotic therapy are mandatory although UTI treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. The use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. Measurements of temperature and pressure during RIRS are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. Ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. Topics of current research are the development of drug eluting and bioresorbable stents. Complications of endoscopic treatment: PCNL is considered the most invasive surgical option. Fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. Major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. Ureteroscopy causes less complications, although some of them can be severe. They depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). Diagnostic work up: Genetic testing consents the diagnosis of monogenetic conditions causing stones. It should be carried out in children and in selected adults. In adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, APRT deficiency, and xanthinuria are excluded. A reliable stone analysis by infrared spectroscopy or X-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. The analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. Scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) is another fundamental research tool for the study of kidney stones. The combination of metagenomic analysis using Next Generation Sequencing (NGS) techniques and the enhanced quantitative urine culture (EQUC) protocol can be used to evaluate the urobiome of renal stone formers. Twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary pH with a digital pH meter. Urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. Urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. At the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. Patients should be evaluated for the association with systemic pathologies. PROPHYLAXIS Personalized medicine and public health interventions are complementary to prevent stone recurrence. Personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. The more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. Primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. Renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. Stone analysis allows the identification of most "high-risk" patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). Patients at "high-risk" forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. Particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. FUTURE RESEARCH Application of Artificial Intelligence are promising for automated identification of ureteral stones on CT imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. The synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation.
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Affiliation(s)
- Athanasios Papatsoris
- 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens; U-merge Scientific Office.
| | - Alberto Budia Alba
- Urology Department, La Fe University and Polytechnic Hospital, Valencia.
| | | | | | | | | | | | - Antònia Costa-Bauzá
- Laboratory of Renal Lithiasis Research, University Institute of Health Sciences Research (IUNICS-IdISBa), University of Illes Balears, Palma de Mallorca.
| | - Athanasios Dellis
- 2nd Department of Surgery, Aretaieion Academic Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens.
| | | | - Giovanni Gambaro
- Division of Nephrology, Department of Medicine, University Hospital of Verona.
| | - Bogdan Geavlete
- "Carol Davila" University of Medicine and Pharmacy & "Saint John" Emergency Clinical Hospital, Bucharest.
| | - Adam Halinski
- Private Medical Center "Klinika Wisniowa" Zielona Gora.
| | - Bernhard Hess
- Internal Medicine & Nephrology, KidneyStoneCenter Zurich, Klinik Im Park, Zurich.
| | | | - Dirk Kok
- Saelo Scientific Support, Oegstgeest.
| | | | - Luis Llanes
- Urology Department, University Hospital of Getafe, Getafe, Madrid.
| | | | - Elenko Popov
- Department of Urology, UMHAT "Tzaritza Yoanna-ISUL", Medical University, Sofia.
| | | | - Federico Soria
- Experimental Surgery Department, Ramón y Cajal University Hospital, Madrid.
| | - Kyriaki Stamatelou
- MESOGEIOS Nephrology Center, Haidari Attica and NEPHROS.EU Private Clinic, Athens.
| | | | - Christian Tuerk
- Urologic Department, Sisters of Charity Hospital and Urologic Praxis, Wien.
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10
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Pszczolinski R, Acquaviva C, Berrahal I, Biebuyck N, Burtey S, Clabault K, Dossier C, Guillet M, Hemery F, Letavernier E, Rousset-Rouvière C, Bacchetta J, Moulin B. Primary hyperoxaluria in adults and children: a nationwide cohort highlights a persistent diagnostic delay. Clin Kidney J 2024; 17:sfae099. [PMID: 38737343 PMCID: PMC11087826 DOI: 10.1093/ckj/sfae099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Indexed: 05/14/2024] Open
Abstract
Background Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The primary objective of this study is to assess the current diagnostic delay for PH. Methods This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis. Results A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults [median (interquartile range)]: 1.2 (0.1-3.0) versus 30 (17-36) years, respectively (P < .0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases. Conclusion This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis.
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Affiliation(s)
- Romain Pszczolinski
- Service de néphrologie-dialyse-transplantation, Hôpitaux universitaires de Strasbourg, Strasbourg, France
| | - Cécile Acquaviva
- Service de biochimie et biologie moléculaire, CHU de Lyon HCL – GH Est, Lyon, France
| | | | - Nathalie Biebuyck
- Service de néphrologie pédiatrique, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Stéphane Burtey
- Service de néphrologie et de transplantation rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France
- C2VN, Aix-Marseille Université/INSERM/INRAE, Marseille, France
| | - Karine Clabault
- Service de néphrologie, Hôpital Privé de l'Estuaire, Le Havre, France
| | - Claire Dossier
- Service de néphrologie pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Matthieu Guillet
- Service de néphrologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Floriane Hemery
- Service de pédiatrie, CHU de Montpellier, Montpellier, France
| | - Emmanuel Letavernier
- Service d'Explorations fonctionnelles multidisciplinaires, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Caroline Rousset-Rouvière
- Service de pédiatrie multidisciplinaire, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France
| | - Justine Bacchetta
- Service de néphrologie-rhumatologie-dermatologie pédiatriques, CHU de Lyon HCL – GH Est-Hôpital Femme Mère Enfant, Lyon, France
| | - Bruno Moulin
- Service de néphrologie-dialyse-transplantation, Hôpitaux universitaires de Strasbourg, Strasbourg, France
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11
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Huang Y, Zhu W, Zhou J, Huang Q, Zeng G. Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs. Biomolecules 2024; 14:511. [PMID: 38785918 PMCID: PMC11117870 DOI: 10.3390/biom14050511] [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: 03/20/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 05/25/2024] Open
Abstract
Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently excreted in the urine. Calcium oxalate deposition in the renal tubules and interstitium triggers renal injury, precipitating systemic oxalate build-up and subsequent secondary organ impairment. Recent explorations of novel therapeutic strategies have challenged and necessitated the reassessment of established management frameworks. The execution of diverse clinical trials across various medication classes has provided new insights and knowledge. With the evolution of PH treatments reaching a new milestone, prompt and accurate diagnosis is increasingly critical. Developing early, effective management and treatment plans is essential to improve the long-term quality of life for PH patients.
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Affiliation(s)
- Yueqi Huang
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.H.); (J.Z.)
| | - Wei Zhu
- Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China;
| | - Jia Zhou
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.H.); (J.Z.)
| | - Qiulin Huang
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.H.); (J.Z.)
| | - Guohua Zeng
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.H.); (J.Z.)
- Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China;
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12
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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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13
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Mrabet S, BenHmida M. Late Presentation of Primary Oxalosis, Microcrystalline Arthropathy, and Tumoral Calcinosis: A Case Report and a Literature Review. Curr Rheumatol Rev 2024; 20:455-458. [PMID: 38243963 DOI: 10.2174/0115733971271874231118154332] [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: 07/29/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Primary hyperoxaluria consists of a group of inherited disorders with enzymatic defects in the glyoxylate pathway, leading to decreased oxalate metabolism. The resulting oxalic deposition is specifically responsible for kidney disease and joint disease. Neonatal oxalosis is the most severe form of primary hyperoxia type 1, with the onset of end-stage renal disease in childhood. CASE PRESENTATION A 55-year-old hemodialysis man was referred to Nephrology because of inflammatory polyarthralgia and periarticular swelling evolving for six months. He had been on hemodialysis for six years for end-stage chronic renal failure, diagnosed at the same time as primary hyperoxaluria. Radiological investigation showed a rugby jersey appearance on the lumbar spine, budding calcium tone opacities next to large joints and clavicles, vascular calcifications and tumoral calcinosis. The synovial fluid contained a few cells with polymorphic intracellular crystals. We ruled out hyperparathyroidism, hypoparathyroidism, and related phosphocalcic disorders, and we retained arthropathy and tumoral calcinosis secondary to primary hyperoxaliuria. The patient also had congestive heart failure. Despite intensification of hemodialysis, he did not improve and died at the age of 56 in the context of cachexia. CONCLUSION This rare case documents the possible occurrence of late clinical presentation and long survival in primary oxalosis with extra renal complications.
