Urinary Oxalate Excretion Research Articles

Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria

BackgroundPrimary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase.MethodsA survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group “Rare Forms of Nephrolithiasis and Nephrocalcinosis” of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy.ResultsForty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants.ConclusionsThe data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.Graphical abstract

End Point Considerations for Clinical Trials in Enteric Hyperoxaluria.

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration-approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Determinants on urinary excretion of oxalate and other key factors related to urolithiasis among patients with chronic kidney disease: a single center study

PurposeUrolithiasis is a known risk factor for chronic kidney disease (CKD). However, how CKD might affect the risk of incidence of urolithiasis is not widely studied.MethodsUrinary excretion of oxalate as well as other key factors related to urolithiasis was analyzed in a single center study of 572 patients with biopsy-proven kidney disease.ResultsThe mean age of the cohort was 44.9 years and 60% were males. The mean eGFR was 65.9 ml/min/1.73 m2. Median urinary excretion of oxalate was 14.7 (10.4–19.1) mg/24-h and associated with current urolithiasis (OR 12.744, 95% CI: 1.564–103.873 per one logarithm transformed unit of urinary oxalate excretion). Oxalate excretion was not associated with eGFR and urinary protein excretion. Oxalate excretion was higher in patients with ischemia nephropathy as compared with patients with glomerular nephropathy and tubulointerstitial nephropathy (16.4 vs 14.8 vs 12.0 mg, p = 0.018). And ischemia nephropathy (p = 0.027) was associated with urinary oxalate excretion on adjusted linear regression analysis. Urinary excretion of calcium and uric acid was correlated with eGFR and urinary protein excretion (all p < 0.001), with ischemia nephropathy and tubulointerstitial nephropathy associated with uric acid excretion (both p < 0.01) as well. Citrate excretion was correlated with eGFR (p < 0.001) on adjusted linear regression.ConclusionExcretion of oxalate and other key factors related to urolithiasis was differentially associated with eGFR, urinary protein, and pathological changes in CKD patients. The influence of these intrinsic traits of the underlining kidney disease should be considered when evaluating urolithiasis risk in patients with CKD.

#5036 THE OUTCOME OF LUMASIRAN TREATMENT IN 10 PAEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1

Abstract Background and Aims In primary hyperoxaluria type 1 (PH 1) a rare enzymatic defect in the liver leads to a hepatic overproduction of oxalate. The resulting hyperoxaluria can cause nephrocalcinosis, urolithiasis and renal failure. Conservative treatment options such as hyperhydration, citrate and pyridoxine aim to slow the progression of the disease with a liver transplant currently being the only curative treatment. Since November 2020 Lumasiran is approved for use in patients with PH 1. Lumasiran reduces the hepatic oxalate production by RNA interference and may hence reduce hyperoxaluria. To date there is limited real world data available on the effectiveness of the treatment with Lumasiran. Method This observational study looked at the outcome of Lumasiran treatment in 10 patients under the age of 18 years with genetically confirmed PH 1. The primary end point was percentage reduction in plasma oxalate in the two patients on haemodialysis and percentage reduction of urinary oxalate excretion in the patients with preserved renal function. Secondary end points were change in nephrocalcinosis, urolithiasis and renal function. The follow up time was 6 months in one patient and 12 months in the other nine patients. Results Four of the patients were girls and the median age at the start of treatment was 5.25 years (range 0.3-17.9 years). One of the two patients on haemodialysis showed a decrease in plasma oxalate which allowed for a reduction of dialysis frequency from 5x/week to 3x/week whilst the other patient's dialysis had to be intensified due to worsening systemic oxalosis. In the patients with preserved renal function the median reduction of urinary oxalate was 71% (range 10–91%) after 6 months and 78% (range 61–86%) after 12 months. Two patients reached values in the age specific normal range (Matos et al.). Lumasiran was discontinued after 4 months in one patient and after 8 months in another one due to treatment failure. An improvement in nephrocalcinosis was seen in three patients and two patients showed a subjective reduction in urolithiasis. Renal function improved slightly in one patient and remained stable in the others. Injection site reactions were the only observed side effects. Conclusion Our data highlights the heterogeneity of the disease and treatment response to Lumasiran. Despite promising data regarding the benefits of Lumasiran 2 of 10 patients did not benefit from Lumasiran injections. Hence, it is imperative to regularly re-evaluate hyperoxaluria during treatment with Lumasiran. Ideally the data should be entered into a registry for PH 1 patients to monitor the effectiveness and side effects of this novel drug not only in the short- but also the long term.

