Excess Oxalate Research Articles

Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption

Primary hyperoxaluria type 1 (PH1) is a severe genetic metabolic disorder caused by mutations in the AGXT gene, leading to defects in enzymes crucial for glyoxylate metabolism. PH1 is characterized by severe, potentially life-threatening manifestations due to excessive oxalate accumulation, which leads to calcium oxalate crystal deposits in the kidneys and, ultimately, renal failure and systemic oxalosis. Existing substrate reduction therapies, such as inhibition of liver-specific glycolate oxidase (GO) encoded by HAO1 using siRNA or CRISPR/Cas9 delivered by adeno-associated virus (AAV), either require repeated dosing or have raised safety concerns. To address these limitations, our study employed lipid nanoparticles (LNPs) for CRISPR/Cas9 delivery to rapidly generate a PH1 mouse model and validate the therapeutic efficacy of LNP-CRISPR/Cas9 targeting the Hao1 gene. The LNP-CRISPR/Cas9 system exhibited efficient editing of the Hao1 gene, significantly reducing GO expression and lowering urinary oxalate levels in treated PH1 mice. Notably, these effects persisted for 12 months with no significant off-target effects, liver-induced toxicity, or substantial immune responses, highlighting the approach's safety and specificity. Furthermore, the developed humanized mouse model validated the efficacy of our therapeutic strategy. These findings support LNP-CRISPR/Cas9 targeting HAO1 as a promising and safer alternative for PH1 treatment with a single administration.

Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs.

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.

The Clinical and Pathological Characteristics of Patients with Oxalate Nephropathy.

Key PointsOxalate nephropathy is an underrecognized cause of CKD and ESKDWe present one of the largest native oxalate nephropathy cohorts to date from a tertiary care institution in the United StatesOxalate 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 managementBackgroundOxalate 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.MethodsWe 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.ResultsWe identified 60 native biopsies with oxalate deposits and excluded patients with clinically insignificant biopsies (n=12) or lack of data (n=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 injuryn=17 (54.8%) and diabetic glomerulosclerosisn=7 (22.6%). Severe and moderate interstitial fibrosis was present in 38.7% (n=12) and 51.6% (n=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.ConclusionsON 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.PodcastThis article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2024_01_26_KID0000000000000340.mp3

Purslane-induced oxalate nephropathy: case report and literature review

BackgroundThe 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 presentationWe 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.ConclusionsOur 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.

Primary hyperoxaluria: The Baragwanath experience


 Background. Primary hyperoxaluria (PH) is a rare autosomal recessive condition characterised by defects in the metabolism of glyoxylate which leads to excess oxalate production. It is an important disease to diagnose as it can progress to kidney failure (KF).
 Objective. To describe the characteristics, diagnosis and management of PH in South Africa and to identify any determinants of KF and death.
 Method. A retrospective study of all children younger than 16 years of age, diagnosed with PH at the Paediatric Renal Unit, Chris Hani Baragwanath Academic Hospital, from 1984 - 2017.
 Results. A total of 24 patients were identified, of which 20 records were available for complete analysis. The median age of presentation was 6.0 years. The common clinical presentations were urolithiasis (90%), KF (85%), nephrocalcinosis (75%), urinary tract infections (55%) and haematuria (30%). Nephrocalcinosis was better detected on abdominal radiograph compared with ultrasonography. Both nephrocalcinosis (p=0.009) and haematuria (p=0.018) were significantly associated with KF. Five patients had A112D genetic mutation in the AGXT. Fourteen received dialysis and four were transplanted. The mortality rate in this study was 58.3%.
 Conclusion. Clinicians should have a high index of suspicion for PH in patients presenting with haematuria, urolithiasis and KF. This study supports the measurement of urine oxalate levels and abdominal radiographs in screening for PH in children presenting in KF.

PCR17 Utility Estimates for Treatment in Primary Hyperoxaluria Type 1

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic overproduction of oxalate. Excretion of excess oxalate by the kidneys leads to recurrent kidney stones, nephrocalcinosis, progressive kidney disease, and multiorgan damage from systemic oxalosis. Patients progressing to or presenting with kidney failure require invasive approaches such as dialysis and liver and/or kidney transplantation. There is currently little evidence about the impact of PH1 on health-related quality of life (HRQoL). This study aimed to understand the burden of PH1 on patients by eliciting utilities to support future economic evaluations.