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Affiliation(s)
- Sanda Mrabet
- Department of Nephrology, Dialysis, and Transplantation, Sahloul University Hospital, Sousse, Tunisia
| | - Mohamed BenHmida
- Department of Nephrology, Dialysis, and Transplantation, Hedi Chaker University Hospital, Sfax, Tunisia
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14
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Gogate A, Belcourt J, Shah M, Wang AZ, Frankel A, Kolmel H, Chalon M, Stephen P, Kolli A, Tawfik SM, Jin J, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin. Pharmacol Rev 2023; 76:49-89. [PMID: 37696583 PMCID: PMC10753797 DOI: 10.1124/pharmrev.123.000815] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 08/25/2023] [Accepted: 09/06/2023] [Indexed: 09/13/2023] Open
Abstract
Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, α-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising, fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. SIGNIFICANCE STATEMENT: Systemic diseases of liver origin (SDLO) contain rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO. This article aims to provide the most updated information on targeting the liver with antisense oligonucleotides and small interfering RNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of SDLO, which currently have no or limited options for treatment.
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Affiliation(s)
- Anagha Gogate
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Jordyn Belcourt
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Milan Shah
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Alicia Zongxun Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Alexis Frankel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Holly Kolmel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Matthew Chalon
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Prajith Stephen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Aarush Kolli
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Sherouk M Tawfik
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Jing Jin
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Raman Bahal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Theodore P Rasmussen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - José E Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
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15
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Wu J, Song J, He Y, Zhong C, Yang Q, Li Q, Wang M. Case series and literature review of primary hyperoxaluria type 1 in Chinese patients. Urolithiasis 2023; 51:123. [PMID: 37874369 PMCID: PMC10598140 DOI: 10.1007/s00240-023-01494-8] [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: 07/15/2023] [Accepted: 09/20/2023] [Indexed: 10/25/2023]
Abstract
Based on the single-center case reports and all reported patients with primary hyperoxaluria type 1 (PH1) in China, this study discussed the clinical and genetic characteristics of this disease retrospectively. We reported and validated a novel genetic variation c.302 T > G: the clinical phenotypes of the two siblings were similar, in which both had onset in infancy, mainly manifested as renal insufficiency, and died within 6 months out of end-stage renal disease. The literature review is the first to summarize the Chinese patients with PH1 up to now. Forty-eight Chinese patients were included, containing 7 adults and 41 children. The median onset age was 51 months, and the ratio of male to female was 2.69:1. It showed a poor prognosis: 51.1% of Chinese primary hyperoxaluria type 1 patients suffered from end-stage renal disease, and 38.9% of patients died. Urolithiasis was the most common clinical manifestation both in adults and children, while infant-onset patients generally presented with renal insufficiency and had a higher mortality of 75.0%. One hundred and forty-nine AGXT mutant alleles are currently known in the Chinese population, c.33dupC and c.815_816insGA were the most common AGXT genes, accounting for 12.0% and 10.1% of allele frequencies, respectively. The exons 1, 2, 6, and 8 were the most common locations of gene variants, accounting for 78% of all variants, which will be promising targets of DNA sequencing for primary hyperoxaluria type 1.
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Affiliation(s)
- Jiayu Wu
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Jing Song
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Yanzhao He
- University of Leeds, Woodhouse, Leeds, LS2 9JT, UK
| | - Cheng Zhong
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Qin Yang
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Qiu Li
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Mo Wang
- Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
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16
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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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17
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Metry EL, Garrelfs SF, Deesker LJ, Acquaviva C, D’Ambrosio V, Bacchetta J, Beck BB, Cochat P, Collard L, Hogan J, Ferraro PM, Franssen CF, Harambat J, Hulton SA, Lipkin GW, Mandrile G, Martin-Higueras C, Mohebbi N, Moochhala SH, Neuhaus TJ, Prikhodina L, Salido E, Topaloglu R, Oosterveld MJ, Groothoff JW, Peters-Sengers H. Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium. Kidney Int Rep 2023; 8:2029-2042. [PMID: 37849991 PMCID: PMC10577369 DOI: 10.1016/j.ekir.2023.07.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/10/2023] [Accepted: 07/24/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. Methods In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. Results The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P < 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. Conclusion In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.
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Affiliation(s)
- Elisabeth L. Metry
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Sander F. Garrelfs
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Lisa J. Deesker
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Cecile Acquaviva
- Service de Biochimie et Biologie Moléculaire, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, Hospices Civils de Lyon, France
| | - Viola D’Ambrosio
- Department of Nephrology, Catholic University of the Sacred Heart, Rome, Italy
| | - Justine Bacchetta
- Centre de Référence des Maladies Rares Néphrogones, Hospices Civils de Lyon et Université Claude-Bernard Lyon 1, Lyon, France
| | - Bodo B. Beck
- Institute of Human Genetics, Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany
- Center for Rare and Hereditary Kidney Disease Cologne, University Hospital of Cologne, Cologne, Germany
| | - Pierre Cochat
- Centre de Référence des Maladies Rares Néphrogones, Hospices Civils de Lyon et Université Claude-Bernard Lyon 1, Lyon, France
| | - Laure Collard
- Department of Pediatric Nephrology, Center Hospitalier Universitaire Liège, Liège, Belgium
| | - Julien Hogan
- Department of Pediatric Nephrology, Assistance Publique–Hôpitaux de Paris Robert-Debré, University of Paris, Paris, France
| | | | - Casper F.M. Franssen
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jérôme Harambat
- Department of Pediatrics, Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France
| | - Sally-Anne Hulton
- Department of Nephrology, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
| | - Graham W. Lipkin
- Department of Nephrology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Giorgia Mandrile
- Genetic Unit and Thalassemia Center, San Luigi University Hospital, Orbassano, Italy
| | - Cristina Martin-Higueras
- Institute of Biomedical Technology, CIBERER, University of Laguna, San Cristóbal de La Laguna, Spain
| | - Nilufar Mohebbi
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | | | - Thomas J. Neuhaus
- Department of Pediatrics, Children’s Hospital Lucerne, Lucerne, Switzerland
| | - Larisa Prikhodina
- Department of Inherited and Acquired Kidney Diseases, Veltishev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Moscow, Russia
| | - Eduardo Salido
- Department of Pathology, Center for Biomedical Research on Rare Diseases, Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain
| | - Rezan Topaloglu
- Division of Pediatric Nephrology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Michiel J.S. Oosterveld
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jaap W. Groothoff
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Hessel Peters-Sengers
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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18
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Klib M, Ghandour M, Wannous H. Urinary stone disease in Syrian children. Pediatr Nephrol 2023; 38:2699-2709. [PMID: 36662300 DOI: 10.1007/s00467-022-05860-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND Pediatric urinary stone disease (USD) is a costly medical problem. This study aims to assess the clinical characteristics and outcomes of common and rare causes of pediatric USD. METHODS A retrospective descriptive cohort study included all children < 13 years of age with confirmed USD admitted to the Children's University Hospital in Damascus, Syria, from January 2013 to December 2019. The study sample was divided into two groups based on etiologies: common and rare causes groups. RESULTS We evaluated 235 patients; 147 of them were males, and the male-to-female ratio was 1.7:1. The common causes group consisted of 203 patients (mean age 3.52 ± 3.66 years) and mainly included metabolic disorders (45.5%) and anatomical abnormalities (22.3%), while the rare causes group included 32 cases (mean age 4.93 ± 4.08 years), 12 patients with uric acid stones (37.5%), 7 patients with cystinuria (21.9%), and primary hyperoxaluria in 5 patients (15.6%). In addition, 39.6% of study patients were born to consanguineous marriages. Sixty-two patients developed AKI, and eleven patients had chronic kidney disease (CKD). Patients with rare causes were more likely to have AKI, CKD, bilateral stones, and recurrent stones (P-value < 0.05). Stone analysis was performed on 83 patients, and the main stone types were calcium oxalate (34.9%), uric acid (14.4%), and struvite stones (12%). Surgery was the most performed treatment in 101 patients (56.7%). CONCLUSION Patients with rare causes of pediatric USD are at a higher risk for severe complications and require early diagnosis and management. The high rate of uric acid stones in our society requires further evaluation for possible underlying causes. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Mohamad Klib
- Faculty of Medicine, Damascus University, Damascus, Syria.
