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Journal of Medical Case Reports Oct 2023Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting...
BACKGROUND
Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation.
CASE PRESENTATIONS
We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents.
CONCLUSIONS
Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate.
Topics: Male; Child; Humans; Female; Adult; Hyperoxaluria, Primary; Kidney; Oxalates; Kidney Calculi; Renal Insufficiency
PubMed: 37803380
DOI: 10.1186/s13256-023-04129-z -
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 -
International Journal of Molecular... Mar 2024Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney... (Review)
Review
Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney stones are mineral deposits in the calyces or the pelvis, free or attached to the renal papillae. They contain crystals and organic components, and they are made when urine is supersaturated with minerals. Calcium-containing stones are the most common, with calcium oxalate as the main component of most stones. However, many of these form on a calcium phosphate matrix called Randall's plaque, which is found on the surface of the kidney papilla. The etiology is multifactorial, and the recurrence rate is as high as 50% within 5 years after the first stone onset. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more effective drugs. This review aims to understand the pathophysiology and the main molecular mechanisms known to date to prevent recurrences, which requires behavioral and nutritional interventions, as well as pharmacological treatments that are specific to the type of stone.
Topics: Humans; Kidney Calculi; Kidney Medulla; Calcium Oxalate; Minerals; Body Fluids
PubMed: 38474319
DOI: 10.3390/ijms25053075 -
Actas Urologicas Espanolas 2024Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes... (Review)
Review
Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes both surgical and pharmacologic interventions. Though surgery may be necessary under certain circumstances, pharmacologic treatment is a more affordable, readily available, and a less invasive option for patients. A comprehensive scoping review was conducted to summarize the available literature on the pharmacologic strategies for managing the predominant stone types including calcium oxalate, calcium phosphate, uric acid, struvite, and cystine stones. Central to these therapeutic approaches is the regulation of factors such as urine pH, stone crystallization, and patient metabolics that precipitate stone development and growth. This review highlights the pharmacological options available for treating each kidney stone type, emphasizing the importance of patient tailored medical management that should be considered by every physician.
Topics: Humans; Kidney Calculi; Calcium Oxalate; Uric Acid; Hydrogen-Ion Concentration
PubMed: 38043680
DOI: 10.1016/j.acuroe.2023.11.008 -
Scientific Reports Dec 2021The present work focuses on the revealing the patterns of copper oxalates formation under the influence of lichens and fungi by combination of the results of field...
The present work focuses on the revealing the patterns of copper oxalates formation under the influence of lichens and fungi by combination of the results of field studies and model experiments. These findings create the scientific basis for the potential microbial technology applications (ore enrichment, monuments conservation, environment bioremediation, etc.). Copper oxalate moolooite Cu(CO)·HO was discovered in saxicolous lichen Lecidea inops on the weathered chalcopyrite ore of Voronov Bor deposit (Central Karelia, Russia). Bioinspired syntheses of moolooite and wheatleyite NaCu(CO) 2HO with the participation of the microscopic fungi Aspergillus niger (active producer of oxalic acid) were carried out on weathered Cu-ore from the Voronov Bor deposit. It was shown that morphology of moolooite crystals is controlled both by the underlying rock and by the species composition of microorganisms. Iron ions (sourced from the underlying rock) in the crystallization medium inhibits the moolooite formation. The observed intensive dissolution of moolooite crystals are well explained by washing effect of the intratalline solutions which depends on repeatedly dehydration / rehydration cycles in the lichens. Joint interpretation of original and published data shows that moolooite along with other cooper oxalates are biominerals.
Topics: Aspergillus niger; Biochemical Phenomena; Biodegradation, Environmental; Copper; Crystallization; Fungi; Geology; Ions; Iron; Lichens; Microscopy, Electron, Scanning; Oxalates; Oxalic Acid; Sulfides; X-Ray Diffraction
PubMed: 34930985
DOI: 10.1038/s41598-021-03600-5 -
Molecules (Basel, Switzerland) Aug 2021The present study is focused on the effect of biofilm medium chemistry on oxalate crystallization and contributes to the study of the patterns of microbial...
