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Urolithiasis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Primary hyperoxaluriaAutosomal recessive inheritance.Type 1: Mutation AGXT gene (chromosome 2q)Deficiency of hepatic alanine-glycoxylate aminotransferase (AGT).Glycoxylate to glycolate conversion failure.Type 2: Mutation GRHPR gene (chromosome 9q)Deficiency of glycoxylate and hydroxypyruvate reductase (GRHPR).Glycoxylate to glycolate conversion failure.Type 3: Mutation HOGA1 gene (chromosome 10q)Deficiency of 4-hydroxy-2-oxoglutarate –(HOGA).Failure of HOGA break down.Increased glycoxylate build up → oxidation into oxalic, glycolic, glyoxylic acids50% have end-stage renal failure by early adulthood.
Lumasiran: expanding the treatment options for patients with primary hyperoxaluria type 1
Published in Expert Opinion on Orphan Drugs, 2021
Glyoxylate is generated during glycine and hydroxyproline catabolism that occur in the peroxisome and mitochondrion, respectively. In humans, glycolate is an important precursor [26], with peroxisomal glyoxylate produced from the activity of glycolate oxidase (GO, a flavin mononucleotide-dependent-α-hydroxy acid oxidase encoded by the HAO1 gene). AGT, a pyridoxal 5ʹ phosphate dependent enzyme, catalyzes the metabolism of peroxisomal glyoxylate by transferring the amino group from alanine to glyoxylate to produce pyruvate and glycine. Alternatively, excess peroxisomal glyoxylate is transported to the cytoplasm, where it is either reduced to glycolate by glyoxylate reductase hydroxypyruvate reductase (GRHPR) or oxidized to oxalate by L-lactate dehydrogenase (LDH). Oxalate cannot be further metabolized and is excreted in urine.
Established and recent developments in the pharmacological management of urolithiasis: an overview of the current treatment armamentarium
Published in Expert Opinion on Pharmacotherapy, 2020
Mohamed Abou Chakra, Athanasios E. Dellis, Athanasios G. Papatsoris, Mohamad Moussa
The primary hyperoxalurias type I–III (PH I–III) is relatively a rare autosomal recessive disorder of glyoxylate metabolism, resulting in markedly increased endogenous oxalate synthesis. PH1 is the most common and severe form of PH. It accounts for approximately 80% of the cases of PH and is caused by a defect in the vitamin B6 dependent hepatic peroxisomal enzyme, Alanine Glyoxalate Aminotransferase (AGT) [88]. PH2 represents about 10% of the patients with PH. A dysfunction of the enzyme glyoxalate/hydroxypyruvate reductase (GRHPR) occurs secondary to a mutation in the GRHPR gene located on chromosome 10 [89]. PH3 arises from mutations in the HOGA1 gene which encodes the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase [90]. SH is usually a consequence of malabsorptive states, including inflammatory bowel disease, small bowel or gastric surgery, chronic pancreatitis, and systemic sclerosis with bowel involvement [91]. Enteric hyperoxaluria is typically seen in patients suffering from gastrointestinal disorders such as short bowel syndrome, chronic inflammatory bowel disease, celiac disease, secondary pancreatic insufficiency, and alterations in intestinal oxalate degrading microorganisms(Oxalobacter formigens) [91].
Why is diagnosis, investigation, and improved management of kidney stone disease important? Non-pharmacological and pharmacological treatments for nephrolithiasis
Published in Expert Review of Clinical Pharmacology, 2022
Viola D’Ambrosio, Shabbir Moochhala, Robert J Unwin, Pietro Manuel Ferraro
But what is new or on the horizon? Sadly, not much when it comes to the treatment of the more common calcium oxalate and phosphate stone types (see Table 2). In contrast, novel treatments have been developed for patients with primary hyperoxaluria, one of which may have broader value in renal stone disease. Primary hyperoxaluria (PH) is a rare (1 in 150,000), but potentially devastating, group of recessive genetic disorders associated with increased oxalate production and excretion causing recurrent renal stones (and in severe cases renal failure), and resulting from enzyme deficiencies involved in glyoxylate metabolism (see Figure 1). Depending on the gene mutations, PH is classified as PH types 1, 2 and 3. PH1 is the more severe form and accounts for ca. 70% of cases and is due to mutations in alanine-glyoxylate aminotransferase (AGT), a peroxisomal enzyme found in the liver that converts glyoxylate to glycine; PH2 and PH3 account for ca. 10% of cases and are due to mutations in glyoxylate and hydroxypyruvate reductase (GRHPR) and 4-hydroxy-2-oxoglutarate aldolase (HOGA), respectively [71]. There was no effective treatment for PH1, other than strategies to limit dietary oxalate intake and absorption from the gut (see earlier), to maintain a high fluid intake, vitamin B6 supplementation in some responsive patients, and eventually combined liver and kidney transplantation in those developing renal failure, until the novel approach of inhibiting another liver peroxisomal enzyme, glyoxylate oxidase (GO), which converts glyoxylate to oxalate (Figure 1). This was achieved first in preclinical studies using RNA interference (siRNA) against GO, and was followed by a recent successful and promising 6-month clinical trial in 39 patients given monthly doses of siRNA (Lumasiran) by subcutaneous injection, which led to a significant and sustained reduction in oxalate excretion [72].