| | - Munir Ghandour
- Department of Internal Medicine, Al-Mouwasat University Hospital, Damascus University, Damascus, Syria
| | - Hala Wannous
- Department of Pediatric Nephrology, Children's University Hospital, Damascus University, Damascus, Syria
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19
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Lombardi Y, Isnard P, Chavarot N, Chauvet S, Martinez F, Thervet É, Anglicheau D, Karras A. Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1. Am J Kidney Dis 2023; 82:113-116. [PMID: 36693470 DOI: 10.1053/j.ajkd.2022.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 12/08/2022] [Indexed: 01/22/2023]
Abstract
Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.
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Affiliation(s)
- Yannis Lombardi
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Sorbonne Université, Paris, France
| | - Pierre Isnard
- Department of Pathology, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Nathalie Chavarot
- Department of Kidney Transplantation, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Sophie Chauvet
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Frank Martinez
- Department of Kidney Transplantation, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Éric Thervet
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Dany Anglicheau
- Department of Kidney Transplantation, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Alexandre Karras
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France.
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20
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Aziz F, Jorgenson M, Garg N. Secondary oxalate nephropathy and kidney transplantation. Curr Opin Organ Transplant 2023; 28:15-21. [PMID: 36342385 DOI: 10.1097/mot.0000000000001035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
PURPOSE OF REVIEW Secondary hyperoxaluria is associated with poor kidney allograft outcomes after the kidney transplant. Calcium oxalate (CaOx) deposition is common in early allograft biopsies leading to acute tubular necrosis and poor kidney allograft function. Though treatment options for secondary hyperoxaluria are limited, it is crucial to identify patients at increased risk of oxalate nephropathy after the transplant. RECENT FINDINGS Recent data suggest that significant changes in renal replacement therapies and dietary modifications in high-risk patients can prevent kidney allograft damage from the calcium oxalate deposition leading to improve allograft outcomes. SUMMARY The accurate and timely diagnosis of secondary oxalate nephropathy in kidney transplant recipients is paramount to preserving graft function in the long-term. This review will discuss the incidence, risk factors, prevention, and management of oxalate nephropathy in the kidney allograft.
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Affiliation(s)
- Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health
| | - Margaret Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health
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21
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Hayes W, Sas DJ, Magen D, Shasha-Lavsky H, Michael M, Sellier-Leclerc AL, Hogan J, Ngo T, Sweetser MT, Gansner JM, McGregor TL, Frishberg Y. Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial. Pediatr Nephrol 2023; 38:1075-1086. [PMID: 35913563 PMCID: PMC9925547 DOI: 10.1007/s00467-022-05684-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 06/30/2022] [Accepted: 07/01/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. METHODS Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months). RESULTS Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). CONCLUSIONS Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Wesley Hayes
- Department of Paediatric Nephrology, Great Ormond Street Hospital, London, UK.
| | - David J. Sas
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, MN USA
| | - Daniella Magen
- Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel
| | | | - Mini Michael
- Division of Nephrology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX USA
| | - Anne-Laure Sellier-Leclerc
- Hôpital Femme Mère Enfant and Centre d’Investigation Clinique Inserm, Hospices Civils de Lyon, ERKnet, Bron, France
| | - Julien Hogan
- Pediatric Nephrology Department, Hopital Robert-Debré, APHP, Paris, France
| | - Taylor Ngo
- Alnylam Pharmaceuticals, Cambridge, MA USA
| | | | | | | | - Yaacov Frishberg
- Division of Pediatric Nephrology, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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22
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Xin Q, Dong Y, Guo W, Zhao X, Liu Z, Shi X, Lang Y, Shao L. Four novel variants identified in primary hyperoxaluria and genotypic and phenotypic analysis in 21 Chinese patients. Front Genet 2023; 14:1124745. [PMID: 37139236 PMCID: PMC10150119 DOI: 10.3389/fgene.2023.1124745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/04/2023] [Indexed: 05/05/2023] Open
Abstract
Background: Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype. Methods: Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed. Results: We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T > G and c.823_824del) in AGXT gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in GRHPR gene, respectively. A possible PH3 hotspot variant c.769T > G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A > C may be identified as potentially vitamin B6-sensitive genotypes. Conclusion: In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases.
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Affiliation(s)
- Qing Xin
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao, China
| | - Yameng Dong
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao, China
| | - Wencong Guo
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao, China
| | - Xiangzhong Zhao
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhiying Liu
- Renal Division, Peking University First Hospital, Beijing, China
| | - Xiaomeng Shi
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao, China
| | - Yanhua Lang
- Department of Nursing, Qingdao Municipal Hospital, Qingdao, China
- *Correspondence: Yanhua Lang, ; Leping Shao,
| | - Leping Shao
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao, China
- *Correspondence: Yanhua Lang, ; Leping Shao,
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23
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Three Tesla magnetic resonance imaging detects oxalate osteopathy in patients with primary hyperoxaluria type I. Pediatr Nephrol 2022:10.1007/s00467-022-05836-3. [PMID: 36472654 DOI: 10.1007/s00467-022-05836-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/16/2022] [Accepted: 11/17/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND With declining kidney function and therefore increasing plasma oxalate, patients with primary hyperoxaluria type I (PHI) are at risk to systemically deposit calcium-oxalate crystals. This systemic oxalosis may occur even at early stages of chronic kidney failure (CKD) but is difficult to detect with non-invasive imaging procedures. METHODS We tested if magnetic resonance imaging (MRI) is sensitive to detect oxalate deposition in bone. A 3 Tesla MRI of the left knee/tibial metaphysis was performed in 46 patients with PHI and in 12 healthy controls. In addition to the investigator's interpretation, signal intensities (SI) within a region of interest (ROI, transverse images below the level of the physis in the proximal tibial metaphysis) were measured pixelwise, and statistical parameters of their distribution were calculated. In addition, 52 parameters of texture analysis were evaluated. Plasma oxalate and CKD status were correlated to MRI findings. MRI was then implemented in routine practice. RESULTS Independent interpretation by investigators was consistent in most cases and clearly differentiated patients from controls. Statistically significant differences were seen between patients and controls (p < 0.05). No correlation/relation between the MRI parameters and CKD stages or Pox levels was found. However, MR imaging of oxalate osteopathy revealed changes attributed to clinical status which differed clearly to that in secondary hyperparathyroidism. CONCLUSIONS MRI is able to visually detect (early) oxalate osteopathy in PHI. It can be used for its monitoring and is distinguished from renal osteodystrophy. In the future, machine learning algorithms may aid in the objective assessment of oxalate deposition in bone. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information.
