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Primary hyperoxaluria.

ABSTRACT: Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. Diagnosis is often delayed and is based on clinical and sonographic findings, urinary oxalate assessment, DNA analysis, and, if necessary, direct AGT activity measurement in liver biopsy tissue. Early initiation of conservative treatment, including high fluid intake, inhibitors of calcium oxalate crystallization, and pyridoxine in responsive cases, can help to maintain renal function in compliant subjects. In end-stage renal disease patients, the best outcomes have been achieved with combined liver-kidney transplantation which corrects the enzyme defect.

SUBMITTER: Harambat J

PROVIDER: S-EPMC3124893 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Primary hyperoxaluria.

Harambat Jérôme J Fargue Sonia S Bacchetta Justine J Acquaviva Cécile C Cochat Pierre P

International journal of nephrology 20110616

Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates lea ...[more]

PMID: 21748001

Similar Datasets

Improving Treatment Options for Primary Hyperoxaluria.

Project description: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.

| S-EPMC9329168 | biostudies-literature

New therapeutics for primary hyperoxaluria type 1.

Project description:Purpose of reviewPrimary 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 findingsUse 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.SummaryNovel 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.

| S-EPMC9232952 | biostudies-literature

Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria.

Project description:Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known.Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection.Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3.Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.

| S-EPMC6054332 | biostudies-literature

Is stiripentol truly effective for treating primary hyperoxaluria?

Project description: Not available

| S-EPMC7857785 | biostudies-literature

Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria.

Project description:Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1.Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements.Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1? (MIP-1?) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1?, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005).PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.

| S-EPMC4904731 | biostudies-literature

Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients.

Project description:BackgroundPrimary 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 .MethodsEight 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.ResultsTotal 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.ConclusionsThis 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.

| S-EPMC8638398 | biostudies-literature

Mutations in DHDPSL are responsible for primary hyperoxaluria type III.

Project description:Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.

| S-EPMC2933339 | biostudies-literature

4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3.

Project description:Primary hyperoxaluria type 3 (PH3) is a recently identified inborn error of 4-hydroxyproline metabolism causing kidney stone disease. Diagnosis to date has relied on mutation detection. The excretion of 4-hydroxyglutamate (4OHGlu) was investigated in controls and a cohort of nine patients with PH3 and their parents using flow injection tandem mass spectrometry. 4OHGlu was stable in acidified urine samples and was not influenced by diet. Its measurement was readily incorporated into an existing multi-analyte panel for comprehensive screening for inborn errors of metabolism. There was a steady decline with age in 4OHGlu levels, expressed as ?mol/mmol of creatinine, in controls. Levels in patients with PH3 ranged from 6.5 to 98 ?mol/mmol of creatinine and were all significantly increased when compared to age-matched controls (<4.2). Levels in eight parents (obligatory carriers of the corresponding mutation) were moderately, but significantly increased, ranging from 0.6 to 2.5 (age-matched controls <1.4, p?=?0.03). Urine 4OHGlu screening was used to prospectively diagnose PH3 in an 18-month-old boy with calcium oxalate kidney stone disease associated with hyperoxaluria. 4OHGlu was also increased in a stored newborn screening dried blood spot sample from this child (37 ?mol/L, controls <2.53). 4OHGlu testing provides a robust and high-throughput biochemical screen for PH3.

| S-EPMC4270872 | biostudies-literature

Common mutation underlying primary hyperoxaluria type1 in three Indian children.

Project description:Primary hyperoxaluria is an autosomal recessive disorder caused by deficiency of alanine-glyoxylate aminotransferase, which is encoded by the AGXT gene. We report three Indian children with primary hyperoxaluria type1 having a common mutation in this gene. All patients had evidence of chronic kidney disease at the time of diagnosis, with subsequent progression to end-stage renal disease. The detection of an identical mutation in the AGXT gene suggests that specific genetic screening for this mutation may be useful when considering the diagnosis of primary hyperoxaluria type1.

| S-EPMC3573489 | biostudies-literature

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.

Project description:Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

| S-EPMC8274068 | biostudies-literature

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