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American Journal of Physiology. Cell... Jul 2023Kidney stones (KSs) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KSs are...
Kidney stones (KSs) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KSs are composed of calcium oxalate and small increases in urinary oxalate concentration significantly enhance the stone risk. Oxalate also potentially contributes to CKD progression, kidney disease-associated cardiovascular diseases, and poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing enteric oxalate secretion. We previously identified -derived factors secreted in its culture-conditioned medium (CM), which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified Sel1-like proteins as the major -derived secreted factors using mass spectrometry and functional assays. Crystal structures for six proteins were determined to confirm structures and better understand functions. OxBSel1-14-derived small peptides P8 and P9 were identified as the major factors, with P8 + 9 closely recapitulating the CM's effects, acting through the oxalate transporters SLC26A2 and SLC26A6 and PKA activation. Besides C2 cells, P8 + 9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that they work in human tissues. In conclusion, P8 and P9 peptides are identified as the major -derived secreted factors and they have significant therapeutic potential for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KSs, enteric hyperoxaluria, primary hyperoxaluria, CKD, KF, and renal transplant recipients. We previously identified -derived secreted factors stimulating oxalate transport by human intestinal epithelial cells in vitro and reducing urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. We now identified Sel1-like proteins and small peptides as the major secreted factors and they have significant therapeutic potential for hyperoxalemia and hyperoxaluria, impacting the outcomes of patients suffering from kidney stones, primary and secondary hyperoxaluria, chronic kidney disease, kidney failure, and renal transplant recipients.
Topics: Humans; Mice; Animals; Oxalobacter formigenes; Caco-2 Cells; Kidney Transplantation; Oxalates; Hyperoxaluria; Kidney Calculi; Epithelial Cells; Peptides; Renal Insufficiency; Renal Insufficiency, Chronic
PubMed: 37125773
DOI: 10.1152/ajpcell.00466.2021 -
Kidney360 Jan 2024Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care...
KEY POINTS
Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care institution in the United States. Oxalate nephropathy has multiple etiologies and given its clinical course and poor prognosis, attention must be paid to screening for risk factors to guide prompt diagnosis and management.
BACKGROUND
Oxalate nephropathy (ON) is characterized by deposition of calcium oxalate crystals in the kidney and is commonly under-recognized. Causes of ON include primary hyperoxaluria, enteric hyperoxaluria, and ingestion of excess oxalate or its precursors.
METHODS
We report the clinical and pathological characteristics of one of the largest series of native kidney ON to date, from January 2015 to March 2023 at the Cleveland Clinic.
RESULTS
We identified 60 native biopsies with oxalate deposits and excluded patients with clinically insignificant biopsies (=12) or lack of data (=17). Thirty-one patients with native ON were described. The mean age at diagnosis was 66.2 years (±12.1), and 58.1% were female. 87.1% had hypertension, 58.1% had diabetes, 42% had nephrolithiasis, and 77.4% had underlying CKD, with a mean baseline creatinine of 1.8 mg/dl ±1.3. The mean creatinine at biopsy was 5.2 mg/dl ±1.7. Kidney biopsies showed abundant calcium oxalate crystal deposits, and 27 of 31 biopsies had additional diagnoses, the most common of which were acute tubular injury =17 (54.8%) and diabetic glomerulosclerosis =7 (22.6%). Severe and moderate interstitial fibrosis was present in 38.7% (=12) and 51.6% (=16) of biopsies, respectively. Ten had a single etiology of ON, ten had a multifactorial etiology (both enteric hyperoxaluria and high precursor intake), and 11 had an unclear etiology. Notably, only seven patients had a history of gastric bypass. The mean duration of follow-up was 26.8 months, and 26 patients had follow-up data >1 year. Of these, 21 required dialysis, and five were dialysis-free at presentation. Five of the 26 were deceased at 1 year, with 12 patients (38.7%) deceased at last follow-up. Seventeen patients received targeted management, while nine patients did not receive targeted treatment, and all nine required hemodialysis. More patients (31.6%) had vitamin C intake after the coronavirus disease 2019 pandemic (2020–2023) versus 16.7% before 2020.
CONCLUSIONS
ON presents as AKI or acute on CKD. The prognosis is poor with most patients requiring dialysis at presentation with high morbidity and mortality. Clinicians need to be aware of the risk factors associated with ON to aid prompt diagnosis and management.