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24
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Abid A, Raza A, Aziz T, Khaliq S. HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association. Hum Mutat 2022; 43:1757-1779. [PMID: 36259736 DOI: 10.1002/humu.24490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/16/2022] [Accepted: 10/17/2022] [Indexed: 12/14/2022]
Abstract
Primary hyperoxalurias (PH) are a group of rare heterogeneous disorders characterized by deficiencies in glyoxylate metabolism. To date, three genes have been identified to cause three types of PH (I, II, and III). The HOGA1 gene caused type III in around 10% of the PH cases. Disease-associated pathogenic variants have been reported from several populations and a comprehensive spectrum of these mutations and genotype-phenotype correlation has never been presented. In this study, we describe new cases of the HOGA1 gene pathogenic variants identified in our population. We report the first case of ESKD with successful kidney transplantation with 5 years of follow-up. Furthermore, a comprehensive overview of PH type III associated HOGA1 gene variants was carried out. Compiling the data from the literature, we reviewed 57 distinct HOGA1 gene pathogenic variants in 175 patients worldwide. The majority of reported variants are missense variants that predicted a loss of function mechanism as the underlying pathology. There has been evidence of the presence of founder mutations in several populations like Europeans, Ashkenazi Jews, Arab, and Chinese populations. No significant genotype-phenotype correlation was identified concerning the ages of onset of the disease and biochemical and metabolic parameters. Nephrocalcinosis was rare in patients with disease-associated variants. Most of the patients were presented with urolithiasis early in life; only five cases reported disease progression after the second decade of life. The establishment of impairment of renal function in 8% of all the reported cases makes this type a relatively severe form of primary hyperoxaluria, not a benign etiology as suggested previously.
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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
| | - Tahir Aziz
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Shagufta Khaliq
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.,Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore, Pakistan
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25
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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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26
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Long-term outcomes after pre-emptive liver transplantation in primary hyperoxaluria type 1. Pediatr Nephrol 2022; 38:1811-1820. [PMID: 36449101 DOI: 10.1007/s00467-022-05803-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the liver defect of oxalate metabolism, which leads to kidney failure and systemic manifestations. Until recently, liver transplantation was the only definitive treatment. The timing of liver transplantation can be early, while kidney function is still normal (pre-emptive liver transplantation-PLT), or when the patient reaches stage 5 chronic kidney disease (CKD) and needs combined liver-kidney transplantation. We aimed to determine the long-term kidney outcomes of PLT in PH1 patients. METHODS A retrospective single-center study of PH1 patients who were followed in our center between 1997 and 2017. We compared the kidney outcomes of patients who underwent PLT to those who presented with preserved kidney function and did not undergo PLT. RESULTS Out of 36 PH1 patients, 18 patients were eligible for PLT (eGFR > 40 mL/min/1.73 m2 at the time of diagnosis). Seven patients underwent PLT (PLT group), while 11 continued conservative treatments (PLTn group). In the PLT group, the median eGFR at the time of PLT and at the end of the follow-up period (14-20 years) was 72 (range 50-89) and 104 (range 86-108) mL/min/1.73 m2, respectively, and no patient died or reached stage 5 CKD. In the PLTn group, eight patients (72.7%) reached stage 5 CKD (median time to kidney replacement therapy was 11 years), and two patients died from disease complications (18.2%). CONCLUSIONS Pre-emptive liver transplantation preserved kidney function in patients with PH1 in our cohort. Early intervention can prevent kidney failure and systemic oxalosis in PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.
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27
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Liu A, Zhao J, Shah M, Migliorati JM, Tawfik SM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies. ACS Pharmacol Transl Sci 2022; 5:1007-1016. [PMID: 36407951 PMCID: PMC9667536 DOI: 10.1021/acsptsci.2c00110] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Indexed: 11/28/2022]
Abstract
Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.
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Affiliation(s)
- Anna Liu
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Jenny Zhao
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Milan Shah
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Julia M. Migliorati
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Sherouk M. Tawfik
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Raman Bahal
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Theodore P. Rasmussen
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Jose E. Manautou
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
| | - Xiao-bo Zhong
- Department of Pharmaceutical
Sciences, School of Pharmacy, University
of Connecticut, Storrs, Connecticut06269, United States
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Ni T, Sun Z, Zhao F. A case report of invasive infantile primary hyperoxaluria type 1 and literature review. CEN Case Rep 2022; 12:159-163. [PMID: 36194362 PMCID: PMC10151289 DOI: 10.1007/s13730-022-00740-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Infantile primary hyperoxaluria type 1 (PH1) is the most devastating primary hyperoxaluria (PH) subtype as it leads to early end-stage kidney disease (ESKD) associated with high mortality. We report a case of a three-month-old female Chinese infant who was diagnosed with PH1 by renal biopsy and genetic studies. She carried two heterozygous mutations in the alanine-glyoxylate and serine pyruvate aminotransferase (AGXT) gene, one of which has never been previously reported. The patient had multiple organ failures caused by kidney failure, which was improved by extracorporeal membrane oxygenation and continuous renal replacement therapy. However, her primary disease responded poorly to conservative treatment. Fortunately, after waiting for four months, the patient underwent a successful combined liver-kidney transplantation and has progressed well so far. This case highlights the importance of suspecting PH in infant patients with ESKD of uncertain etiology, as early initiation of therapy prevents poor outcomes.
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Affiliation(s)
- Tong Ni
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenzhen Sun
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Fei Zhao
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.
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Soliman NA, Elmonem MA, Abdelrahman SM, Nabhan MM, Fahmy YA, Cogal A, Harris PC, Milliner DS. Clinical and molecular characterization of primary hyperoxaluria in Egypt. Sci Rep 2022; 12:15886. [PMID: 36151119 PMCID: PMC9508166 DOI: 10.1038/s41598-022-17980-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes (AGXT, GRHPR or HOGA1). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT, with none detected in GRHPR or HOGA1. We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.
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Affiliation(s)
- Neveen A Soliman
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University, Cairo, Egypt.,EGORD, Egyptian Group of Orphan Renal Diseases, Cairo, Egypt
| | - Mohamed A Elmonem
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt. .,Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt.
| | - Safaa M Abdelrahman
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University, Cairo, Egypt.,EGORD, Egyptian Group of Orphan Renal Diseases, Cairo, Egypt
| | - Marwa M Nabhan
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University, Cairo, Egypt.,EGORD, Egyptian Group of Orphan Renal Diseases, Cairo, Egypt
| | - Yosra A Fahmy
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University, Cairo, Egypt.,EGORD, Egyptian Group of Orphan Renal Diseases, Cairo, Egypt
| | - Andrea Cogal
- Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA.,Rare Kidney Stone Consortium (RKSC), Rochester, MN, USA
| | - Peter C Harris
- Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA.,Rare Kidney Stone Consortium (RKSC), Rochester, MN, USA
| | - Dawn S Milliner
- Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA.,Rare Kidney Stone Consortium (RKSC), Rochester, MN, USA
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30
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Singh P, Vaughan LE, Schulte PJ, Sas DJ, Milliner DS, Lieske JC. Estimated GFR Slope Across CKD Stages in Primary Hyperoxaluria Type 1. Am J Kidney Dis 2022; 80:373-382. [PMID: 35306035 PMCID: PMC9398980 DOI: 10.1053/j.ajkd.2022.01.428] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 01/14/2022] [Indexed: 01/27/2023]
Abstract
RATIONALE & OBJECTIVE Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism that results in early-onset kidney stone disease, nephrocalcinosis, and kidney failure. There is an unmet need for reliable markers of disease progression to test effectiveness of new treatments for patients with PH. In this study, we assessed the rate of estimated glomerular filtration rate (eGFR) decline across chronic kidney disease (CKD) glomerular filtration rate (GFR) categories (CKD G2-G5) in a cohort of patients with PH1. STUDY DESIGN Retrospective observational study. SETTING & PARTICIPANTS Patients with PH1 enrolled in the Rare Kidney Stone Consortium (RKSC) registry who did not have kidney failure at diagnosis and who had at least 2 eGFR values recorded from within 1 month of diagnosis until their last contact date or incident kidney failure event. PREDICTORS CKD GFR category, baseline patient and laboratory characteristics. OUTCOME Annualized rate of eGFR decline. ANALYTICAL APPROACH Generalized estimating equations and linear regression were used to evaluate the associations between CKD GFR category, baseline patient and laboratory characteristics, and annual change in eGFR during follow-up. RESULTS Compared with the slope in CKD G2 (-2.3 mL/min/1.73 m2 per year), the mean annual eGFR decline was nominally steeper in CKD G3a (-5.3 mL/min/1.73 m2 per year) and statistically significantly more rapid in CKD G3b and G4 (-14.7 and -16.6 mL/min/1.73 m2 per year, respectively). In CKD G2, older age was associated with a more rapid rate of eGFR decline (P = 0.01). A common PH1-causing variant of alanine glyoxylate aminotransferase, a glycine to arginine substitution at amino acid 170 (G170R), appeared to be associated with less severe annual decline in eGFR. LIMITATIONS Data at regular time points were not available for all patients due to reliance on voluntary reporting in a retrospective rare disease registry. CONCLUSIONS The eGFR decline was not uniform across CKD GFR categories in this PH1 population, with a higher rate of eGFR decline in CKD G3b and G4. Thus, CKD GFR category needs to be accounted for when analyzing eGFR change in the setting of PH1.