OXALATE-CALCIUM RATIOS OF COMMON CEREALS CONSUMED IN EASTERN NIGERIA

The importance of Oxalate content of an individual plant in limiting total dietary calcium availability is of significance when the ratio oxalic to calcium (oxa:cal.) is greater than one. Food with oxal: cal ratio greater than two, have no utilizable calcium and contain excess oxalate while foodstuff with oxal:cal. of about one provides little calcium but do not inhibit the utilization of calcium provided by other products. The study analysed three commonly consumed cereals of oxalic acids and calcium by rigorous classical quantitative method of precipitation/titration and atomic absorption spectrophotometry, respectively. The result should oxal:cal. ratios>1 for all the cereals indicating that the cereals have no utilizable calcium, thus contain excess oxalate which not only complex the calcium contained in the food but also that derived from other food sources eaten together with it. This can result in deficiency of such an essential mineral as calcium in the body and even render the body prone to bone diseases and possibility of developing kidney stones due to calcium oxalate formation (calcium oxalate being the most common component of kidney stone).

POS-438 Long-term Treatment With Lumasiran: Results From the Phase 2 Open-Label Extension Study

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic overproduction of oxalate. Excretion of excess oxalate by the kidneys leads to recurrent kidney stones, nephrocalcinosis, progressive kidney disease, and multiorgan damage from systemic oxalosis. Lumasiran is a subcutaneously administered, liver-directed RNA interference (RNAi) therapeutic to reduce urinary oxalate (UOx) excretion in patients with PH1. Treatment with lumasiran demonstrated substantial reductions in UOx excretion and an acceptable safety profile in pediatric and adult patients with PH1.

Synergistic effect of ultrasonication and sulfate radical on recovering cobalt and lithium from the spent lithium-ion battery

Ultrasonication has been mechanically applied widely in the recycling of spent lithium-ion (SLI) batteries while its influence on chemical pathways has barely been reported. In this study, ultrasonication and sulfate radicals were used in a coupling system to obtain efficient recoveries of Co and Li from SLI batteries. The synergistic effect of ultrasonication and sulfate radicals on recycling was quantitatively analysed by significance analysis and surface responses in a central composite design. The employment of persulfate significantly affected the whole recycling process during the sonication. Factors including acoustic time, operating powers, and temperature all had a significant effect on the recoveries of Co and Li. The maximum recovery efficiencies of Co and Li of 97.33% and 99.25%, respectively, and the minimum loss rate of Al of 4.13% were simultaneously obtained by the fitting predictor. The optimal combination of factors for the sonication system included an acoustic time (min) of 5.5, an operating power (W) of 168, a temperature (°C) of 86, and a ratio of cathode foil to S-solution (mg/mL) of 1:60. A moiety of cathode active material was directly separated from the aluminium collector by sulfate radical-related reactions. Co and Li cations dissolved from LiCoO2 by carbon dioxide radicals were reprecipitated by excess oxalate. The research demonstrated the positively synergistic influence caused by ultrasonication and sulfate radicals on achieving efficient recoveries of Co and Li from SLI batteries, explicitly expanding the technical choices for the recycling procedure.

Nephrolithiasis (part 2): Diagnosis, management and prevention of recurrent nephrolithiasis

Work-up of patients with calcium oxalate stones should be restricted to those who have multiple episodes (50% of stone formers). There are exceptions, such as pilots, fire-workers, people in the armed forces, those with a single kidney and children (<19 years old). The most important aspect of therapy is to correct dietary aberrations, i.e. the ‘clinic effect’. The four golden rules to correct dietary influences are to maintain an adequate 24-hour urine volume, to restrict salt intake, to avoid red meat and to avoid a diet high in oxalate. In particular, Ceylon tea is contraindicated, as it contains excess oxalate. Drink coffee instead. In patients with hypocitraturia, the drug of choice is potassium citrate, which is the only acceptable urinary alkaliser. Other preparations, such as Urolyte-U, Citrosoda, etc., all have a high sodium content, which will influence urinary calcium excretion. In patients with ongoing hypercalciuria, thiazides are contraindicated in the management of recurrent calcium oxalate stones, and indapamide is the drug of choice. The treatment and follow-up are lifelong. In addition, poor adherence to treatment, coupled with repeated urological procedures, may result in renal functional deterioration and even occasionally renal failure.