Effect of preoperative metabolic profiling to reduce the risk of kidneystones after bariatric surgery in patients with a historyofstoneformation.

Roux-en-Y gastric bypass (RYGB) is associated with an increased risk of kidney stone formation. This is not observed after sleeve gastrectomy (SG). Aim of this study was to assess whether preoperative metabolic profiling is helpful in selecting the most optimal bariatric procedure for patients with a kidney stone history. General hospital, the Netherlands. Patients with a kidney stone history and in the run up to bariatric surgery were screened with non-contrast abdominal computed tomography (CT), serum profiling, and 24-hour urine analysis. Those with stones on radiologic imaging and/or high preoperative urinary oxalate were advised to undergo SG instead of RYGB. Pre- and postoperative urine and serum profile differences between both groups were evaluated retrospectively. Postoperatively, RYGB (N = 28, M:F = 8:20) was associated with a 23.5% reduction in urinary volume, a 85% increase in urinary oxalate excretion with a 230% increase in calcium oxalate (CaOx) supersaturation and a 62% decrease in urinary citrate. Although SG (N = 30, M:F = 12:18) was also associated with a reduction in urinary volume, it had no adverse effects on urinary oxalate and citrate excretion, nor on calcium oxalate supersaturation (CaOx-SS). Both RYGB and SG showed favorable effects on postoperative sodium, calcium, uric acid, and phosphate excretion. This study indicates that preoperative metabolic profiling is important to select the optimal bariatric procedure in patients with an a priori increased risk of kidney stone development. These patients should be strongly encouraged to undergo SG instead of RYGB to prevent progressive or recurrent kidney stone disease.

Increased abundance of bacteria of the family Muribaculaceae achieved by fecal microbiome transplantation correlates with the inhibition of kidney calcium oxalate stone deposition in experimental rats.

The incidence of nephrolithiasis is increasing rapidly worldwide. Calcium oxalate is the most common constituent, contributing to approximately 80% of all kidney stones. The gut microbiome, through its oxalate-degrading ability, may play a role in decreasing morbidity due to urinary calculus. Fecal microbiome transplantation (FMT) has been reported to be effective in restoring the gastrointestinal microbial community in different conditions. The transplantation of whole communities that have oxalate-degrading function may be a more effective strategy than the transplantation of isolated strains. FMT was carried out in male guinea pigs and male Sprague-Dawley laboratory rats (SDRs). Fresh feces were collected from guinea pigs housed in metabolic cages. SDRs were divided into four groups: two groups received standard rat chow (SC) (groups SC and SC + FMT), and two groups were fed a 5% potassium oxalate diet (OD) (groups OD + phosphate-buffered saline (PBS) and OD + FMT). On day 14, groups OD + PBS, OD + FMT, and SC + FMT received either PBS or guinea pig feces by esophageal gavage. The composition of the microbiota of guinea pigs and SDRs was analyzed using a 16S rRNA gene sequencing approach. Biochemical analysis of urine samples from SDRs revealed the presence of calcium oxalate (CaOx) crystals, which were presumed to originate from kidney stones. Renal function was examined using real-time PCR analysis and immunohistochemical staining for renin, angiotensin-converting enzyme, and osteopontin (OPN) expression. FMT resulted in a gut microbiota that was a mixture of guinea pig and SDR bacteria. A microbial network involving Muribaculaceae, Lactobacillus, and Bifidobacterium was activated by FMT in group OD + FMT. As a result, urinary oxalate, calcium, uric acid, creatinine and urea in urine samples were reduced significantly. Similarly, significant reduction of uric acid and blood urea nitrogen to creatinine ratio in serum samples was observed (p < 0.05). Microscopic observations revealed a high CaOx crystal score (4+) in the kidneys of rats in group OD + PBS, whereas a lower score (2+) was observed in the rats in group OD + FMT. Up-regulation of OPN and down-regulation of renin were also associated with FMT. A microbial network involving Muribaculaceae and other oxalate-degrading bacteria achieved by FMT was capable of reducing urinary oxalate excretion and CaOx crystal deposition in the kidney through increasing intestinal oxalate degradation. FMT may exert a renoprotective function in oxalate-related kidney stones.

