{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:45:31Z","timestamp":1790196331954,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"Supplement_1","license":[{"start":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T00:00:00Z","timestamp":1652745600000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006400","name":"Alnylam Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006400","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the AGXT gene that encodes the hepatic peroxisomal enzyme alanine\u2013glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients\u2019 pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase\/hydroxypyruvate reductase (GR\/HPR), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase (HOGA1) and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease\/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential \u2018game changer\u2019 in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and\/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.<\/jats:p>","DOI":"10.1093\/ckj\/sfab245","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T20:12:48Z","timestamp":1638562368000},"page":"i17-i22","source":"Crossref","is-referenced-by-count":39,"title":["Primary hyperoxaluria type 1: novel therapies at a glance"],"prefix":"10.1093","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0578-2529","authenticated-orcid":false,"given":"Justine","family":"Bacchetta","sequence":"first","affiliation":[{"name":"Service de N\u00e9phrologie, Rhumatologie et Dermatologie P\u00e9diatriques, Centre de R\u00e9f\u00e9rence des Maladies R\u00e9nales Rares N\u00e9phrogones, Fili\u00e8res Maladies Rares ORKID et ERK-Net, CHU de Lyon, Bron, France"},{"name":"INSERM 1033, Facult\u00e9 de M\u00e9decine Lyon Est, Universit\u00e9 Claude Bernard Lyon1, Lyon, France"},{"name":"Facult\u00e9 de M\u00e9decine Lyon Est, Universit\u00e9 Claude Bernard Lyon 1, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Lieske","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA"},{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"2022051716285360600_bib1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1056\/NEJMra1301564","article-title":"Primary hyperoxaluria","volume":"369","author":"Cochat","year":"2013","journal-title":"N Engl J Med"},{"key":"2022051716285360600_bib2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/ki.2009.435","article-title":"Genotype\u2013phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome","volume":"77","author":"Harambat","year":"2010","journal-title":"Kidney Int"},{"key":"2022051716285360600_bib3","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/ki.2009.237","article-title":"Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1","volume":"76","author":"Fargue","year":"2009","journal-title":"Kidney Int"},{"key":"2022051716285360600_bib4","first-page":"1729","article-title":"Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment","volume":"27","author":"Cochat","year":"2012"},{"key":"2022051716285360600_bib5","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"2022051716285360600_bib6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N Engl J Med"},{"key":"2022051716285360600_bib7","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJMoa1913805","article-title":"Inclisiran for the treatment of heterozygous familial hypercholesterolemia","volume":"382","author":"Raal","year":"2020","journal-title":"N Engl J Med"},{"key":"2022051716285360600_bib8","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1056\/NEJMoa1913147","article-title":"Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria","volume":"382","author":"Balwani","year":"2020","journal-title":"N Engl J Med"},{"key":"2022051716285360600_bib9","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1056\/NEJMoa1615758","article-title":"Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol","volume":"376","author":"Ray","year":"2017","journal-title":"N Engl J Med"},{"key":"2022051716285360600_bib10","article-title":"The nonclinical disposition and PK\/PD properties of Galnac-conjugated siRNA are highly predictable and build confidence in translation to man. 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