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Kidney International Reports Jun 2024Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate...
INTRODUCTION
Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through the activity of its oxalate-degrading enzymes (ODEs). In this cross-sectional study, we leverage multiomics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome.
METHODS
Patients diagnosed with type 1 primary hyperoxaluria (PH), enteric hyperoxaluria (EH), and CKS were screened for inclusion in the study. Participants completed a food frequency questionnaire recording their dietary oxalate content while fecal oxalate levels were ascertained. DNA and RNA were extracted from stool samples and sequenced. Metagenomic (MTG) and metatranscriptomic (MTT) data were processed through our bioinformatics pipelines, and microbiome diversity, differential abundance, and networks were subject to statistical analysis in relationship with oxalate levels.
RESULTS
A total of 38 subjects were recruited, including 13 healthy participants, 12 patients with recurrent CKS, 8 with PH, and 5 with EH. Urinary and fecal oxalate were significantly higher in the PH and the EH population compared to healthy controls. At the community level, alpha-diversity and beta-diversity indices were similar across all populations. The respective contributions of single bacterial species to the total oxalate degradative potential were similar in healthy and PH subjects. MTT-based network analysis identified the most interactive bacterial network in patients with PH. Patients with EH had a decreased abundance of multiple major oxalate degraders.
CONCLUSION
The composition and inferred activity of oxalate-degrading microbiota were differentially associated with host clinical conditions. Identifying these changes improves our understanding of the relationships between dietary constituents, microbiota, and oxalate homeostasis, and suggests new therapeutic approaches protecting against hyperoxaluria.
PubMed: 38899198
DOI: 10.1016/j.ekir.2024.03.004 -
Biomolecules Apr 2024Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently... (Review)
Review
Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently excreted in the urine. Calcium oxalate deposition in the renal tubules and interstitium triggers renal injury, precipitating systemic oxalate build-up and subsequent secondary organ impairment. Recent explorations of novel therapeutic strategies have challenged and necessitated the reassessment of established management frameworks. The execution of diverse clinical trials across various medication classes has provided new insights and knowledge. With the evolution of PH treatments reaching a new milestone, prompt and accurate diagnosis is increasingly critical. Developing early, effective management and treatment plans is essential to improve the long-term quality of life for PH patients.
Topics: Humans; Hyperoxaluria, Primary; Calcium Oxalate; Oxalates; Quality of Life
PubMed: 38785918
DOI: 10.3390/biom14050511 -
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 -
Current Opinion in Nephrology and... Jul 2024Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion... (Review)
Review
PURPOSE OF REVIEW
Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion of oxalate leading to the deposition of calcium oxalate stones in the urinary tract. This review describes the molecular aspects of PHs and their relevance for the clinical management of patients.
RECENT FINDINGS
Recently, the study of PHs pathogenesis has received great attention. The development of novel in vitro and in vivo models has allowed to elucidate how inherited mutations lead to enzyme deficit, as well as to confirm the pathogenicity of newly-identified mutations. In addition, a better knowledge of the metabolic consequences in disorders of liver glyoxylate detoxification has been crucial to identify the key players in liver oxalate production, thus leading to the identification and validation of new drug targets.
SUMMARY
The research on PHs at basic, translational and clinical level has improved our knowledge on the critical factors that modulate disease severity and the response to the available treatments, leading to the development of new drugs, either in preclinical stage or, very recently, approved for patient treatment.
Topics: Humans; Hyperoxaluria, Primary; Animals; Mutation; Liver; Glyoxylates; Genetic Predisposition to Disease; Phenotype; Oxalates
PubMed: 38602143
DOI: 10.1097/MNH.0000000000000987 -
Kidney International Reports Nov 2023
PubMed: 38025235
DOI: 10.1016/j.ekir.2023.09.012 -
Annals of Laboratory Medicine May 2024Plasma oxalate measurements can be used for the screening and therapeutic monitoring of primary hyperoxaluria. We developed a gas chromatography-mass spectrometry...
BACKGROUND
Plasma oxalate measurements can be used for the screening and therapeutic monitoring of primary hyperoxaluria. We developed a gas chromatography-mass spectrometry (GC-MS) assay for plasma oxalate measurements with high sensitivity and suitable testing volumes for pediatric populations.
METHODS
Plasma oxalate was extracted, derivatized, and analyzed by GC-MS. We measured the ion at m/z 261.10 to quantify oxalate and the C-oxalate ion (m/z: 263.15) as the internal standard. Method validation included determination of the linear range, limit of blank, limit of detection, lower limit of quantification, precision, recovery, carryover, interference, and dilution effect. The cut-off value between primary and non-primary hyperoxaluria in a pediatric population was analyzed.
