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Genes Aug 2023Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet,... (Review)
Review
Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
Topics: Humans; Oxalates; Diabetes Mellitus, Type 2; Hyperoxaluria, Primary; Kidney; Nephrolithiasis; Hypertension
PubMed: 37761859
DOI: 10.3390/genes14091719 -
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 -
Nephrology, Dialysis, Transplantation :... Jan 2024
Topics: Adult; Humans; Renal Dialysis; Hyperoxaluria, Primary; Oxalates; Hyperoxaluria
PubMed: 37708050
DOI: 10.1093/ndt/gfad184 -
Cureus Jul 2023Primary hyperoxaluria (PH) is a rare genetic condition that disrupts the normal process of glyoxylate metabolism, resulting in an overproduction of oxalate. This...
Primary hyperoxaluria (PH) is a rare genetic condition that disrupts the normal process of glyoxylate metabolism, resulting in an overproduction of oxalate. This excessive oxalate production leads to the accumulation of calcium oxalate (known as oxalosis) throughout various organs in the body. The urinary tract, specifically the renal parenchyma, is the first location where the deposition of calcium oxalate begins in PH. These deposits are responsible for nephrocalcinosis and tubule‑interstitial nephritis which leads to end‑stage renal failure. This is then followed by the accumulation of oxalate in other organs including the bone marrow. Herein, we report the case of a 22-year-old male patient who presented with bicytopenia; he had a history of end-stage renal disease preceded by recurrent urolithiasis and nephrolithiasis episodes since the age of 3 years. A bone marrow biopsy was performed for evaluation of the bicytopenia which led to the diagnosis of PH.
PubMed: 37637636
DOI: 10.7759/cureus.42469 -
Cureus Jul 2023Oxalate nephropathy represents a frequently overlooked etiology of renal failure, characterized by the deposition of calcium oxalate crystals within the renal...
Oxalate nephropathy represents a frequently overlooked etiology of renal failure, characterized by the deposition of calcium oxalate crystals within the renal parenchyma. This progressive form of kidney disease is marked by a significant increase in serum creatinine (Cr) level accompanied by evidence of oxalate crystal deposition on renal biopsy causing tubular obstruction and tubular injury leading to fibrosis. In all instances of oxalate nephropathy, examination of stones consistently exhibits multiple birefringent calcium oxalate crystals under polarized light. This case report details the clinical course of a patient who initially presented with progressively worsening renal function and ultimately developed end-stage kidney disease (ESKD) as a consequence of idiopathic hyperoxaluria.
PubMed: 37621792
DOI: 10.7759/cureus.42402 -
Biochimica Et Biophysica Acta.... Jan 2024N-propargylglycine prevents 4-hydroxyproline catabolism in mouse liver and kidney. N-propargylglycine is a novel suicide inhibitor of PRODH2 and induces mitochondrial...
N-propargylglycine prevents 4-hydroxyproline catabolism in mouse liver and kidney. N-propargylglycine is a novel suicide inhibitor of PRODH2 and induces mitochondrial degradation of PRODH2. PRODH2 is selectively expressed in liver and kidney and contributes to primary hyperoxaluria (PH). Preclinical evaluation of N-propargylglycine efficacy as a new PH therapeutic is warranted.
Topics: Animals; Mice; Alkynes; Glycine; Hyperoxaluria; Kidney
PubMed: 37586438
DOI: 10.1016/j.bbadis.2023.166848 -
Orphanet Journal of Rare Diseases Aug 2023Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish... (Review)
Review
Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.
Topics: Humans; Adult; Chondrocalcinosis; Gout; Joint Diseases; Metabolism, Inborn Errors; Hepatolenticular Degeneration
PubMed: 37563694
DOI: 10.1186/s13023-023-02810-6 -
International Journal of Nephrology 2023Primary hyperoxaluria type 1 (PH1) is a rare and inherited condition of urolithiasis. The aim of our study was to analyze clinical, paraclinical, and evolutionary...
INTRODUCTION
Primary hyperoxaluria type 1 (PH1) is a rare and inherited condition of urolithiasis. The aim of our study was to analyze clinical, paraclinical, and evolutionary aspects of PH1 in adult patients in our Nephrology department.
METHODS
We conducted a retrospective single-center study between 1990 and 2021. We collected patients followed for PH1 confirmed by genetic study and/or histopathological features of renal biopsy and morphoconstitutional analysis of the calculi.
RESULTS
There were 25 patients with a gender ratio of 1.78. The median age at onset of symptoms was 18 years. A delay in diagnosis more than 10 years was noted in 13 cases. The genetic study found the I244T mutation in 17 cases and 33-34 InsC in 4 cases. A kidney biopsy was performed in 5 cases, on a native kidney in 4 cases and on a graft biopsy in one case. The analysis of calculi was done in 10 cases showing type Ic in 2 cases. After a median follow-up of 13 years (1 year-42 years), 14 patients progressed to end-stage chronic renal failure (ESRD). The univariate study demonstrated a remarkable association with progression to ESRD in our population (44% vs. 56%) RR = 13.32 (adjusted ORs (95% CI): 2.82-62.79) ( < 0.01).
CONCLUSION
Progression to ESRD was frequent in our series. Early diagnosis and adequate management can delay such an evolution.
PubMed: 37521011
DOI: 10.1155/2023/2874414 -
Case Reports in Nephrology and Dialysis 2023The primary hyperoxalurias (PHs) are a group of diseases characterized by kidney stones, nephrocalcinosis, and chronic kidney disease. At stages of advanced kidney...
The primary hyperoxalurias (PHs) are a group of diseases characterized by kidney stones, nephrocalcinosis, and chronic kidney disease. At stages of advanced kidney disease, glomerular filtration of oxalate becomes insufficient, plasma levels increase, and tissue deposition may occur. Hemodialysis is often unable to overcome the excess hepatic oxalate production. The current surgical management of primary hyperoxaluria type 1 (PH1) is combined liver kidney transplantation. In a subset of PH1 patients who respond to pyridoxine, kidney-only transplantation has been successfully performed. Recently, kidney-only transplantation has also been performed in PH1 patients receiving a small interfering RNA therapy called lumasiran. This drug targets the hepatic overproduction of oxalate, making kidney-only transplantation a potentially practical novel approach for managing PH1 patients with advanced kidney disease. It is unknown if similar effects could be seen with a different small interfering RNA agent called nedosiran. This article will briefly review PH1, describe the small interfering RNA therapies being used to treat PH, summarize the reported cases of kidney-only transplantation performed with lumasiran, and detail a case of kidney-only transplantation performed in a PH1 patient receiving nedosiran.
PubMed: 37497389
DOI: 10.1159/000531053 -
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