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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 -
Urolithiasis Apr 2023Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative...
Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.
Topics: Humans; Hyperoxaluria, Primary; Hyperoxaluria; Oxalates; Glomerular Filtration Rate
PubMed: 37118061
DOI: 10.1007/s00240-023-01453-3 -
Urolithiasis Apr 2023Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney...
Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney failure, and serious complications due to systemic oxalosis, resulting in significant morbidity. We investigated the burden of PH among affected patients and caregivers. This cross-sectional, web-based survey was used to quantify the burden of PH, in terms of healthcare resource utilization, health-related quality of life, and work productivity and activity impairment among adults (≥ 18 years) with PH and caregivers of children (≤ 17 years) with PH in the US. Among the 20 respondents, there were 7 adults with PH and 13 caregivers of children with PH. Adherence to hyperhydration was noted as the most, or one of the most, difficult aspects of PH by 56% of respondents. Most patients (95%) had experienced painful kidney stone events, one-third had visited the emergency room, and 29% were hospitalized for complications due to PH. Of the 24% of patients on dialysis, all found the procedure burdensome. Adult patients' quality of life was negatively affected across several domains. Most respondents (81%) reported that PH had a negative effect on their finances. Employed adult patients and caregivers, and children with PH, had moderate impairment in work productivity, school attendance, and activity. Anxiety about future PH-related sequelae was moderate to high. These findings highlight the need for improvements in PH medical management. A plain language summary is available in the supplementary information.
Topics: Quality of Life; Cross-Sectional Studies; Hyperoxaluria, Primary; United States; Web Browser; Internet; Health Surveys; Patient Acceptance of Health Care; Delivery of Health Care; Efficiency; Humans; Male; Female; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Health Services
PubMed: 37067624
DOI: 10.1007/s00240-023-01436-4 -
Frontiers in Pediatrics 2023Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage...
INTRODUCTION
Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare.
METHODS
All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively.
RESULTS
Eighteen patients (infantile PH1 = 10, juvenile PH1 = 8) underwent transplantation (CLKT = 17, SLKT = 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1), = 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 ( = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, = 0.59).
DISCUSSION
In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.
PubMed: 37009285
DOI: 10.3389/fped.2023.1157215 -
Transplantation Direct Apr 2023Enteric hyperoxalosis (EH) is an emerging cause of kidney transplantation (KT) dysfunction. We sought to determine the prevalence of EH and factors that affect plasma...
UNLABELLED
Enteric hyperoxalosis (EH) is an emerging cause of kidney transplantation (KT) dysfunction. We sought to determine the prevalence of EH and factors that affect plasma oxalate (POx) among at-risk KT candidates.
METHODS
We prospectively measured POx among KT candidates evaluated at our center from 2017 to 2020 with risk factors for EH namely bariatric surgery, inflammatory bowel disease, or cystic fibrosis. EH was defined by a POx ≥10 μmol/L. Period-prevalence of EH was calculated. We compared mean POx across 5 factors: underlying condition, chronic kidney disease (CKD) stage, dialysis modality, phosphate binder type, and body mass index.
RESULTS
Of 40 KT candidates screened, 23 had EH for a 4-y period prevalence of 58%. Mean POx was 21.6 ± 23.5 μmol/L ranging from 0 to 109.6 μmol/L. 40% of screened had POx >20 μmol/L. Sleeve gastrectomy was the most common underlying condition associated with EH. Mean POx did not differ by underlying condition ( = 0.27), CKD stage ( = 0.17), dialysis modality ( = 0.68), phosphate binder ( = 0.58), and body mass index ( = 0.56).
CONCLUSIONS
Bariatric surgery and inflammatory bowel disease were associated with a high prevalence of EH among KT candidates. Contrary to prior studies, sleeve gastrectomy was also associated with hyperoxalosis in advanced CKD. POx concentrations observed in EH reached levels associated with tissue and potentially allograft deposition. Concentrations can be as high as that seen in primary hyperoxaluria. More studies are needed to assess if POx is indeed a modifiable factor affecting allograft function in patients with EH.
PubMed: 37009166
DOI: 10.1097/TXD.0000000000001464 -
Obesity Surgery May 2023Obesity is associated with increased incidence of kidney stones, a risk further increased by metabolic and bariatric surgery, particularly after procedures with a...