RESULTS
The detection limit was 0.78 μmol/L, and the linear range was up to 80.0 μmol/L. The between-day precision was 5.7% at 41.3 μmol/L and 13.1% at 1.6 μmol/L. The carryover was <0.2%. The recovery rate ranged from 90% to 110%. Interference analysis showed that Hb did not interfere with plasma oxalate quantification, whereas intralipids and bilirubin caused false elevation of oxalate concentrations. A cut-off of 13.9 μmol/L showed 63% specificity and 77% sensitivity, whereas a cut-off of 4.15 μmol/L showed 100% specificity and 20% sensitivity. The minimum required sample volume was 250 μL. The detected oxalate concentrations showed interference from instrument conditioning, sample preparation procedures, medications, and various clinical conditions.
CONCLUSIONS
GC-MS is a sensitive assay for quantifying plasma oxalate and is suitable for pediatric patients. Plasma oxalate concentrations should be interpreted in a clinical context.
Topics: Humans; Child; Gas Chromatography-Mass Spectrometry; Oxalates; Hyperoxaluria, Primary
PubMed: 37904578
DOI: 10.3343/alm.2023.0178 -
Frontiers in Pediatrics 2024Primary hyperoxaluria type 1 is characterized by hepatic oxalate overproduction, leading to nephrocalcinosis, kidney stones, kidney failure and systemic oxalosis,...
BACKGROUND
Primary hyperoxaluria type 1 is characterized by hepatic oxalate overproduction, leading to nephrocalcinosis, kidney stones, kidney failure and systemic oxalosis, including oxalate osteopathy. Combined liver-kidney transplantation (CLKT) and kidney after liver transplantation (KALT) were established therapeutic options to stop the devastating consequences of oxalate bone disease.
METHODS
We describe a retrospective cohort of 10 children with PH1who were referred to our hospital from different countries for combined transplantation. Demographic and clinical data were collected and symptoms of bone disease, conventional radiological examinations, plasma oxalate levels and other determinants of calcium-phosphate metabolism were compared pre and post transplantation.
RESULTS
Ten patients (7 male, median age 5.8 years, median follow-up time 8.1 years) were included in this study. Seven patients were diagnosed with infantile oxalosis and 9 patients received an intensified dialysis regime prior to transplantation. In one patient the transplanted kidney never achieved primary function and the boy remained on HD. All other patients remained without graft failure and retained stable kidney and liver function. Prior to transplantation, seven patients suffered from severe skeletal pain and three children presented with 1-3 series of pathological fractures. Pathological fractures did no longer occur in children who underwent successful CLKT or KALT. Plasma oxalate levels dropped within 6 months following Tx. Determinants of calcium-phosphorus metabolism did not differ significantly in comparison to other HD children. Seven of ten children showed a restricted growth at the time of transplantation and presented a moderate catch-up-growth at the time of last follow-up.
CONCLUSIONS
Patients with PH1 suffer from severe consequences of a disturbed bone metabolism. However, bone health and growth can partially improve following CLKT/KALT.
PubMed: 38455394
DOI: 10.3389/fped.2024.1353880 -
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 -
Nephrology, Dialysis, Transplantation :... Jun 2023
Topics: Humans; Oxalates; Renal Dialysis; Hyperoxaluria, Primary; Glycolates; Hyperoxaluria
PubMed: 36898675
DOI: 10.1093/ndt/gfad049 -
Nephrology, Dialysis, Transplantation :... Mar 2024Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high a heritability of nephrolithiasis, but data on prevalence...
BACKGROUND
Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high a heritability of nephrolithiasis, but data on prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.
METHODS
We performed whole exome sequencing in 787 participants of the Bern Kidney Stone Registry, an unselected cohort of adults with ≥ 1 past kidney stone episode (KSF), and 114 non-stone-forming individuals (NKSF). An exome-based panel of 34 established nephrolithiasis genes was analyzed and variants assessed according to ACMG criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.
RESULTS
Mean age of KSF was 47±15 years, and 18% were first time KSF. A Mendelian kidney stone disease was present in 2.9% (23 of 787) of KSF. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n=13), Vitamin D-24 hydroxylase deficiency (CYP24A1; n=5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n=3). 8.1% (64 of 787) of KSF were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n=37), CLDN16 (n=8) and CYP24A1 (n=8). KSF with Mendelian disease had a lower age at the first stone event (30±14 years vs. 36±14 years, p=0.003), were more likely to have cystine stones (23.4% vs. 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% vs. 52.5%) compared to KSF without genetic diagnosis. The phenotype of KSF with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSF without diagnostic variants. In NKSF, no Mendelian disease was detected, and LP/P variants were significantly less prevalent compared to KSF (1.8% vs. 8.1%).
CONCLUSION
Mendelian disease is uncommon in unselected adult KSF, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSF.
PubMed: 38544324
DOI: 10.1093/ndt/gfae074