The present study is focused on the effect of biofilm medium chemistry on oxalate crystallization and contributes to the study of the patterns of microbial biomineralization and the development of nature-like technologies, using the metabolism of microscopic fungi. Calcium oxalates (weddellite and whewellite in different ratios) were synthesized by chemical precipitation in a weakly acidic environment (pH = 4-6), as is typical for the stationary phase of micromycetes growth, with a ratio of Ca/CO = 4.0-5.5, at room temperature. Additives, which are common for biofilms on the surface of stone in an urban environment (citric, malic, succinic and fumaric acids; and K, Mg, Fe, Sr, SO, PO and CO ions), were added to the solutions. The resulting precipitates were studied via X-ray powder diffraction (XRPD), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDXS). It was revealed that organic acids, excreted by micromicetes, and some environmental ions, as well as their combinations, significantly affect the weddellite/whewellite ratio and the morphology of their phases (including the appearance of tetragonal prism faces of weddellite). The strongest unique effect leading to intensive crystallization of weddellite was only caused by the presence of citric acid additive in the medium. Minor changes in the composition of the additive components can lead to significant changes in the weddellite/whewellite ratio. The effect of the combination of additives on this ratio does not obey the law of additivity. The content of weddellite in the systems containing a representative set of both organic acids and environmental ions is ~20 wt%, which is in good agreement with natural systems.
Topics: Biofilms; Calcium Oxalate; Crystallization; Hydrogen-Ion Concentration
PubMed: 34443617
DOI: 10.3390/molecules26165030 -
Nature Communications Jun 2023Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown,...
Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.
Topics: Humans; Animals; Aconitate Hydratase; Caenorhabditis elegans; Oxaloacetic Acid; Oxaloacetates; Unfolded Protein Response; Mammals
PubMed: 37349299
DOI: 10.1038/s41467-023-39393-6 -
BMC Medicine Oct 2022Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive...
BACKGROUND
Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships.
METHODS
We examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9-11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%).
RESULTS
Overall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07-2.14; P-values <5.2×10). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82-0.84; P-value <5.2×10). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001).
CONCLUSIONS
The metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality.
Topics: Male; Humans; Chromatography, Liquid; beta Carotene; alpha-Tocopherol; Endocannabinoids; Finland; Cysteine; Fibrinopeptide B; Tandem Mass Spectrometry; Prostatic Neoplasms; Fatty Acids; Amino Acids; Choline; Glutamates; Phospholipids; Oxalates; Fatty Acids, Unsaturated; Lipoproteins, HDL; Cholesterol
PubMed: 36280842
DOI: 10.1186/s12916-022-02561-4 -
Zoological Research Nov 2023Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I (PH1), the most common and...
Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I (PH1), the most common and life-threatening type of primary hyperoxaluria. The compact Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) from the and (Cpf1) protein simplifies multiplex gene editing and allows for all-in-one adeno-associated virus (AAV) delivery. We hypothesized that the multiplex capabilities of the Cpf1 system could help minimize oxalate formation in PH1 by simultaneously targeting the hepatic hydroxyacid oxidase 1 ( ) and lactate dehydrogenase A ( ) genes. Study cohorts included treated PH1 rats ( rats injected with AAV-AsCpf1 at 7 days of age), phosphate-buffered saline (PBS)-injected PH1 rats, untreated PH1 rats, and age-matched wild-type (WT) rats. The most efficient and specific CRISPR RNA (crRNA) pairs targeting the rat and genes were initially screened . experiments demonstrated efficient genome editing of the and genes, primarily resulting in small deletions. This resulted in decreased transcription and translational expression of and . Treatment significantly reduced urine oxalate levels, reduced kidney damage, and alleviated nephrocalcinosis in rats with PH1. No liver toxicity, ex-liver genome editing, or obvious off-target effects were detected. We demonstrated the AAV-AsCpf1 system can target multiple genes and rescue the pathogenic phenotype in PH1, serving as a proof-of-concept for the development of multiplex genome editing-based gene therapy.
Topics: Animals; Rats; Gene Editing; Hyperoxaluria, Primary; Liver; Oxalates
PubMed: 37759334
DOI: 10.24272/j.issn.2095-8137.2022.495 -
Genetics in Medicine : Official Journal... Mar 2023Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for...
PURPOSE
Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.
METHODS
Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.
RESULTS
Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca uptake, demonstrating loss of function.
CONCLUSION
Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
Topics: Humans; Calcium Oxalate; Nephrolithiasis; Mutation, Missense; Sulfate Transporters; Receptors, Purinergic P2
PubMed: 36571463
DOI: 10.1016/j.gim.2022.11.019