Effect of Copper and Zinc Ions on Biochemical and Molecular Characteristics of Calcium Oxalate Renal Stones: a Controlled Clinical Study.

Contradictory results are existed in the literature regarding the impact of trace elements on the pathogenesis of calcium oxalate (CaOx) stone patients. Therefore, the aim of our study was to investigate the effect of Cu and Zn on biochemical and molecular characteristics of CaOx stones. Plasma and urine concentrations of Cu and Zn in 30 CaOx stones patients and 20 controls were determined by flame atomic absorption spectrometry (FAAS). Urinary levels of citric acid and oxalate were measured by commercial spectrophotometric kits. Blood levels of glutathione reduced (GSH) and catalase (CAT) were determined as markers of antioxidant activity, while blood malondialdehyde (MDA) and urine level of nitric oxide (NO) were used to assess oxidative stress. Gene expression of MAPk pathway (ERK, P38, and JNK) were estimated. The plasma and urine levels of Cu were significantly increased in the patient group compared to those of controls, while the levels of Zn were decreased. Excessive urinary excretion of citric acid and oxalate were found among CaOx stone patients. The GSH and CAT concentration were significantly reduced in CaOx stones patients compared to healthy group. The plasma MDA and urine NO concentration were significantly increased in CaOx stones patients compared to control group. The expressions of the studied genes were significantly increased in CaOx stones patients. These findings suggest that alteration in Cu and Zn might contribute to pathogenesis of CaOx patients through oxidative stress and MAPK pathway genes (ERK, P38 and JNK).

Sel1-like proteins and peptides are the major Oxalobacter formigenes-derived factors stimulating oxalate transport by human intestinal epithelial cells.

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 Oxalobacter formigenes (O. formigenes)-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 O. formigenes-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 O. formigenes-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.NEW & NOTEWORTHY We previously identified Oxalobacter formigenes-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.

MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA

You have accessJournal of UrologyCME1 Apr 2023MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA William DeFoor, Joonsue Lee, Nehus Edward, Marion Schulte, Sydney Huesman, Ashleigh Libs, and Prasad Devarajan William DeFoorWilliam DeFoor More articles by this author , Joonsue LeeJoonsue Lee More articles by this author , Nehus EdwardNehus Edward More articles by this author , Marion SchulteMarion Schulte More articles by this author , Sydney HuesmanSydney Huesman More articles by this author , Ashleigh LibsAshleigh Libs More articles by this author , and Prasad DevarajanPrasad Devarajan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Medically complex, gastrostomy-fed children are particularly vulnerable to forming kidney stones. We have previously shown that there are elevated urinary oxalate levels in patients using enteral feeding formulas primarily based on soy protein, a known high oxalate food. Enteric hyperoxaluria may predispose patients to calcium oxalate stones. The objective of this study is assess if targeted dietary intervention decreases urinary oxalate excretion. METHODS: A retrospective cohort study was performed on medically complex children with cerebral palsy and severe developmental delay presenting to a high-volume Pediatric Stone Center with nephrolithiasis from 2015 to 2020. Inclusion criteria included those who underwent a dietary and urinary metabolic evaluation before and after the index visit. Diets were analyzed by a registered dietitian. Urinary metabolites including calcium, oxalate, and citrate as well as the supersaturations of calcium oxalate and calcium phosphate were analyzed via two 24-hour urine collections. Dietary oxalate load was determined by evaluating individual recipes for known high oxalate ingredients or soy-based formulas. Patients were stratified into those on a low versus high oxalate diet. Statistical analysis was performed using paired t-tests. RESULTS: A total of 13 medically complex stone-forming children met inclusion criteria. All patients were non-ambulatory. 11 of 13 (85%) were primarily fed via gastrostomy. Of the 13 patients, 4 were on a low oxalate diet and 9 were found to have a diet of high oxalate foods. The baseline urinary oxalate excretion (26 vs. 71 mg/m2/day, P = 0.001) and supersaturation of calcium oxalate (6.1 vs. 14.3, P=0.01) were lower in those with a low oxalate diet. Four patients on high oxalate diets were targeted for lowering the enteral oxalate load. A follow-up urinary metabolic evaluation was performed a mean of 6.5 months after the dietary intervention. The urinary oxalate level decreased from 71 to 33 mg/m2/day (P=0.049). Urinary excretion of calcium and citrate as well as the supersaturation of calcium phosphate were similar following dietary modifications. CONCLUSIONS: Urinary oxalate excretion and supersaturation of calcium oxalate were elevated in medically complex stone-forming children with high dietary oxalate content. Targeted dietary intervention to reduce the oxalate load in enteral formulas can lead to a substantial decrease in urinary oxalate excretion. Further investigation is required to determine if this leads to lower stone recurrence, hospitalizations, and the need for surgical interventions. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information William DeFoor More articles by this author Joonsue Lee More articles by this author Nehus Edward More articles by this author Marion Schulte More articles by this author Sydney Huesman More articles by this author Ashleigh Libs More articles by this author Prasad Devarajan More articles by this author Expand All Advertisement PDF downloadLoading ...

MP10-01 EFFICACY AND SAFETY OF LUMASIRAN IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1: 36-MONTH ANALYSIS OF THE ILLUMINATE-A TRIAL

You have accessJournal of UrologyCME1 Apr 2023MP10-01 EFFICACY AND SAFETY OF LUMASIRAN IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1: 36-MONTH ANALYSIS OF THE ILLUMINATE-A TRIAL John Lieske, Jeffrey Saland, Jaap Groothoff, Yaacov Frishberg, Hadas Shasha-Lavsky, Daniella Magen, Shabbir Moochhala, Eva Simkova, Martin Coenen, Wesley Hayes, Julien Hogan, Anne-Laure Sellier-Leclerc, Yinggu Bao, John Gansner, and Sally-Anne Hulton John Lieske John Lieske More articles by this author , Jeffrey SalandJeffrey Saland More articles by this author , Jaap GroothoffJaap Groothoff More articles by this author , Yaacov FrishbergYaacov Frishberg More articles by this author , Hadas Shasha-LavskyHadas Shasha-Lavsky More articles by this author , Daniella MagenDaniella Magen More articles by this author , Shabbir MoochhalaShabbir Moochhala More articles by this author , Eva SimkovaEva Simkova More articles by this author , Martin CoenenMartin Coenen More articles by this author , Wesley HayesWesley Hayes More articles by this author , Julien HoganJulien Hogan More articles by this author , Anne-Laure Sellier-LeclercAnne-Laure Sellier-Leclerc More articles by this author , Yinggu BaoYinggu Bao More articles by this author , John GansnerJohn Gansner More articles by this author , and Sally-Anne HultonSally-Anne Hulton More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by hepatic oxalate overproduction leading to kidney stones and progressive kidney disease. Lumasiran is an RNAi therapeutic approved for the treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate levels in pediatric and adult patients. Here, we report data from the 36-month (M) analysis of ILLUMINATE-A, a Phase 3 trial of lumasiran (NCT03681184). METHODS: ILLUMINATE-A is an ongoing Phase 3 trial in patients age ≥6 years with genetically confirmed PH1 and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A 6M double-blind, placebo-controlled primary analysis period is followed by an extension period (up to 54M) in which all patients receive lumasiran. RESULTS: Of 39 patients enrolled, 24/26 in the lumasiran/lumasiran group and 13/13 in the placebo/lumasiran group entered and continue in the extension period. Mean 24-hour UOx reduction at M36 relative to baseline was 63% in the lumasiran/lumasiran group and 55% in the placebo/lumasiran group (M30 post–lumasiran initiation). At M36, the proportion of patients achieving 24-hour UOx excretion ≤1.5× upper limit of normal was 76% in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group. Mean baseline-to-M36 reductions in plasma oxalate were 36% and 37% in the lumasiran/lumasiran and placebo/lumasiran groups, respectively. In both groups, eGFR remained stable through M36. Kidney stone event rates decreased from 3.19/person-year during the 12M before consent to 0.70/person-year in the lumasiran/lumasiran group and from 0.54/person-year to 0.39/person-year in the placebo/lumasiran group. Medullary nephrocalcinosis generally remained stable or improved. The most common lumasiran-related adverse events were mild injection-site reactions (36% of patients). CONCLUSIONS: Long-term treatment with lumasiran led to sustained UOx reduction through M36, with an acceptable safety profile in patients with PH1 and encouraging clinical outcomes data. Source of Funding: Alnylam Pharmaceuticals © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Lieske More articles by this author Jeffrey Saland More articles by this author Jaap Groothoff More articles by this author Yaacov Frishberg More articles by this author Hadas Shasha-Lavsky More articles by this author Daniella Magen More articles by this author Shabbir Moochhala More articles by this author Eva Simkova More articles by this author Martin Coenen More articles by this author Wesley Hayes More articles by this author Julien Hogan More articles by this author Anne-Laure Sellier-Leclerc More articles by this author Yinggu Bao More articles by this author John Gansner More articles by this author Sally-Anne Hulton More articles by this author Expand All Advertisement PDF downloadLoading ...