Diminishment of Nrf2 Antioxidative Defense Aggravates Nephrotoxicity of Melamine and Oxalate Coexposure.

Chronic kidney disease (CKD) usually causes devastating healthy impacts on patients. However, the causes affecting the decline of kidney function are not fully revealed, especially the involvement of environmental pollutants. We have revealed that exposure to melamine, a ubiquitous chemical in daily life, is linked to adverse kidney outcomes. Hyperoxaluria that results from exposure to excessive oxalate, a potentially nephrotoxic terminal metabolite, is reportedly associated with CKD. Thus, we explored whether interaction of these two potential nephrotoxicants could enhance kidney injury. We established a renal proximal tubular HK-2 cell model and a Sprague–Dawley rat model of coexposure to melamine with sodium oxalate or hydroxy-L-proline to investigate the interacting adverse effects on kidneys. Melamine and oxalate coexposure enhanced the levels of reactive oxygen species, lipid peroxidation and oxidative DNA damage in the HK-2 cells and kidney tissues. The degrees of tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated under the coexposed condition, which may result from the diminishment of Nrf2 antioxidative capacity. To conclude, melamine and oxalate coexposure aggravates renal tubular injury via impairment of antioxidants. Accumulative harmful effects of exposure to multiple environmental nephrotoxicants should be carefully investigated in the etiology of CKD progression.

Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria.

Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release-a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.

MO047STABLE EGFR IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN, REGARDLESS OF KIDNEY FUNCTION AT START OF TREATMENT

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic oxalate overproduction. Excess oxalate is excreted by the kidneys, leading to recurrent kidney stones, nephrocalcinosis, and progressive kidney disease. Patients with PH1 generally experience a slow decline in kidney function over time that can be punctuated by abrupt worsening precipitated by infection, obstructing stones, or dehydration. Approximately half of patients with PH1 progress to kidney failure by early adulthood, and nearly all by 60 years of age. Lumasiran is an RNAi therapeutic indicated for the treatment of PH1 in all age groups. In clinical trials, treatment with lumasiran resulted in substantial reductions in urinary and plasma oxalate in pediatric and adult patients, with an acceptable safety profile. This analysis evaluates the change in kidney function of patients with PH1 with an eGFR of ≥30 mL/min/1.73m2 enrolled in clinical trials of lumasiran. Method We analyzed kidney function from 75 patients with PH1, age ≥12 months old, eGFR ≥30 mL/min/1.73m2, enrolled in 3 clinical trials of lumasiran (Phase 2 open-label extension, and Phase 3 ILLUMINATE-A and ILLUMINATE-B). In these trials, eGFR was calculated with the Modification of Diet in Renal Disease (MDRD) Study equation in adults or the bedside Schwartz equation in children. The effect of lumasiran on eGFR was assessed by baseline eGFR subgroup: ≥90, <90, 60 to <90, 45 to <60, and 30 to <45 mL/min/1.73m2. Results Of 75 patients available for analysis, 46 were treated with lumasiran from the start of the study through the Month 12 visit. eGFR remained stable in all eGFR subgroups. Patients with eGFR ≥90 mL/min/1.73m2 at baseline (N=16) demonstrated fluctuations in mean values by timepoint, with a mean change (95% CI) from baseline of -1 (-8, 6) mL/min/1.73m2 at Month 12. In patients with eGFR <90 mL/min/1.73m2 (N=30), no change in mean eGFR from baseline was observed at Month 12; the mean change (95% CI) was 0 (-3, 3). When evaluating subgroups with impaired kidney function, variations in the mean change were observed at Month 12 due to small sample sizes. For patients with eGFR 60 to <90 mL/min/1.73m2 (N=22), the mean change (95% CI) was -2 (-5, 1). For patients with eGFR 45 to <60 mL/min/1.73m2 (N=5), the mean change (95% CI) was 3 (-8, 14). For patients with eGFR 30 to <45 mL/min/1.73m2 (N=3), the mean change (95% CI) was 9 (7, 11). Conclusion Patients with PH1 had stable kidney function over time with lumasiran treatment, regardless of kidney function at baseline. Given the progressive kidney function decline that is characteristic of PH1, the eGFR stability observed during 12 months of treatment with lumasiran is encouraging. Kidney function will continue to be monitored for the duration of the lumasiran clinical trials.