PODCAST
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2024_01_26_KID0000000000000340.mp3
Topics: Humans; Hyperoxaluria; Renal Insufficiency; Oxalates
PubMed: 38095544
DOI: 10.34067/KID.0000000000000340 -
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 -
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 -
Progress in Molecular Biology and... 2024The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have...
The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.
Topics: Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering; RNA, Messenger; Amyloid Neuropathies, Familial
PubMed: 38359998
DOI: 10.1016/bs.pmbts.2023.12.014 -
Nephrology (Carlton, Vic.) Apr 2024Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are...
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are nephrocalcinosis/nephrolithiasis, causing impaired kidney function. We aimed to evaluate the clinical characteristics and overall outcomes of paediatric PH1 patients in Turkey.
METHODS
This is a nationwide, multicentre, retrospective study evaluating all available paediatric PH1 patients from 15 different paediatric nephrology centres in Turkey. Detailed patient data was collected which included demographic, clinical and laboratory features. Patients were classified according to their age and characteristics at presentation: patients presenting in the first year of life with nephrocalcinosis/nephrolithiasis (infantile oxalosis, Group 1), cases with recurrent nephrolithiasis diagnosed during childhood (childhood-onset PH1, Group 2), and asymptomatic children diagnosed with family screening (Group 3).
RESULTS
Forty-eight patients had a mutation consistent with PH1. The most common mutation was c.971_972delTG (25%). Infantile oxalosis patients had more advanced chronic kidney disease (CKD) or kidney failure necessitating dialysis (76.9% vs. 45.5%). These patients had much worse clinical course and mortality rates seemed to be higher (23.1% vs. 13.6%). Patients with fatal outcomes were the ones with significant comorbidities, especially with cardiovascular involvement. Patients in Group 3 were followed with better outcomes, with no kidney failure or mortality.
CONCLUSION
PH1 is not an isolated kidney disease but a systemic disease. Family screening helps to preserve kidney function and prevent systemic complications. Despite all efforts made with traditional treatment methods including transplantation, our results show devastating outcomes or mortality.
Topics: Humans; Child; Nephrocalcinosis; Retrospective Studies; Kidney Failure, Chronic; Renal Dialysis; Hyperoxaluria, Primary; Nephrolithiasis; Hyperoxaluria; Renal Insufficiency
PubMed: 38290500
DOI: 10.1111/nep.14273 -
Kidney International Mar 2024Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate...
Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate stones, and a high risk of progressive kidney damage. PH1 is caused by inherent genetic defects of the alanine glyoxylate aminotransferase (AGXT) gene. The in vivo repair of disease-causing genes was exceedingly inefficient before the invention of base editors which can efficiently introduce precisely targeted base alterations without double-strand DNA breaks. Adenine base editor (ABE) can precisely convert A·T to G·C with the assistance of specific guide RNA. Here, we demonstrated that systemic delivery of dual adeno-associated virus encoding a split-ABE8e could artificially repair 13% of the pathogenic allele in Agxt rats, a model of PH1, alleviating the disease phenotype. Specifically, ABE treatment partially restored the expression of alanine-glyoxylate-aminotransferase (AGT), reduced endogenous oxalate synthesis and alleviated calcium oxalate crystal deposition. Western blot and immunohistochemistry confirmed that ABE8e treatment restored AGT protein expression in hepatocytes. Moreover, the precise editing efficiency in the liver remained stable six months after treatment. Thus, our findings provided a prospect of in vivo base editing as a personalized and precise medicine for PH1 by directly correcting the mutant Agxt gene.
Topics: Humans; Rats; Animals; Child; Calcium Oxalate; Gene Editing; RNA, Guide, CRISPR-Cas Systems; Hyperoxaluria, Primary; Transaminases; Alanine; Hyperoxaluria; Mutation
PubMed: 38142039
DOI: 10.1016/j.kint.2023.11.029 -
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 -
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 -
Pediatric Nephrology (Berlin, Germany) Apr 2024Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. (Review)
Review
BACKGROUND
Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited.
METHODS
We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists.
RESULTS
We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established.
CONCLUSIONS
PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.
Topics: Child; Humans; Infant; Genetic Profile; Hyperoxaluria, Primary; Nephrolithiasis; Renal Insufficiency, Chronic
PubMed: 37914965
DOI: 10.1007/s00467-023-06200-9