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Affiliation(s)
- Prince Singh
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Lisa E Vaughan
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - Phillip J Schulte
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - David J Sas
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Dawn S Milliner
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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Primary hyperoxaluria: The Baragwanath experience. SOUTH AFRICAN JOURNAL OF CHILD HEALTH 2022. [DOI: 10.7196/sajch.2022.v16i2.1872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Background. Primary hyperoxaluria (PH) is a rare autosomal recessive condition characterised by defects in the metabolism of glyoxylate which leads to excess oxalate production. It is an important disease to diagnose as it can progress to kidney failure (KF).
Objective. To describe the characteristics, diagnosis and management of PH in South Africa and to identify any determinants of KF and death.
Method. A retrospective study of all children younger than 16 years of age, diagnosed with PH at the Paediatric Renal Unit, Chris Hani Baragwanath Academic Hospital, from 1984 - 2017.
Results. A total of 24 patients were identified, of which 20 records were available for complete analysis. The median age of presentation was 6.0 years. The common clinical presentations were urolithiasis (90%), KF (85%), nephrocalcinosis (75%), urinary tract infections (55%) and haematuria (30%). Nephrocalcinosis was better detected on abdominal radiograph compared with ultrasonography. Both nephrocalcinosis (p=0.009) and haematuria (p=0.018) were significantly associated with KF. Five patients had A112D genetic mutation in the AGXT. Fourteen received dialysis and four were transplanted. The mortality rate in this study was 58.3%.
Conclusion. Clinicians should have a high index of suspicion for PH in patients presenting with haematuria, urolithiasis and KF. This study supports the measurement of urine oxalate levels and abdominal radiographs in screening for PH in children presenting in KF.
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Abstract
PURPOSE OF REVIEW Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes hepatic overproduction of oxalate and, often, nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. The purpose of the review is to provide an update on current emerging therapies for the treatment of PH1. RECENT FINDINGS Use of ribonucleic acid interference (RNAi) therapeutics that target the liver to block production of key enzymes along pathways that generate oxalate is a promising approach. Available evidence supports the efficacy of both Lumasiran (targeting glycolate oxidase) and Nedosiran (targeting hepatic lactate dehydrogenase (LDHa)) to reduce urinary oxalate excretion in PH1. The efficacy of alternative approaches including stiripentol (an anticonvulsant drug that also targets LDHa), lanthanum (a potential gastrointestinal oxalate binder), and Oxalobacter formigenes (a bacterium that can degrade oxalate within the gastrointestinal tract and may also increase its secretion from blood) are all also under study. Genetic editing tools including clustered regularly interspaced short palindromic repeats/Cas9 are also in preclinical study as a potential PH1 therapeutic. SUMMARY Novel treatments can reduce the plasma oxalate concentration and urinary oxalate excretion in PH1 patients. Thus, it is possible these approaches will reduce the need for combined kidney and liver transplantation to significantly decrease the morbidity and mortality of affected patients.
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Affiliation(s)
| | - John C Lieske
- Division of Nephrology and Hypertension
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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Abstract
The primary hyperoxalurias are three rare inborn errors of the glyoxylate metabolism in the liver, which lead to massively increased endogenous oxalate production, thus elevating urinary oxalate excretion and, based on that, recurrent urolithiasis and/or progressive nephrocalcinosis. Frequently, especially in type 1 primary hyperoxaluria, early end-stage renal failure occurs. Treatment possibilities are scare, namely, hyperhydration and alkaline citrate medication. In type 1 primary hyperoxaluria, vitamin B6, though, is helpful in patients with specific missense or mistargeting mutations. In those vitamin B6 responsive, urinary oxalate excretion and concomitantly urinary glycolate is significantly decreased, or even normalized. In patients non-responsive to vitamin B6, RNA interference medication is now available. Lumasiran® is already available on prescription and targets the messenger RNA of glycolate oxidase, thus blocking the conversion of glycolate into glyoxylate, hence decreasing oxalate, but increasing glycolate production. Nedosiran blocks liver-specific lactate dehydrogenase A and thus the final step of oxalate production. Similar to vitamin B6 treatment, where both RNA interference urinary oxalate excretion can be (near) normalized and plasma oxalate decreases, however, urinary and plasma glycolate increases with lumasiran treatment. Future treatment possibilities are on the horizon, for example, substrate reduction therapy with small molecules or gene editing, induced pluripotent stem cell-derived autologous hepatocyte-like cell transplantation, or gene therapy with newly developed vector technologies. This review provides an overview of current and especially new and future treatment options.
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Affiliation(s)
| | - Cristina Martin-Higueras
- German Hyperoxaluria Center, Bonn, Germany.
- Institute of Biomedical Technologies, CIBERER, Campus de Ofra s/n 38200, University of La Laguna, Tenerife, Spain.
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Hulton SA, Groothoff JW, Frishberg Y, Koren MJ, Overcash JS, Sellier-Leclerc AL, Shasha-Lavsky H, Saland JM, Hayes W, Magen D, Moochhala SH, Coenen M, Simkova E, Garrelfs SF, Sas DJ, Meliambro KA, Ngo T, Sweetser MT, Habtemariam BA, Gansner JM, McGregor TL, Lieske JC. Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1. Kidney Int Rep 2022; 7:494-506. [PMID: 35257062 PMCID: PMC8897294 DOI: 10.1016/j.ekir.2021.12.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/03/2021] [Indexed: 01/09/2023] Open
Abstract
Introduction Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.
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Affiliation(s)
- Sally A. Hulton
- Department of Nephrology, Birmingham Women’s and Children’s Hospital, Birmingham, UK
| | - Jaap W. Groothoff
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Yaacov Frishberg
- Division of Pediatric Nephrology, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Michael J. Koren
- Jacksonville Center for Clinical Research, Jacksonville, Florida, USA
| | | | - Anne-Laure Sellier-Leclerc
- Hôpital Femme Mère Enfant and Centre d’Investigation Clinique Institut National de la Santé et de la Recherche Médicale, Hospices Civils de Lyon, ERKnet, Bron, France
| | - Hadas Shasha-Lavsky
- Pediatric Nephrology Unit, Galilee Medical Center and Azrieli Faculty of Medicine, Bar-Ilan University, Nahariya, Israel
| | | | - Wesley Hayes
- Department of Pediatric Nephrology, Great Ormond Street Hospital, London, UK
| | - Daniella Magen
- Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel
| | | | - Martin Coenen
- Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Eva Simkova
- Al Jalila Children’s Hospital, Dubai, United Arabs Emirates
| | - Sander F. Garrelfs
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - David J. Sas
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Taylor Ngo
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | | | | | | | | | - John C. Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
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35
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Therapeutic RNA-silencing oligonucleotides in metabolic diseases. Nat Rev Drug Discov 2022; 21:417-439. [PMID: 35210608 DOI: 10.1038/s41573-022-00407-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design and optimization of synthetic nucleic acid chemistry, in combination with the development of highly selective and efficient conjugate delivery technology platforms, have established and validated oligonucleotides as a new class of drugs. To date, there are five marketed oligonucleotide therapies, with many more in clinical studies, for both rare and common liver-driven metabolic diseases. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in metabolism, review past and current clinical trials, and discuss ongoing challenges and possible future developments.