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship

Patients with urolithiasis, and particularly those with hypercalciuria, frequently have a marked reduction of bone mineral content up to the levels of osteoporosis, with a significant increase in bone fracture risk. For these reasons, the indication to prescribe vitamin D and/or calcium supplementations is very frequent in such patients. On the other hand, both calcium supplementation, and even more vitamin D therapy, can worsen the risk of developing urolithiasis by increasing calcium, phosphate, and oxalate urinary excretion. Despite the clinical and practical relevance of this issue, the evidence on this topic is scarce and contradictory. Therefore, some concerns exist about how and whether to prescribe such supplements to a patient with a history of kidney stones. In this narrative review, we resume some pivotal pathophysiological concepts strictly related to the dealt topic, and we draw some considerations and personal opinions on the pros and cons of such prescriptions. Finally, we share with the reader our pragmatic algorithm for handling the urolithiasis risk in patients who have strong indications to be prescribed vitamin D and calcium supplementations.

Primary hyperoxaluria I, II, III types in children (review of literature)

This review presents the latest data on the classification, pathogenesis, clinical and genetic features, and therapy of primary hyperoxaluria types I, II, and III in children with autosomal recessive inheritance. ORPHA portal of orphan diseases presents genes responsible for primary hyperoxaluria type I AGXT (93598); type II and type II GRHPR (93599), type III HOGA1 (93600). Worldwide genetic studies have established the pathogenesis, clinical phenotype and genotype features of primary hyperoxaluria. The pathogenesis of primary hyperoxaluria in children is based on impaired hepatic glyoxylate metabolism. The enzyme AGT catalyzes the conversion of L-alanine and glyoxylate to pyruvate and glycine, with vitamin B6 (pyridoxine) serving as a coenzyme for this reaction. Increased production of endogenous oxalate leads to increased blood oxalate concentrations and urinary oxalate excretion with the formation of renal calcium oxalate crystals and radiopaque concrements (calcium oxalate monohydrate – vevelite, calcium oxalate dihydrate – vedellite). High risk of progression to chronic kidney disease in primary hyperoxaluria in children of types I and II. Systemic oxalosis develops with increasing serum oxalate levels and the formation of calcium oxalate crystals with deposition in many organs and tissues. Therapy for primary hyperoxaluria in children includes: hydration (3l/m2/day) and citrates 100–150 mg/kg/day (potassium citrate 0.3–0.5 mmol/kg/day), pyridoxine at a dose of 5 to 20 mg/kg/day for vitamin B6 sensitive type I primary hyperoxaluria. Administration of oxalobacter formigenes and diet is effective. Combined liver and then kidney transplantation or simultaneous liver and kidney transplantation in patients with type I PH in B6-insensitive and isolated liver transplantation in B6-sensitive variants are performed. Timely molecular genetic testing in children with nephrocalcinosis makes it possible to establish a clinical and genetic diagnosis of type I, II, III PH, to carry out a personalised approach to treatment and to predict future health status.

Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1

Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1

Cucumis callosus (Rottl.) Cogn. fruit extract ameliorates calcium oxalate urolithiasis in ethylene glycol induced hyperoxaluric Rat model

Cucumis callosus dry fruits are traditionally used as folk remedy to treat conditions like urethral irritations, urine stoppage or dribbling and other urinary ailments of man in north-west India. But no study is reported to validate this ethnic practice of using Cucumis fruit in urolithiasis. To evaluate anti-urolithiatic potential of Cucumis, hyperoxaluria was induced in rats by supplying 0.75% ethylene glycol (EG) + 1% ammonium chloride (AC) in drinking water for 14 days. Anti-urolithiatic activity of Cucumis callosus hydro-ethanolic extract (CCHEE) was assessed by measuring blood and urine biochemical parameters, oxidative stress indices, histopathology and osteopontin (OPN) expression. Administration of EG-AC to rats caused hyperoxaluria, crystalluria, azotaemia, oxidant/antioxidant imbalance (increase in lipid peroxidation (LPO), and decrease in glutathione (GSH) and catalase (CAT)), up-regulation of OPN and calcium oxalate (CaOx) crystal deposition in kidney. Treatment of afflicted rats with Cucumis fruits extract restored renal function to a great extent (CCHEE group), testified by improvement of stated parameters. Findings demonstrate curative efficacy of Cucumis fruit extract in EG induced urolithiasis of rats. The restoration of renal function was possibly by regulating renal stone formation via reducing urinary oxalate excretion, correcting oxidant/antioxidant imbalances, and reduced expression of OPN. Hence, results of this study validate the ethnic practice of using Cucumis fruit and conclude that fruit extracts have beneficial effects on CaOx urolithiasis and renal function.

Lumasiran (Oxlumo)

&#x0D; CADTH recommends that Oxlumo be reimbursed by public drug plans for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients if certain conditions are met.&#x0D; Oxlumo should only be covered to treat those with a genetically confirmed diagnosis of PH1 and whose urine oxalate excretion is not normalized with standard of care therapy (including 3 to 6 months of vitamin B6).&#x0D; Oxlumo should only be reimbursed if its cost is reduced and it is initially prescribed by a nephrologist or metabolic diseases specialist experienced in the diagnosis and management of PH1.&#x0D;

Urinary Risk Profile, Impact of Diet, and Risk of Calcium Oxalate Urolithiasis in Idiopathic Uric Acid Stone Disease.

The role of diet in the pathogenesis of uric acid (UA) nephrolithiasis is incompletely understood. This study investigated the effect of dietary intervention on the risk of UA stone formation under standardized conditions. Twenty patients with idiopathic UA stone disease were included in the study. Dietary intake and 24 h urinary parameters were collected on the usual diet of the patients and a standardized balanced mixed diet. Although urinary UA excretion did not change, the relative supersaturation of UA decreased significantly by 47% under the balanced diet primarily due to the significant increase in urine volume and pH. Urinary pH was below 5.8 in 85% of patients under the usual diet, and in 60% of patients under the balanced diet. The supersaturation of calcium oxalate declined significantly under the balanced diet due to the significant decrease in urinary calcium and oxalate excretion and the increase in urine volume. Dietary intervention is a key component in the management of UA nephrolithiasis. Urinary calcium and oxalate excretion should also be monitored in patients with pure UA calculi to reduce the risk of mixed stone formation with calcium oxalate. Lower urinary pH in UA stone patients can only be partially explained by diet.

