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Urologia Internationalis 1997
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Contributions To Nephrology 1997
Review
Topics: Calcium Oxalate; Glyoxylates; Humans; Hyperoxaluria, Primary; Liver; Microbodies; Mutation; Oxalates; Oxalic Acid; Transaminases
PubMed: 9399058
DOI: 10.1159/000059893 -
The New England Journal of Medicine Apr 2017
Topics: Child, Preschool; Hematuria; Humans; Hyperoxaluria, Primary; Kidney Calculi; Male; Oxalates; Radiography, Abdominal; Transaminases
PubMed: 28402768
DOI: 10.1056/NEJMicm1609986 -
Kidney International Jan 2023Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal... (Randomized Controlled Trial)
Randomized Controlled Trial
Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.
Topics: Humans; Hyperoxaluria; Hyperoxaluria, Primary; Oxalates; RNA Interference; Double-Blind Method
PubMed: 36007597
DOI: 10.1016/j.kint.2022.07.025 -
Journal of Inherited Metabolic Disease Jul 2017During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches.... (Review)
Review
During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches. The availability of PH mouse models has facilitated preclinical studies testing innovative treatments. PHs are autosomal recessive diseases where the enzymatic deficit plays a central pathogenic role. Thus, molecular therapies aimed at restoring such deficit or limiting the consequences of the metabolic derangement could be envisioned, keeping in mind the specific challenges posed by the cell-autonomous nature of the deficiency. Various molecular approaches like enzyme replacement, substrate reduction, pharmacologic chaperones, and gene and cell therapies have been explored in cells and mouse models of disease. Some of these proof-of-concept studies have paved the way to current clinical trials on PH type 1, raising hopes that much needed treatments will become available for this severe inborn error of metabolism.
Topics: Animals; Calcium Oxalate; Disease Models, Animal; Enzyme Replacement Therapy; Female; Genetic Therapy; Humans; Hyperoxaluria, Primary; Kidney; Liver; Male; Mice; Mice, Knockout; Molecular Chaperones; Molecular Targeted Therapy
PubMed: 28425073
DOI: 10.1007/s10545-017-0045-3 -
Expert Opinion on Emerging Drugs Dec 2018: Currently, three types of primary hyperoxaluria (PH I-III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease... (Review)
Review
: Currently, three types of primary hyperoxaluria (PH I-III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease hallmark is an increased endogenous oxalate production and thus massively elevated urinary excretion of oxalate and other type-specific metabolites. Hyperoxaluria induces the formation of calcium-oxalate kidney stones and/or nephrocalcinosis. In addition to that, a chronic inflammasome activation by hyperoxaluria per se, often leads to an early deterioration of kidney function, regularly resulting in end-stage renal disease (ESRD) at least in patients with type I PH. Except for vitamin B6 treatment in PH I, therapeutic regimen nowadays consists only of supportive measures, like significantly increased fluid intake and medication increasing the urinary solubility like alkaline citrate. : Disease burden can be severe, and both clinicians and scientist are eager in finding new therapeutic approaches. The currently ongoing clinical studies and promising research in this field are reported in this paper. To present a complete overview, we searched electronic databases, like Clinical trial gov, National Center for Biotechnology Information PubMed, congress reports, press releases and personal information acquired at congresses and conventions. Searches were conducted using the following medical headings: (primary) hyperoxaluria, PH, therapy, treatment and research. : There is light on the horizon that new treatment options will be available in due time, as there are several promising therapeutic agents currently under investigation, some being at the first levels of drug development, but some already in ongoing clinical trials (phase I-III).
Topics: Animals; Carboxy-Lyases; Humans; Hyperoxaluria, Primary; Oxalobacter formigenes; RNA Interference
PubMed: 30540923
DOI: 10.1080/14728214.2018.1552940 -
Nature Reviews. Urology Mar 2022Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease.... (Review)
Review
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.
Topics: Female; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Oxalates
PubMed: 34880452
DOI: 10.1038/s41585-021-00543-4 -
European Journal of Pediatrics May 1990Primary hyperoxaluria type I is a metabolic disorder caused by the deficiency of the peroxisomal alanine:glyoxylate aminotransferase. The disease is inherited as an... (Review)
Review
Primary hyperoxaluria type I is a metabolic disorder caused by the deficiency of the peroxisomal alanine:glyoxylate aminotransferase. The disease is inherited as an autosomal recessive trait. The clinical course is outlined based on data from 330 published cases. Diagnostic cornerstones are clinical parameters, urinary excretion of oxalate and glycolate, and the determination of enzyme activity in liver tissue. Principles of conservative treatment, e.g. volume load and pyridoxine substitution, are described as well as experience with different modes of dialysis and transplantation. Kidney transplantation is associated with a high rate of recurrence of the original disease despite excellent management resulting in many instances in early graft loss. Liver transplantation offers the possibility to correct the metabolic defect and to prevent the progression of crystal deposition in the body.
Topics: Age Factors; Alanine Transaminase; Child; Combined Modality Therapy; Female; Genes, Recessive; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Transplantation; Pyridoxine; Renal Dialysis; Transaminases
PubMed: 2189732
DOI: 10.1007/BF01957682 -
European Journal of Pediatrics Jul 1997Primary hyperoxaluria type 2 (PH2) is a rare disease with only 24 patients reported in the literature so far. It should be considered in any patient presenting with... (Review)
Review
UNLABELLED
Primary hyperoxaluria type 2 (PH2) is a rare disease with only 24 patients reported in the literature so far. It should be considered in any patient presenting with urolithiasis or nephrocalcinosis due to hyperoxaluria. The metabolic defect is deficiency of D-glycerate dehydrogenase/glyoxylate reductase leading to characteristic hyperoxaluria and excretion of L-glycerate, the cornerstone of diagnosis of PH 2. Although development of terminal renal failure seems to be less prevalent than in PH 1, recent reports indicate that chronic as well as terminal renal insufficiency may occur. Therefore specific therapeutic measures should aim at reduction of urinary calcium oxalate saturation by potassium citrate or pyrophosphate to reduce the incidence of nephrolithiasis and nephrocalcinosis and thus improve renal survival. Secondary complications (obstruction, urinary tract infections and pyelonephritis) must be avoided. In patients with terminal renal failure isolated renal transplantation seems to carry a high risk of disease recurrence.
CONCLUSION
PH 2 is a rare but important cause of urolithiasis and nephrocalcinosis; long-term follow up is necessary, since the renal prognosis may be worse than previously anticipated.
Topics: Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Nephrocalcinosis; Prognosis; Urinary Calculi
PubMed: 9243228
DOI: 10.1007/s004310050649 -
American Journal of Kidney Diseases :... Feb 2023
Topics: Humans; Hyperoxaluria, Primary; Hyperoxaluria; Oxalates
PubMed: 36184293
DOI: 10.1053/j.ajkd.2022.08.005