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36
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Cornell LD, Amer H, Viehman JK, Mehta RA, Lieske JC, Lorenz EC, Heimbach JK, Stegall MD, Milliner DS. Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transplant 2022; 22:85-95. [PMID: 34174139 PMCID: PMC8710184 DOI: 10.1111/ajt.16732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/30/2021] [Accepted: 06/19/2021] [Indexed: 01/25/2023]
Abstract
Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.
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Affiliation(s)
- Lynn D. Cornell
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905
| | - Hatem Amer
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905
| | - Jason K. Viehman
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota 55905
| | - Ramila A. Mehta
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota 55905
| | - John C. Lieske
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905
| | - Elizabeth C. Lorenz
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905
| | - Julie K. Heimbach
- Division of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota 55905
| | - Mark D. Stegall
- Division of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota 55905
| | - Dawn S. Milliner
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905
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Shee K, Stoller ML. Perspectives in primary hyperoxaluria - historical, current and future clinical interventions. Nat Rev Urol 2021; 19:137-146. [PMID: 34880452 PMCID: PMC8652378 DOI: 10.1038/s41585-021-00543-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/19/2022]
Abstract
Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and combined transplantation of the kidney and liver, of which the liver is the primary source of oxalate production. However, transplantation is associated with many potential complications, including operative risks, graft rejection, post-transplant organ failure, as well as lifelong immunosuppressive medications and their adverse effects. New therapeutics being developed for primary hyperoxalurias take advantage of biochemical knowledge about oxalate synthesis and metabolism, and seek to specifically target these pathways with the goal of decreasing the accumulation and deposition of oxalate in the body. Primary hyperoxalurias are a devastating family of diseases that eventually lead to end-stage renal disease. In this Review, Shee and Stoller discuss current treatment paradigms for primary hyperoxalurias, new therapeutics and their mechanisms of action, and future directions for novel research in the field.
Primary hyperoxalurias (PHs) are a devastating family of rare, autosomal-recessive genetic disorders that lead to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and inevitably transplantation of the kidney and liver, which is associated with high morbidity and the need for lifelong immunosuppression. New therapeutics being developed for PHs take advantage of biochemical knowledge about oxalate synthesis and metabolism to specifically target these pathways, with the goal of decreasing the accumulation and deposition of plasma oxalate in the body. New therapeutics can be divided into classes, and include substrate reduction therapy, intestinal oxalate degradation, chaperone therapy, enzyme restoration therapy and targeting of the inflammasome. Lumasiran, a mRNA therapeutic targeting glycolate oxidase, was the first primary hyperoxaluria-specific therapeutic approved by the European Medicines Agency and the FDA in 2020. Future work includes further clinical trials for promising therapeutics in the pipeline, identification of biomarkers of response to PH-directed therapy, optimization of drug development and delivery of new therapeutics.
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Affiliation(s)
- Kevin Shee
- Department of Urology, UCSF, San Francisco, CA, USA.
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Garrelfs SF, van Harskamp D, Peters-Sengers H, van den Akker CH, Wanders RJ, Wijburg FA, van Goudoever JB, Groothoff JW, Schierbeek H, Oosterveld MJ. Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients. J Am Soc Nephrol 2021; 32:3175-3186. [PMID: 34686543 PMCID: PMC8638398 DOI: 10.1681/asn.2021060729] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism, characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated, and upcoming therapies require more reliable outcome parameters than the currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo . METHODS Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1- 13 C]glycolate, [U- 13 C 2 ]oxalate, and, in a subgroup, [D 5 ]glycine. Isotopic enrichment of 13 C-labeled oxalate and glycolate were measured using a new gas chromatography-tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively. RESULTS Total daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, and controls, respectively ( P =0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1- 13 C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive. CONCLUSIONS This stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans.
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Affiliation(s)
- Sander F. Garrelfs
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Dewi van Harskamp
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Hessel Peters-Sengers
- Center for Experimental Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Ronald J.A. Wanders
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Frits A. Wijburg
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Jaap W. Groothoff
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Henk Schierbeek
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Michiel J.S. Oosterveld
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Poyah P, Bergman J, Geldenhuys L, Wright G, Walsh NM, Hull P, Roche K, West ML. Primary Hyperoxaluria Type 1 (PH1) Presenting With End-Stage Kidney Disease and Cutaneous Manifestations in Adulthood: A Case Report. Can J Kidney Health Dis 2021; 8:20543581211058931. [PMID: 34840803 PMCID: PMC8613886 DOI: 10.1177/20543581211058931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/13/2021] [Indexed: 11/17/2022] Open
Abstract
Rationale: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation. Case Presentation: A 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis. Diagnosis: A diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis. Interventions: She was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities. Outcomes: After 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation. Teaching Points: This case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.
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Affiliation(s)
- Penelope Poyah
- Department of Medicine, Dalhousie University, Halifax, NS, Canada.,Division of Nephrology, Nova Scotia Health Authority, Halifax, NS, Canada
| | - Joel Bergman
- Department of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Laurette Geldenhuys
- Department of Pathology, Dalhousie University and Nova Scotia Health Authority, Halifax, NS, Canada
| | - Glenda Wright
- Department of Pathology, Dalhousie University and Nova Scotia Health Authority, Halifax, NS, Canada
| | - Noreen M Walsh
- Department of Medicine, Dalhousie University, Halifax, NS, Canada.,Department of Pathology, Dalhousie University and Nova Scotia Health Authority, Halifax, NS, Canada
| | - Peter Hull
- Department of Medicine, Dalhousie University, Halifax, NS, Canada.,Division of Clinical Dermatology & Cutaneous Science, Nova Scotia Health Authority, Halifax, NS, Canada
| | - Kristina Roche
- Department of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Michael L West
- Department of Medicine, Dalhousie University, Halifax, NS, Canada.,Division of Nephrology, Nova Scotia Health Authority, Halifax, NS, Canada
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Wang X, Danese D, Brown T, Baldwin J, Sajeev G, Cook EE, Wang Y, Xu C, Yang H, Moritz ML. Primary Hyperoxaluria Type 1 Disease Manifestations and Healthcare Utilization: A Multi-Country, Online, Chart Review Study. Front Med (Lausanne) 2021; 8:703305. [PMID: 34616753 PMCID: PMC8488346 DOI: 10.3389/fmed.2021.703305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/26/2021] [Indexed: 12/02/2022] Open
Abstract
Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney failure is a known consequence of PH1, few studies to date have characterized clinical consequences of PH1 prior to kidney failure, and data on healthcare resource use outcomes across different stages of disease severity in PH1 are also limited. To help fill this knowledge gap, this study characterized the clinical and healthcare resource use (HRU) burden in patients with PH1 with varying stages of kidney disease. Methods: Nephrologists in the United States, Canada, United Kingdom, France, Germany, and Italy abstracted chart data from patients with PH1 under their care via an online questionnaire. Eligible patients had confirmed PH1 and ≥2 office visits from 2016 to 2019. Results: A total of 120 patients were analyzed (median age at diagnosis, 17.4 years old, median age at index 19.5 years old, median eGFR at index 45 ml/min/1.73 m2; median follow-up 1.7 years). During follow-up, the most common PH1 manifestations were kidney stones and urinary tract infections (UTIs, both 56.8%), and the most common symptoms were fatigue/weakness (71.7%) and pain (64.6%). With regard to HRU during follow-up, 37.4% required lithotripsy, 31.3% required ureteroscopy, and 9.6% required nephrolithotomy. PH1-related hospitalizations and emergency/urgent care visits were noted for 84.0 and 81.6% of patients, respectively. Conclusions: The current study demonstrated that patients with PH1 across various stages of kidney disease exhibited a substantial clinical burden, including kidney stones, UTIs, fatigue/weakness, and pain, and required frequent HRU, including kidney stone procedures, hospitalizations, and emergency visits. These findings highlight the significant morbidity and HRU burden in patients with PH1.