PURPOSE
Obesity is associated with increased incidence of kidney stones, a risk further increased by metabolic and bariatric surgery, particularly after procedures with a malabsorptive component. However, there is a paucity in reports on baseline risk factor and on larger population-based cohorts. The objective was to evaluate incidence and risk factors for kidney stones after bariatric surgery by comparing them to an age-, sex-, and geographically matched cohort from the normal population.
MATERIAL AND METHODS
Patients operated with primary Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or biliopancreatic diversion with duodenal switch (BPD-DS) from 2007 until 2017 within the Scandinavian Obesity Surgery registry were matched 1:10 to controls from the normal population. Hospital admission or outpatient visits due to kidney stones registered in the National Patient Registry were considered as endpoint.
RESULTS
The study included 58,366 surgical patients (mean age 41.0±11.1, BMI 42.0±5.68, 76% women) with median follow-up time 5.0 [IQR 2.9-7.0] years and 583,660 controls. All surgical procedures were associated with a significantly increased risk for kidney stones (RYGB, HR 6.16, [95% CI 5.37-7.06]; SG, HR 6.33, [95% CI 3.57-11.25]; BPD/DS, HR 10.16, [95% CI 2.94-35.09]). Higher age, type 2 diabetes hypertension at baseline, and a preoperative history of kidney stones were risk factors for having a postoperative diagnosis of kidney stones.
CONCLUSION
Primary RYGB, SG, and BPD/DS were all associated with a more than sixfold increased risk for postoperative kidney stones. The risk increased with advancing age, two common obesity-related conditions, and among patients with preoperative history of kidney stones.
Topics: Humans; Female; Adult; Middle Aged; Male; Obesity, Morbid; Diabetes Mellitus, Type 2; Incidence; Bariatric Surgery; Gastric Bypass; Obesity; Biliopancreatic Diversion; Kidney Calculi; Gastrectomy; Retrospective Studies
PubMed: 37000381
DOI: 10.1007/s11695-023-06561-y -
Medecine Sciences : M/S Mar 2023
Topics: Humans; Hyperoxaluria; Mutation
PubMed: 36943123
DOI: 10.1051/medsci/2023024 -
Urolithiasis Mar 2023In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic...
In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic testing is the most definitive and preferred diagnostic method, quantification of these metabolites is important for the diagnosis and evaluation of potential therapeutic interventions. Current metabolite quantification methods use laborious, technically highly complex and expensive liquid, gas or ion chromatography tandem mass spectrometry, which are available only in selected laboratories worldwide. Incubation of ortho-aminobenzaldehyde (oABA) with glyoxylate generated from glycolate using recombinant mouse glycolate oxidase (GO) and glycine leads to the formation of a stable dihydroquinazoline double aromatic ring chromophore with specific peak absorption at 440 nm. The urinary limit of detection and estimated limit of quantification derived from eight standard curves were 14.3 and 28.7 µmol glycolate per mmol creatinine, respectively. High concentrations of oxalate, lactate and L-glycerate do not interfere in this assay format. The correlation coefficient between the absorption and an ion chromatography tandem mass spectrometry method is 93% with a p value < 0.00001. The Bland-Altmann plot indicates acceptable agreement between the two methods. The glycolate quantification method using conversion of glycolate via recombinant mouse GO and fusion of oABA and glycine with glyoxylate is fast, simple, robust and inexpensive. Furthermore this method might be readily implemented into routine clinical diagnostic laboratories for glycolate measurements in primary hyperoxaluria type 1.
Topics: Mice; Animals; Hyperoxaluria, Primary; Oxalates; Glycolates; Glyoxylates; Glycine; Hyperoxaluria
PubMed: 36920530
DOI: 10.1007/s00240-023-01426-6 -
Ophthalmology Science Jun 2023To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To...
PURPOSE
To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1.
DESIGN
A cross-sectional study.
PARTICIPANTS
Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children's Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021.
METHODS
The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed.
MAIN OUTCOME MEASURES
Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment.
RESULTS
A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype.
CONCLUSIONS
Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy.
PubMed: 36909147
DOI: 10.1016/j.xops.2022.100268