Contribution of Endogenous Oxalate Synthesis to Urinary Oxalate Excretion

Contribution of Endogenous Oxalate Synthesis to Urinary Oxalate Excretion

Application of multivariate joint modeling of longitudinal biomarkers and time-to-event data to a rare kidney stone cohort.

Time-dependent Cox proportional hazards regression is a popular statistical method used in kidney disease research to evaluate associations between biomarkers collected serially over time with progression to kidney failure. Typically, biomarkers of interest are considered time-dependent covariates being updated at each new measurement using last observation carried forward (LOCF). Recently, joint modeling has emerged as a flexible alternative for multivariate longitudinal and time-to-event data. This study describes and demonstrates multivariate joint modeling using as an example the association of serial biomarkers (plasma oxalate [POX] and urinary oxalate [UOX]) and kidney function among patients with primary hyperoxaluria in the Rare Kidney Stone Consortium Registry. Time-to-kidney failure was regressed on serially measured biomarkers in two ways: time-dependent LOCF Cox proportional hazards regression and multivariate joint models. In time-dependent LOCF Cox regression, higher POX was associated with increased risk of kidney failure (HR = 2.20 per doubling, 95% CI = [1.38-3.51], p < 0.001) whereas UOX was not (HR = 1.08 per doubling, [0.66-1.77], p = 0.77). In multivariate joint models, estimates suggest higher UOX may be associated with lower risk of kidney failure (HR = 0.42 per doubling [0.15-1.04], p = 0.066), though not statistically significant, since impaired urinary excretion of oxalate may reflect worsening kidney function. Multivariate joint modeling is more flexible than LOCF and may better reflect biological plausibility since biomarkers are not steady-state values between measurements. While LOCF is preferred to naïve methods not accounting for changes in biomarkers over time, results may not accurately reflect flexible relationships that can be captured with multivariate joint modeling.

Acute oxalate nephropathy: A potential cause of acute kidney injury in diabetes mellitus-A case series from a single center.

BackgroundAcute oxalate nephropathy (AON) is an uncommon condition that causes acute kidney injury (AKI), characterized by the massive deposition of calcium oxalate crystals in the renal parenchyma. In previous studies, urinary oxalate excretion has been found to be increased in patients with diabetes mellitus (DM). Here, we report a case series of diabetic patients with AKI with biopsy-proven AON, aiming to alert physicians to the potential of AON as a trigger of AKI in diabetic patients in clinical practice.Materials and methodsCases with pathological diagnosis of AON who presented with AKI clinically and had DM between January 2016 and December 2020 were retrospectively enrolled. Their clinical and pathological manifestations, treatment, and prognosis were collected.ResultsSix male patients with biopsy-proven AON out of a total of 5,883 native kidney biopsies were identified, aged 58.3 ± 9.1 years at the time of kidney biopsy. Only one patient who had received Roux-en-Y gastric bypass surgery took oxalate-rich food before the onset of the disease. None of them had clinical features of enteric malabsorption. Three patients were currently on renin-angiotensin system inhibitor treatment for hypertension, and 5 of them received non-steroidal anti-inflammatory drugs. Three patients presented with oliguria and 4 patients needed dialysis at the beginning with none requiring dialysis at discharge. Four patients received a course of corticosteroid treatment empirically. Among them, two patients had estimated glomerular filtration rate (eGFR) recovered to over 60 ml/min/1.73 m2, while the other two patients remained with kidney dysfunction at the last follow-up. In two patients without corticosteroid treatment, one patient fully recovered with eGFR over 90 ml/min/1.73 m2 and the other patient remained with kidney dysfunction at the last follow-up.ConclusionAON might be a rare but potentially trigger of AKI in patients with DM. A kidney biopsy could help physicians to make the correct diagnosis. The proper treatment to alleviate oxalate-induced injury needs to be further studied.

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n= 29) or PH2 (n= 6) with eGFR≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE],+3507 [788] vs-1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P< 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours;<1.3× ULN) Uox excretion on≥2 consecutive visits starting at day 90 (50% vs 0; P= 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P< 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P= 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.