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Affiliation(s)
- Xiangling Wang
- Center for Personalized Genetic Healthcare, Department of Nephrology and Hypertension, Department of Molecular Medicine, Cleveland Clinic, Cleveland, OH, United States
| | - David Danese
- Alnylam Pharmaceuticals, Inc., Cambridge, MA, United States
| | - Thomas Brown
- Alnylam Pharmaceuticals, Inc., Cambridge, MA, United States
| | | | | | - Erin E Cook
- Analysis Group, Inc., Boston, MA, United States
| | - Yao Wang
- Analysis Group, Inc., Boston, MA, United States
| | - Chunyi Xu
- Analysis Group, Inc., Boston, MA, United States
| | - Hongbo Yang
- Analysis Group, Inc., Boston, MA, United States
| | - Michael L Moritz
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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Shee K, Ahn J, Hamouche F, Mena J, Chi T, Stoller ML. Nedosiran Dramatically Reduces Serum Oxalate in Dialysis-Dependent Primary Hyperoxaluria 1: A Compassionate Use Case Report. Urology 2021; 156:e147-e149. [PMID: 33774044 DOI: 10.1016/j.urology.2021.03.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/14/2021] [Indexed: 10/21/2022]
Abstract
Primary hyperoxaluria 1 (PH1) is a devastating condition involving recurrent urolithiasis, early end-stage renal disease and multisystemic deposition of calcium oxalate crystals. Treatment options for PH1 are limited, inevitably requiring transplantation, usually combined kidney and liver transplant. Here we report successful compassionate use of Nedosiran, an RNA interference targeting lactate dehydrogenase, in an index patient. Monthly Nedosiran injections led to dramatically decreased plasma oxalate levels, decreased frequency of weekly hemodialysis sessions from 6 to 3, and deferral of combined kidney and liver transplant. Nedosiran represents a novel and impactful potential therapeutic for PH1 patients with end-stage renal disease.
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Affiliation(s)
- Kevin Shee
- Department of Urology, UCSF, San Francisco, CA.
| | - Justin Ahn
- Department of Urology, UCSF, San Francisco, CA
| | | | - Jorge Mena
- Department of Urology, UCSF, San Francisco, CA
| | - Thomas Chi
- Department of Urology, UCSF, San Francisco, CA
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Frishberg Y, Deschênes G, Groothoff JW, Hulton SA, Magen D, Harambat J, van’t Hoff WG, Lorch U, Milliner DS, Lieske JC, Haslett P, Garg PP, Vaishnaw AK, Talamudupula S, Lu J, Habtemariam BA, Erbe DV, McGregor TL, Cochat P. Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial. Clin J Am Soc Nephrol 2021; 16:1025-1036. [PMID: 33985991 PMCID: PMC8425611 DOI: 10.2215/cjn.14730920] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 03/22/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
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Affiliation(s)
- Yaacov Frishberg
- Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Georges Deschênes
- Department of Pediatric Nephrology, Hôpital Robert Debré, Paris, France
| | - Jaap W. Groothoff
- Department of Pediatric Nephrology, University of Amsterdam, Amsterdam, The Netherlands
| | - Sally-Anne Hulton
- Department of Nephrology, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
| | - Daniella Magen
- Pediatric Nephrology Institute, Ruth Children's Hospital, Haifa, Israel
| | - Jérôme Harambat
- Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France
| | - William G. van’t Hoff
- Department of Paediatric Nephrology, Great Ormond Street Hospital, London, United Kingdom
| | - Ulrike Lorch
- Richmond Pharmacology Ltd., London, United Kingdom
| | - Dawn S. Milliner
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - John C. Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | | | | | | | | | - Jiandong Lu
- Alnylam Pharmaceuticals, Cambridge, Massachusetts
| | | | | | | | - Pierre Cochat
- Center for Rare Renal Diseases and Institut National de la Santé et de la Recherche Médicale Pediatric Clinical Investigation Center, Hospices Civils de Lyon, Lyon, France,Université de Lyon, Lyon, France
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Abid A. Possible ethnic associations in primary hyperoxaluria type-III-associated HOGA1 sequence variants. Mol Biol Rep 2021; 48:3841-3844. [PMID: 33948853 DOI: 10.1007/s11033-021-06380-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/24/2021] [Indexed: 10/21/2022]
Abstract
Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated pathogenic sequence variants are identified in the gene. A few of the variants are population specific and are considered to have a founder effect in respective populations. The most prevalent variant, c.700+5G>T, identified frequently in Caucasian (allele frequency 0.63) and European (0.35) populations. Two variants, c.860G>T (p.Gly287Val) and c.944_946delAGG (p.Glu315del), account for 95% of the allele count in patients of Ashkenazi Jews ancestry. A possible mutational hot-spot at c.834 position is frequently found mutated in Chinese patients. This observed ethnic associations of HOGA1 alleles span a spectrum ranging from recurrence limited to an ethnic group to a possible founder-effect.
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Affiliation(s)
- Aiysha Abid
- Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.
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Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, Deschênes G, Shasha-Lavsky H, Saland JM, Van't Hoff WG, Fuster DG, Magen D, Moochhala SH, Schalk G, Simkova E, Groothoff JW, Sas DJ, Meliambro KA, Lu J, Sweetser MT, Garg PP, Vaishnaw AK, Gansner JM, McGregor TL, Lieske JC. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med 2021; 384:1216-1226. [PMID: 33789010 DOI: 10.1056/nejmoa2021712] [Citation(s) in RCA: 325] [Impact Index Per Article: 81.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
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Affiliation(s)
- Sander F Garrelfs
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Yaacov Frishberg
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Sally A Hulton
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Michael J Koren
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - William D O'Riordan
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Pierre Cochat
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Georges Deschênes
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Hadas Shasha-Lavsky
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Jeffrey M Saland
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - William G Van't Hoff
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Daniel G Fuster
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Daniella Magen
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Shabbir H Moochhala
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Gesa Schalk
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Eva Simkova
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Jaap W Groothoff
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - David J Sas
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Kristin A Meliambro
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Jiandong Lu
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Marianne T Sweetser
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Pushkal P Garg
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Akshay K Vaishnaw
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - John M Gansner
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - Tracy L McGregor
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
| | - John C Lieske
- From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.)
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Ranawaka R, Dayasiri K, Gamage M. Combined liver and kidney transplantation in children and long-term outcome. World J Transplant 2020; 10:283-290. [PMID: 33134116 PMCID: PMC7579435 DOI: 10.5500/wjt.v10.i10.283] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/17/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Combined liver-kidney transplantation (CLKT) is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual (usually a cadaver) to the same recipient during a single surgical procedure. Most common indications for CLKT in children are autosomal recessive polycystic kidney disease and primary hyperoxaluria type 1. Atypical haemolytic uremic syndrome, methylmalonic academia, and conditions where liver and renal failure co-exists may be indications for CLKT. CLKT is often preferred over sequential liver-kidney transplantation due to immunoprotective effects of transplanted liver on renal allograft; however, liver survival has no significant impact. Since CLKT is a major surgical procedure which involves multiple and complex anastomosis surgeries, acute complications are not uncommon. Bleeding, thrombosis, haemodynamic instability, infections, acute cellular rejections, renal and liver dysfunction are acute complications. The long-term outlook is promising with over 80% 5-year survival rates among those children who survive the initial six-month postoperative period.