Clinical experience of using denosumab in the treatment of hypercalcemia and oxalate osteopathy for a young patient with primary hyperoxaluria type 1.

Primary hyperoxaluria are a group of rare genetic diseases caused by defective glyoxylate metabolism leading to excessive oxalate production and deposition into the tissues (oxalosis). Clinical manifestations include recurrent nephrolithiasis and nephrocalcinosis, rapidly progressive chronic kidney disease subsequently leading to end-stage renal disease, systemic oxalosis, PTH-independent hypercalcemia, pancytopenia, oxalate osteopathy with osteosclerosis, pathological fractures and endocrinopathy. Regardless of the type of primary hyperoxaluria any conservative therapy is palliative and can only slow the progression of the disease but not prevent it completely. We report the case of a young male patient with genetically confirmed primary hyperoxaluria type 1 complicated by severe oxalate osteopathy and hypercalcemia, who received a combined liver/ kidney transplant after 10 years from the disease. Treatment with human monoclonal antibody to the receptor activator of nuclear factor kappa B ligand (RANKL) — denosumab allowed achieving normalization of calcium-phosphorus metabolism, significantly reduce the activity of bone resorption and improve clinical performance. Knowledge of the features of clinical manifestations, timely diagnosis and treatment of primary hyperoxaluria are important prognostic value for patients.

Imaging of primary hyperoxaluria with classical renal and skeletal changes.

Primary hyperoxaluria (PH) is a rare metabolic disorder with autosomal recessive inheritance pattern which is due to deficiency of alanine-glyoxylate aminotransferase enzyme. It causes defective glyoxylate metabolism in liver which in turn leads to excessive oxalate production and deposition. Supersaturation of oxalic acid in urine (>45 mg/day) is known as hyperoxaluria which causes nephrolithiasis, cortical nephrocalcinosis and renal insufficiency. Secondary hyperoxaluria is due to over ingestion of oxalic acids or its precursors or can be due to its reduced excretion. Deposition of these highly insoluble calcium oxalate crystals (serum oxalate >30.0 mmol/L) in extra-renal tissues is known as systemic oxalosis. Here we present a rare case of infantile presentation, where nephrocalcinosis sets in at a very early age without nephrolithiasis, leading to ESRD in very early childhood and extra renal deposition in skeletal system.

Interactions Between Phytochemicals and Minerals in Terminalia ferdinandiana and Implications for Mineral Bioavailability.

Oxalic and phytic acid are phytochemicals considered to be anti-nutritional factors as they are predominantly found as oxalates and phytates bound to minerals like calcium and potassium. Studies have associated excessive oxalate consumption with increased urinary excretion of oxalate (hyperoxaluria) and calcium oxalate kidney stone formation, and excessive phytate consumption with decreased bioaccessibility and bioavailability of certain minerals and reduced utilization of dietary protein. However, other studies suggest that dietary consumption of phytate may be beneficial and inhibit formation of calcium oxalate kidney stones. In light of these conflicting reports, dietary intake of oxalate and phytate enriched plants should be considered in relation to potential health outcomes following consumption. Terminalia ferdinandiana is one such plant and is investigated here with respect to oxalate, phytate, and mineral contents. Assessment of oxalate and phytate contents in T. ferdinandiana fruit, leaf, and seedcoat tissues through hydrolysis into acid forms revealed oxalic acid contents ranging from 327 to 1,420 mg/100 g on a dry weight (DW) basis whilst phytic acid contents ranged from 8.44 to 121.72 mg/100 g DW. Calcium content in the different tissues ranged from 131 to 1,343 mg/100 g. There was no correlation between oxalic acid and calcium, however a significant, positive correlation was observed between phytic acid and calcium (r = 0.9917; p < 0.001), indicating that tissues rich in phytic acid also contain higher levels of calcium. The high content of phytic acid in comparison to oxalic acid in T. ferdinandiana fruit found in this study and the dietary significance of this in terms of calcium bioavailability, needs to be investigated further.

