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Pediatric Nephrology (Berlin, Germany) Jan 2024Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis,... (Observational Study)
Observational Study
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1.
METHODS
For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6).
RESULTS
Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups.
CONCLUSIONS
Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Humans; Child; Adolescent; Child, Preschool; Oxalates; Nephrocalcinosis; Hyperoxaluria, Primary; Kidney Calculi
PubMed: 37458799
DOI: 10.1007/s00467-023-06074-x -
BMC Nephrology Jul 2023The kidney is particularly vulnerable to toxins due to its abundant blood supply, active tubular reabsorption, and medullary interstitial concentration. Currently,... (Review)
Review
BACKGROUND
The kidney is particularly vulnerable to toxins due to its abundant blood supply, active tubular reabsorption, and medullary interstitial concentration. Currently, calcium phosphate-induced and calcium oxalate-induced nephropathies are the most common crystalline nephropathies. Hyperoxaluria may lead to kidney stones and progressive kidney disease due to calcium oxalate deposition leading to oxalate nephropathy. Hyperoxaluria can be primary or secondary. Primary hyperoxaluria is an autosomal recessive disease that usually develops in childhood, whereas secondary hyperoxaluria is observed following excessive oxalate intake or reduced excretion, with no difference in age of onset. Oxalate nephropathy may be overlooked, and the diagnosis is often delayed or missed owning to the physician's inadequate awareness of its etiology and pathogenesis. Herein, we discuss the pathogenesis of hyperoxaluria with two case reports, and our report may be helpful to make appropriate treatment plans in clinical settings in the future.
CASE PRESENTATION
We report two cases of acute kidney injury, which were considered to be due to oxalate nephropathy in the setting of purslane (portulaca oleracea) ingestion. The two patients were elderly and presented with oliguria, nausea, vomiting, and clinical manifestations of acute kidney injury requiring renal replacement therapy. One patient underwent an ultrasound-guided renal biopsy, which showed acute tubulointerstitial injury and partial tubular oxalate deposition. Both patients underwent hemodialysis and were discharged following improvement in creatinine levels.
CONCLUSIONS
Our report illustrates two cases of acute oxalate nephropathy in the setting of high dietary consumption of purslane. If a renal biopsy shows calcium oxalate crystals and acute tubular injury, oxalate nephropathy should be considered and the secondary causes of hyperoxaluria should be eliminated.
Topics: Humans; Aged; Portulaca; Calcium Oxalate; Hyperoxaluria; Oxalates; Acute Kidney Injury; Acute Disease
PubMed: 37443012
DOI: 10.1186/s12882-023-03236-9 -
Kidney International Reports Jul 2023
PubMed: 37441487
DOI: 10.1016/j.ekir.2023.03.013 -
International Journal of Molecular... Jun 2023Human lactate dehydrogenase (LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, LDHA and LDHB are the predominant ones. In the...
Human lactate dehydrogenase (LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, LDHA and LDHB are the predominant ones. In the last few years, LDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. LDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new LDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (-) by reaction between flavylium salts (-) and several nucleophiles (-). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC values lower than 10 µM against LDHA and better activity than our previously reported compound . In order to know the selectivity of the synthesized compounds against LDHA, their LDHB inhibitory activities were also measured. In particular, compounds , , , and have shown the lowest IC values against LDHA (3.6-12.0 µM) and the highest selectivity rate (>25). Structure-activity relationships have been deduced. Kinetic studies using a Lineweaver-Burk double-reciprocal plot have indicated that both enantiomers of and behave as noncompetitive inhibitors on LDHA enzyme.
Topics: Humans; Kinetics; Biological Products; Structure-Activity Relationship; Alkanes; Molecular Docking Simulation; Molecular Structure
PubMed: 37373073
DOI: 10.3390/ijms24129925 -
Journal of Nephrology Jul 2023Primary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive...
Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria.
BACKGROUND
Primary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase.
METHODS
A survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group "Rare Forms of Nephrolithiasis and Nephrocalcinosis" of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy.
RESULTS
Forty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants.
CONCLUSIONS
The data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.
Topics: Humans; Nephrocalcinosis; Hyperoxaluria, Primary; Nephrologists; Nephrology; Oxalates; Kidney Calculi
PubMed: 37358729
DOI: 10.1007/s40620-023-01693-x -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Apr 2023Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which... (Review)
Review
Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.
Topics: Infant; Humans; Hypercalciuria; Kidney Calculi; Urolithiasis; Nephrocalcinosis; Metabolism, Inborn Errors
PubMed: 37283101
DOI: 10.3724/zdxbyxb-2022-0698 -
Urolithiasis Jun 2023
PubMed: 37273015
DOI: 10.1007/s00240-023-01455-1 -
Antioxidants (Basel, Switzerland) Apr 2023The clinical manifestation of primary hyperoxaluria includes hyperoxaluria and recurrent urinary calculi. In this study, an oxidative damage model was constructed based...
The clinical manifestation of primary hyperoxaluria includes hyperoxaluria and recurrent urinary calculi. In this study, an oxidative damage model was constructed based on oxalate damage to the human renal proximal tubular epithelial cells (HK-2), and a comparative study was carried out on four different sulfated levels of polysaccharides (UPP0, UPP1, UPP2, and UPP3 with sulfate group [-OSO] contents of 1.59%, 6.03%, 20.83%, and 36.39%, respectively) on the repair of oxidatively damaged HK-2 cells. The results showed that after repair by UPPs, cell viability was enhanced, healing ability was improved, the intracellular superoxide dismutase level and mitochondrial membrane potential were increased, malondialdehyde, reactive oxygen species, and intracellular Ca levels were reduced, cellular autophagy was reduced; lysosomal integrity was improved, and cytoskeleton and cell morphology were restored. The ability of repaired cells to endocytose nano-calcium oxalate dihydrate crystals (nano-COD) was enhanced. The activity of UPPs was closely related to their -OSO content. A too high or too low -OSO content was not conducive to polysaccharide activity, and only UPP2 exhibited the best cell repair ability and strongest ability to promote the cell endocytosis of crystals. UPP2 may be used as a potential agent to inhibit CaOx crystal deposition caused by high oxalate concentration.
PubMed: 37237881
DOI: 10.3390/antiox12051015 -
Clinical Case Reports May 2023Genetic counseling and genetic screening for hyperoxaluria should be recommended for children with urinary lithiasis for early management to avoid progression to...
KEY CLINICAL MESSAGE
Genetic counseling and genetic screening for hyperoxaluria should be recommended for children with urinary lithiasis for early management to avoid progression to oxalosis especially if there is a family history of lithiasis.
UNLABELLED
Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT) resulting in overproduction of calcium oxalates. In its later stage, a systemic deposit of calcium oxalates is observed. We present the case of an 8-year-old girl with exceptional neurological involvement secondary to this disease.
PubMed: 37143464
DOI: 10.1002/ccr3.7241 -
Frontiers in Genetics 2023Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to...
Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype. Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed. We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T > G and c.823_824del) in gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in gene, respectively. A possible PH3 hotspot variant c.769T > G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A > C may be identified as potentially vitamin B6-sensitive genotypes. In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases.
PubMed: 37139236
DOI: 10.3389/fgene.2023.1124745