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Cureus Mar 2022Nephrolithiasis (NL) and urolithiasis (UL) are usual reasons for hospitalization and presentation in pediatric outpatient departments and their incidence continues to...
Nephrolithiasis (NL) and urolithiasis (UL) are usual reasons for hospitalization and presentation in pediatric outpatient departments and their incidence continues to rise worldwide. In Morocco, a previous epidemiological study done in the Fez region between January 2003 and November 2013 reported a prevalence of 0.83% of childhood UL. In two studies, heritability accounted for almost half of all NL or nephrocalcinosis (NC) prevalence. Genetic factors must be considered in the etiological diagnosis of urinary lithiasis in Morocco since the frequency of consanguineous marriages is high. Hereditary tubular disorders, especially distal renal tubular acidosis (dRTA) and Dent disease, and metabolic disorders like idiopathic hypercalciuria and hyperoxaluria are the most common causes of medullary NC. Primary hyperoxaluria type 1 (PH1), which can generate an early onset of NC, and often chronic kidney disease (CKD) should always be considered and thoroughly diagnosed. The aim of this work was to establish a molecular diagnosis of PH1 and dRTA and, thus, to predict and explain the disease phenotype in a cohort of 44 Moroccan patients with NL and/or NC by analyzing the and genes that cause NL and/or NC when mutated. Disease phenotype was molecularly explained and solved in six of 44 individuals with NL and/or NC (13.6%). In the pediatric subgroup of individuals, a causative mutation in 16.2% was identified, whereas in the adult cohort no pathogenic mutation was detected. In our patients, PH1 was objectified in 67% of cases followed by dRTA in 33% of cases. We suggest that prompt detection and prophylactic treatment of UL are necessary to limit the risk of everlasting renal damage and thus prevent or delay the progression to CKD.
PubMed: 35505724
DOI: 10.7759/cureus.23616 -
Nephrology, Dialysis, Transplantation :... Jan 2022
Topics: Humans; Hyperoxaluria; Hyperoxaluria, Primary; Retina
PubMed: 32582926
DOI: 10.1093/ndt/gfaa101 -
Molecular Biology Reports Apr 2021Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated... (Review)
Review
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.
Topics: Ethnicity; Founder Effect; Gene Frequency; Humans; Hyperoxaluria, Primary; Oxo-Acid-Lyases; Polymorphism, Genetic
PubMed: 33948853
DOI: 10.1007/s11033-021-06380-3 -
Current Opinion in Nephrology and... Jul 2020Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly... (Review)
Review
PURPOSE OF REVIEW
Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly primary hyperoxaluria type I and II, threatening renal function. Ethylene glycol poisoning may induce the precipitation of calcium oxalate crystals in renal tubules, leading to acute renal failure. In both cases, oxalate results from glyoxylate transformation to oxalate in the liver, by lactate dehydrogenase (LDH) enzymes, especially the LDH-5 isoenzyme. The purpose of the review is to highlight LDH as a potential therapeutic target according to recent publications.
RECENT FINDINGS
Genetic therapy targeting LDH metabolism decreases urine oxalate excretion in rodents. Stiripentol is an antiepileptic drug that has been shown recently to inhibit neuronal LDH-5 isoenzyme. Stiripentol was hypothesized to reduce hepatic oxalate production and urine oxalate excretion. In vitro, stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol oral administration decreases urine oxalate excretion in rats and protects renal function and renal tissue against ethylene glycol intoxication and chronic calcium oxalate crystalline nephropathy.
SUMMARY
The use of stiripentol in-vitro and in-vivo highlights that targeting hepatic LDH by pharmacological or genetic tools may decrease oxalate synthesis, deserving clinical studies.
Topics: Dioxolanes; Humans; Hyperoxaluria; Hyperoxaluria, Primary; L-Lactate Dehydrogenase; Oxalic Acid
PubMed: 32452916
DOI: 10.1097/MNH.0000000000000621 -
Current Opinion in Urology Sep 2018To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis. (Review)
Review
PURPOSE OF REVIEW
To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis.
RECENT FINDINGS
Urolithiasis is related to a broad spectrum of congenital and acquired diseases and its management varies according to the stone type, underlying disease or recurrence rate, but it also changes according to recent findings and developments. As prevalence of urolithiasis is constantly increasing, identification of high-risk stone formers and early treatment is essential. Therefore, genetic evaluation like whole exome sequencing becomes a pertinent part of further diagnostics.
SUMMARY
Stone formation is a very heterogeneous pathomechanism. This prompt us to look at every patient individually particularly in high-risk patients, including stone and 24-h-urine analysis and additional diagnostic work-up based on stone type or underlying disease.
Topics: Acidosis, Renal Tubular; Adenine Phosphoribosyltransferase; Cystic Fibrosis; Cystinuria; Dent Disease; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperoxaluria, Primary; Hyperparathyroidism; Immobilization; Inflammatory Bowel Diseases; Lesch-Nyhan Syndrome; Metabolic Syndrome; Metabolism, Inborn Errors; Nephrocalcinosis; Polycystic Kidney Diseases; Risk Factors; Sarcoidosis; Spinal Cord Injuries; Urinary Bladder, Neurogenic; Urinary Tract Infections; Urolithiasis; Xanthine Dehydrogenase
PubMed: 29957682
DOI: 10.1097/MOU.0000000000000522 -
Revue Medicale de Liege Jul 2022Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate...
Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate transaminase (AGT). Oxalate is a poorly soluble molecule that binds calcium and deposits in the entire organism leading to oxalosis. Its elimination is mainly carried out by kidneys. Hence the first manifestations are frequently of urinary concern and whitout any early care, progression of the disease to end-stage renal failure cannot be avoided. The only etiological treatment has long been combined liver-kidney transplantation because it restaures enzymatic function and replaces pathological kidneys. However, for a few years now, numerous studies are carried out on this subject and promising results have already been published with a new drug, lumasiran. From a clinical case, we describe the different options for the therapeutic management of primary hyperoxaluria type 1.
Topics: Humans; Hyperoxaluria, Primary; Nephrocalcinosis; Oxalates; RNA, Small Interfering
PubMed: 35924494
DOI: No ID Found -
World Journal of Urology Aug 2023The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3).
PURPOSE
The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3).
METHODS
The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards.
RESULTS
A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4-7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58-1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease.
CONCLUSIONS
A hotspot mutation, potential hotspot mutation and genotype-phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.
Topics: Humans; East Asian People; Genotype; Hyperoxaluria, Primary; Mutation; Phenotype; Retrospective Studies; Oxo-Acid-Lyases
PubMed: 37318624
DOI: 10.1007/s00345-023-04461-5 -
International Journal of Surgery... Feb 2023
Topics: Humans; Hyperoxaluria, Primary; RNA, Small Interfering; Hyperoxaluria
PubMed: 36799810
DOI: 10.1097/JS9.0000000000000143 -
Urolithiasis Mar 2023In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic...
In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic testing is the most definitive and preferred diagnostic method, quantification of these metabolites is important for the diagnosis and evaluation of potential therapeutic interventions. Current metabolite quantification methods use laborious, technically highly complex and expensive liquid, gas or ion chromatography tandem mass spectrometry, which are available only in selected laboratories worldwide. Incubation of ortho-aminobenzaldehyde (oABA) with glyoxylate generated from glycolate using recombinant mouse glycolate oxidase (GO) and glycine leads to the formation of a stable dihydroquinazoline double aromatic ring chromophore with specific peak absorption at 440 nm. The urinary limit of detection and estimated limit of quantification derived from eight standard curves were 14.3 and 28.7 µmol glycolate per mmol creatinine, respectively. High concentrations of oxalate, lactate and L-glycerate do not interfere in this assay format. The correlation coefficient between the absorption and an ion chromatography tandem mass spectrometry method is 93% with a p value < 0.00001. The Bland-Altmann plot indicates acceptable agreement between the two methods. The glycolate quantification method using conversion of glycolate via recombinant mouse GO and fusion of oABA and glycine with glyoxylate is fast, simple, robust and inexpensive. Furthermore this method might be readily implemented into routine clinical diagnostic laboratories for glycolate measurements in primary hyperoxaluria type 1.
Topics: Mice; Animals; Hyperoxaluria, Primary; Oxalates; Glycolates; Glyoxylates; Glycine; Hyperoxaluria
PubMed: 36920530
DOI: 10.1007/s00240-023-01426-6 -
American Journal of Physiology. Renal... Mar 2021Primary hyperoxaluria type 1 (PH1) is a severe inherited disorder caused by a genetic defect in alanine-glyoxylate aminotransferase (), which results in recurrent...
Primary hyperoxaluria type 1 (PH1) is a severe inherited disorder caused by a genetic defect in alanine-glyoxylate aminotransferase (), which results in recurrent urolithiasis and renal failure. Animal models that precisely reflect human PH1 phenotypes are lacking. We aimed to develop a novel PH1 rat model and study the mechanisms involved in PH1 deterioration. One cell stage Sprague-Dawley embryos were injected with the CRISPR/Cas9 system to introduce a Q84X mutation in . Liver tissues were harvested to determine expression. Urine oxalate, crystals, and electrolyte levels in and wild-type (WT) littermates were evaluated. Kidney tissues were used for Pizzolato staining and kidney injury evaluation. Data showed that mRNA and protein were absent in rats. At 4 and 24 wk, rats displayed 2.1- and 2.9-fold higher urinary oxalate levels, respectively, compared with WT littermates. As a result, calcium oxalate (CaOx) crystals in urine were revealed in all rats but in none of the WT rats. We also observed bladder stones in 36.4% of rats, of which 44.4% had renal CaOx deposition. Moreover, the elevated serum urea and creatinine levels indicated the impaired renal function in rats. Further investigation revealed significantly increased expression of inflammation-, necroptosis-, and fibrosis-related genes in the kidneys of rats with spontaneous renal CaOx deposition, indicating that these pathways are involved in PH1 deterioration. Collectively, these results suggest that this rat model has broad applicability in mechanistic studies and innovative therapeutics development for PH1 and other kidney stone diseases. Primary hyperoxaluria type 1 is a severe inherited disorder that results in recurrent urolithiasis and renal failure. We generated an alanine-glyoxylate aminotransferase () nonsense mutant rat model that displayed an early onset of hyperoxaluria, spontaneous renal CaOx precipitation, bladder stone, and kidney injuries. Our results suggest an interaction of renal CaOx crystals with the activation of inflammation-, fibrosis-, and necroptosis-related pathways. In all, the rat strain has broad applicability in mechanistic studies and the development of innovative therapeutics.
Topics: Animals; Calcium Oxalate; Hyperoxaluria; Kidney; Kidney Calculi; Mutation; Nephrocalcinosis; Oxalates; Rats; Renal Insufficiency; Transaminases
PubMed: 33491567
DOI: 10.1152/ajprenal.00514.2020