A Prospective, Double-Blind, Randomized, Placebo-Controlled, Crossover Study Using an Orally Administered Oxalate Decarboxylase (OxDC).

Hyperoxaluria is typically associated with excessive oxalate intake in the diet, decreased dietary calcium, hyperabsorption of oxalate, or increased endogenous production of oxalate. The disorder spectrum extends from recurrent kidney stones to ESKD. This clinical trial sought to evaluate the effectiveness of an acid stable oxalate decarboxylase (OxDC) to reduce urinary oxalate in healthy subjects on a high-oxalate diet. In this prospective, double-blind, randomized, placebo-controlled, crossover clinical trial, 33 healthy volunteers were randomized into two crossover sequences separated by a 2-day washout period. A controlled high-oxalate diet (750-800 mg oxalate, 500-550 mg calcium daily) was utilized, and six 24-hour urine collections were measured. Subjects were given approximately 1000 U (micromoles per minute per milligram) of OxDC or placebo with meals three times daily during the 4 days of treatment. Urinary oxalate significantly decreased with OxDC treatment. The baseline corrected within-subject mean reduction in 24-hour urinary excretion (after OxDC dosing versus high-oxalate baseline preceding treatment) was 12.5 mg or 29% (P<0.001). OxDC treatment was effective (>5% reduction) in 31 of 33 subjects (94%). Compared with placebo, OxDC produced a 24% reduction (P<0.001) in 24-hour oxalate excretion. Other urinary parameters (creatinine, uric acid, citrate, magnesium, calcium) were not affected by OxDC. No serious adverse events and no product-related adverse events occurred. An orally administered OxDC is capable of significantly reducing urinary oxalate levels in healthy volunteers on a high-oxalate diet without affecting creatinine clearance, urine creatinine, or other solutes related to supersaturation of calcium oxalate. Evaluation of Nephure, and the Reduction of Dietary Oxalate, in Healthy Volunteers, NCT03661216.

Deleterious AGXT Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep.

Severe oxalate nephropathy has been previously reported in sheep and is mostly associated with excessive oxalate in the diet. However, a rare native Dutch breed (Zwartbles) seems to be predisposed to an inherited juvenile form of primary hyperoxaluria and no causative genetic variant has been described so far. This study aims to characterize the phenotype and genetic etiology of the inherited metabolic disease observed in several purebred Zwartbles sheep. Affected animals present with a wide range of clinical signs including condition loss, inappetence, malaise, and, occasionally, respiratory signs, as well as an apparent sudden unexpected death. Histopathology revealed widespread oxalate crystal deposition in kidneys of the cases. Whole-genome sequencing of two affected sheep identified a missense variant in the ovine AGXT gene (c.584G>A; p.Cys195Tyr). Variants in AGXT are known to cause type I primary hyperoxaluria in dogs and humans. Herein, we present evidence that the observed clinicopathological phenotype can be described as a form of ovine type I primary hyperoxaluria. This disorder is explained by a breed-specific recessively inherited pathogenic AGXT variant. Genetic testing enables selection against this fatal disorder in Zwartbles sheep as well as more precise diagnosis in animals with similar clinical phenotype. Our results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 001672-9940).