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Affiliation(s)
- Randula Ranawaka
- Department of Paediatrics, Faculty of Medicine, University of Colombo and Lady Ridgeway Hospital for Children, Colombo 0094, Sri Lanka
| | - Kavinda Dayasiri
- Department of Paediatrics, Base Hospital Mahaoya, Mahaoya 0094, Sri Lanka
| | - Manoji Gamage
- Department of Clinical Nutrition, Lady Ridgeway Hospital for Children, Colombo 0094, Sri Lanka
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Plasma oxalate levels in primary hyperoxaluria type I show significant intra-individual variation and do not correlate with kidney function. Pediatr Nephrol 2020; 35:1227-1233. [PMID: 32274573 DOI: 10.1007/s00467-020-04531-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 02/14/2020] [Accepted: 03/05/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Primary hyperoxalurias are rare diseases with endogenous overproduction of oxalate, thus leading to hyperoxaluria, hyperoxalemia, urolithiasis, and/or nephrocalcinosis and eventually early kidney failure. Plasma oxalate (POx) is an important diagnostic parameter in clinical studies on primary hyperoxaluria (PH). This is especially the case in kidney failure, where urinary parameters are no longer suitable. We aimed to evaluate whether POx would be an adequate endpoint for clinical studies in PH patients with stable kidney function. In addition, the correlation of POx to serum creatinine (SCr) and calculated glomerular filtration rate (eGFR) was examined. METHODS We retrospectively analyzed follow-up of individual POx values over time, as well as POx correlation to SCr, eGFR, and vitamin B6 (VB6), a common therapeutic in PH1. Results from 187 blood samples taken between 2009 and 2017, during routine laboratory evaluations from 41 patients with PH1 who had neither undergone dialysis nor transplantation, were evaluated. RESULTS Negligibly low correlation coefficients (CCs) between POx vs. SCr (CC = -0.0950), POx vs. eGFR (CC = -0.1237), and POx vs. VB6 (CC = 0.1879) were found, with the exception of CKD stage 3a patients, who showed a positive correlation (CC of - 0.7329, POx vs eGFR). The intra-individual analysis of POx over time showed a high fluctuation of POx values. CONCLUSION We conclude that POx has a limited validity as a primary endpoint for clinical studies in PH1 patients with stable kidney function. In addition, it does not correlate to SCr and eGFR in this group of patients.
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Abukhatwah MW, Almalki SH, Althobaiti MS, Alharbi AO, Almalki NK, Kamal NM. Primary hyperoxaluria Type 1: A case report in an extended family with a novel AGXT gene mutation. Medicine (Baltimore) 2020; 99:e20371. [PMID: 32569165 PMCID: PMC7310847 DOI: 10.1097/md.0000000000020371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 03/12/2020] [Accepted: 04/22/2020] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Primary hyperoxaluria type 1 (PH1) is a genetic autosomal recessively inherited disorder due to mutation in the alanine-glyoxylate aminotransferase (AGXT) gene. It usually presents in children with nephrolithiasis and/or nephrocalcinosis and progressive renal function impairment and end stage renal disease (ESRD). PATIENT CONCERNS A 13 years old Saudi boy with history of recurrent urolithiasis since the age of 2 years presented to us with picture of ESRD. He has strong family history of urolithiasis. DIAGNOSIS Working up the patient suggested the diagnosis of PH1 based on the typical clinical, laboratory, and imaging findings which was genetically proved by positive AXGT gene mutation. The mutation detected was not previously reported in literature. The mutation detected was not previously reported in literature. The novel mutation c. 799A>T p. (IIe267Phe) detected in our patient extend the spectrum of the known AGXT gene mutations. INTERVENTIONS AND OUTCOMES Hemodialysis as a temporary step followed by renal transplantation which is the only cure. CONCLUSION High index of suspicion of PH1 before ESRD should be considered in any patient who has recurrent urolithiasis since early life especially in presence of strong family history.
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Zhao F, Li J, Tang L, Li C, Wang W, Ning C. Characteristics of the genotype and phenotype in Chinese primary hyperoxaluria type 1 populations. Urolithiasis 2020; 49:17-25. [PMID: 32556641 DOI: 10.1007/s00240-020-01201-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 05/29/2020] [Indexed: 11/30/2022]
Abstract
The aim of our study is to explore the relationship between genotype and phenotype in Chinese PH1 patients and determine the putative mutation hotspot regions. This was a retrospective study regarding 13 Chinese PH1 patients. And all sporadic published researches of Chinese PH1 populations were searched and enrolled based on the inclusive standard. All patients presented with multiple urolithiasis or nephrolithiasis. Urinary oxalate values demonstrated an obvious and extensive variability, ranging from 1.01 to 3.85 mmol/1.73 m2. Molecular diagnosis showed that 13 mutant types were detected. Infantile form patient (pt.) 10 and five patients (pts. 5, 7, 8, 9, 12) carrying c.815_816insGA or c.33_34insC demonstrated a worse prognosis, of whom pt. 5 progressed into ESRD 4 years later and died of chronic kidney failure. Based on the integrated Chinese mutation data, two variants (c.815_816insGA and c.33_34insC) were determined as the most common mutations. Besides, c.1049G>A was initially identified in a Chinese patient. Conclusions: heterogeneity between genotype and phenotype was observed and described in Chinese PH1 patients. c.815_816insGA and c.33_34insC which were recognized as AGXT mutation hotspot regions in China implied a poor prognosis. And c.1049G>A was not determined as the race-specific mutation of Pakistani.
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Affiliation(s)
- Fangzhou Zhao
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China
| | - Jun Li
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China.
| | - Lei Tang
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China
| | - Chunming Li
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China
| | - Wenying Wang
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China
| | - Chen Ning
- Department of Urology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, 100050, China
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Zheng R, Li Y, Wang L, Fang X, Zhang J, He L, Yang L, Li D, Geng H. CRISPR/Cas9-mediated metabolic pathway reprogramming in a novel humanized rat model ameliorates primary hyperoxaluria type 1. Kidney Int 2020; 98:947-957. [PMID: 32464217 DOI: 10.1016/j.kint.2020.04.049] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/11/2022]
Abstract
Primary hyperoxaluria type I is caused by mutations in the alanine glyoxylate aminotransferase gene (AGXT), leading to accumulation of glyoxylate and subsequent production of oxalate and urolithiasis. Here, we generated a novel rat model of primary hyperoxaluria type I that carries a D205N mutation in the partially humanized Agxt gene through the CRISPR/Cas9 system. The AgxtD205N mutant rats showed undetectable alanine glyoxylate aminotransferase protein expression, developed hyperoxaluria at 1 month of age and exhibited severe renal calcium oxalate deposition after ethylene glycol challenge. This suggests our novel model is more relevant to the human disease than existing animal models. To test whether this model could be used for the development of innovative therapeutics, SaCas9 targeting hydroxyacid oxidase 1, responsible for metabolizing glycolate into glyoxylate, was delivered via adeno-associated viral vectors into newborn rats with primary hyperoxaluria type 1. This approach generated nearly 30% indels in the Hao1 gene in the liver, leading to 42% lower urine oxalate levels in the treated group than in the control group and preventing the rats with primary hyperoxaluria type 1 from undergoing severe nephrocalcinosis for at least 12 months. Thus, our results demonstrate that this partially humanized AgxtD205N rat strain is a high-performing model of primary hyperoxaluria type 1 for understanding pathology, and the development of novel therapeutics, such as reprogramming of the metabolic pathway through genome editing.
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Affiliation(s)
- Rui Zheng
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China
| | - Yueyan Li
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China
| | - Liren Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xiaoliang Fang
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China
| | - Junqi Zhang
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China
| | - Lei He
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China
| | - Lei Yang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Dali Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
| | - Hongquan Geng
- Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Children's Stone Treatment Center of the National Health and Family Planning Commission of the People's Republic of China, Shanghai, China.
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