MP43-07 RESULTS OF A PHASE 2 STUDY OF RELOXALIASE IN SUBJECTS WITH ADVANCED OXALATE DISORDERS

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (MP43)1 Apr 2020MP43-07 RESULTS OF A PHASE 2 STUDY OF RELOXALIASE IN SUBJECTS WITH ADVANCED OXALATE DISORDERS Felix Knauf, John Lieske, Mira Keddis, Annamaria Kausz, and Charles Scales* Felix KnaufFelix Knauf More articles by this author , John LieskeJohn Lieske More articles by this author , Mira KeddisMira Keddis More articles by this author , Annamaria KauszAnnamaria Kausz More articles by this author , and Charles Scales*Charles Scales* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000898.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Hyperoxaluria (HOx) is a major risk factor for kidney stones, and can also lead to chronic kidney disease (CKD). With decreasing kidney function, plasma oxalate (POx) levels rise, resulting in oxalate deposition in the kidneys and other organs. There is an unmet need in patients with Enteric Hyperoxaluira (EH) and Primary Hyperoxaluira (PH), in whom the systemic and renal oxalate burden can contribute to worsening CKD, potentially leading to end-stage renal disease (ESRD). Reloxaliase is an oral, oxalate-specific enzyme therapy that is designed to degrade oxalate in the gastrointestinal (GI) tract, thereby reducing urinary oxalate (UOx). This study was conducted to evaluate whether reloxaliase can reduce UOx and POx in subjects with PH or severe EH and CKD. METHODS: This 12-week, open-label study of reloxaliase enrolled subjects with EH with CKD and hyperoxalemia (UOx ≥40 mg/24h, eGFR <45 mL/min/1.73m2 and POx >5 μmol/L, n=9 [6 with ESRD]), and PH (UOx ≥40 mg/24h, n=5) who received reloxaliase 7,500 u 5x/day with meals and snacks. POx and 24h UOx were obtained at baseline, Weeks 4, 8 and 12; UOx was not collected in ESRD subjects (eGFR <15 ml/min or dialysis). RESULTS: At the time of this report, 14 subjects were enrolled. In the EH subjects, there was a robust reduction in both UOx and POx as shown in the table below. No consistent effect was observed in PH subjects with normal kidney function. Reloxaliase was well tolerated, there were no study drug related serious adverse events. CONCLUSIONS: A substantial reduction in both POx and UOx was demonstrated in EH subjects with CKD. The mechanism of action of reloxaliase, to degrade oxalate in the GI tract, aligns with the pathophysiology of EH which involves excess oxalate absorption. To our knowledge, this is the first demonstration of a pharmacological therapy for POx reduction in subjects with EH and advanced CKD. This study suggests potential for reloxaliase to address an unmet need in subjects with EH and CKD, as this therapy could reduce systemic oxalate burden. Further clinical studies are warranted. Source of Funding: Allena Pharmaceuticals © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e649-e649 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Felix Knauf More articles by this author John Lieske More articles by this author Mira Keddis More articles by this author Annamaria Kausz More articles by this author Charles Scales* More articles by this author Expand All Advertisement PDF downloadLoading ...

Oxalate Content of Enteral Nutrition Formulas.

Patients requiring oral and/or enteral nutrition support, delivered via nasogastric, gastric, or intestinal routes, have a relatively high incidence of calcium oxalate (CaOx) kidney stones. Nutrition formulas are frequently made from corn and/or or soy, both of which contain ample oxalate. Excessive oxalate intake contributes to hyperoxaluria (>45 mg urine oxalate/day) and CaOx stones especially when unopposed by concomitant calcium intake, gastrointestinal malabsorption is present, and/or oxalate degrading gut bacteria are limiting or absent. Our objective was to assess the oxalate content of commonly used commercial enteral nutrition formulas. Enteral nutrition formulas were selected from the formulary at our clinical inpatient institution. Multiple samples of each were assessed for oxalate concentration with ion chromatography. Results from 26 formulas revealed highly variable oxalate concentration ranging from 4 to 140 mg oxalate/L of formula. No definitive patterns for different types of formulas (eg, flavored vs unflavored, high protein vs not) were evident. Coefficients of variation for all formulas ranged from 0.68% to 43% (mean ± SD 19% ± 12%; median 18%). Depending on the formula and amount delivered, patients requiring nutrition support could obtain anywhere from 12 to 150 mg oxalate/day or more and are thus at risk for hyperoxaluria and CaOx stones.