Urinary Oxalate Excretion Research Articles

Empagliflozin reduces renal calcium oxalate deposition in hyperoxaluria rats induced with ethylene glycol-ammonium chloride

A retrospective study reported that empagliflozin reduced the risk of urinary stone events in patients with diabetes mellitus. To further investigate empagliflozin's potential, we conducted an animal experiment to determine whether empagliflozin can prevent renal stone formation in hyperoxaluria rats. Hyperoxaluria rat models were constructed by administrating 0.75 % ethylene glycol and 1 % ammonium chloride in water. The empagliflozin-treated rats were gauged with empagliflozin at different concentrations, and their body weight and blood sugar data were recorded. After 30 days of treatment, we obtained 24-h urine, kidney, and blood samples. The urine samples were subjected to component detection. Blood samples were prepared for component detection and cytokines detection. Renal samples were subjected to von Kossa staining, transmission electron microscopy, immunohistochemistry, and transcriptome sequencing analysis. Results showed that in empagliflozin-treated hyperoxaluria rats, renal crystal deposition and mitochondria injury, urinary concentration, and excretion of oxalate were significantly decreased. Additionally, plasma levels of VEGF, IL-2, IL-1β, and MCP-1 were decreased. Immunohistochemistry showed that renal expression of KIM-1, MCP-1 was significantly decreased in empagliflozin-treated hyperoxaluria rats. Transcriptome sequencing of renal tissue represented that 25 genes were down-regulated while 12 were up-regulated in empagliflozin-treated hyperoxaluria rats. These regulated genes were mainly enriched in fatty acid metabolism, insulin resistance, muscle contraction, bile secretion, and parathyroid metabolism. Our animal experiments found that empagliflozin could reduce urinary concentration and excretion of oxalate and inhibit renal inflammation, then abating renal calcium oxalate deposition in hyperoxaluria rats in a non-diabetic state.

High-Oxalate Diets Increase Urinary Oxalate Excretion and Nanocrystalluria in Healthy Adults and Calcium Oxalate Kidney Stone Formers

High-Oxalate Diets Increase Urinary Oxalate Excretion and Nanocrystalluria in Healthy Adults and Calcium Oxalate Kidney Stone Formers

Metabolic Profile of Calcium Oxalate Stone Patients with Enteric Hyperoxaluria and Impact of Dietary Intervention.

This study investigated the risk profile and the impact of dietary intervention in calcium oxalate stone formers with enteric hyperoxaluria under controlled, standardized conditions. Thirty-seven patients were included in the study. Dietary and 24-h urinary parameters were obtained on the self-selected diet and a balanced, standardized diet. Tests for [13C2]oxalate absorption, calcium- and ammonium chloride-loading were performed. Mean [13C2]oxalate absorption was 18.8%. A significant positive association was observed between urinary oxalate excretion and intestinal oxalate absorption. In addition, urinary oxalate excretion was significantly correlated with dietary oxalate intake. Mean urinary oxalate excretion decreased from 0.841 mmol/24 h on the usual diet to 0.662 mmol/24 h on the balanced diet, corresponding to a reduction of 21.3%. Besides hyperoxaluria, hypocitraturia and hypomagnesuria were the most common urinary abnormalities at baseline, being present in 83.8% and 81.1% of patients, respectively. Urinary citrate increased by 50.9% and magnesium excretion increased by 25.2% on the balanced diet. As a result, the relative supersaturation of calcium oxalate declined significantly (by 36.2%) on the balanced diet. Since 41% of patients on the balanced diet still had a urine volume of less than 2.0 L/24 h, efforts should be made to increase urine volume by increasing fluid intake and reducing intestinal fluid losses. Dietary intervention proved to be effective in reducing urinary oxalate excretion and should be a cornerstone of the treatment of patients with enteric hyperoxaluria.

The Evolving Role of Genetic Testing in Monogenic Kidney Stone Disease: Spotlight on Primary Hyperoxaluria.

Multiple factors are thought to give rise to common, recurrent kidney stone disease, but for monogenic stone disorders a firm diagnosis is possible through genetic testing. The autosomal recessive primary hyperoxalurias (PH) are rare forms of monogenic kidney stone disease. All 3 types of PH are caused by inborn errors of glyoxylate metabolism in the liver, leading to hepatic oxalate overproduction and excessive renal urinary oxalate excretion. These conditions are characterized by kidney stones, nephrocalcinosis, progressive chronic kidney disease, and kidney failure. Systemic oxalosis, the extra-renal deposition of oxalate resulting in severe morbidity and mortality, occurs in chronic kidney disease when oxalate clearance by the kidneys declines. Novel small interfering RNA-based therapeutics targeting the liver to reduce urinary oxalate excretion have been approved, introducing precision medicine to treat primary hyperoxaluria type 1. The goal of this narrative review is to address the benefits and practicalities of genetic testing for suspected monogenic kidney stone disease and the critical roles of a multidisciplinary team. We collated our procedures, education, training, and workflows to help other clinicians integrate genetic assessment into their diagnostic routines. In our experience, increased access to genetic testing facilitates early detection of PH and other monogenic causes of kidney stone disease so that individualized care can be instituted promptly. Alongside biochemical assessments, more widespread genetic testing may ensure more timely diagnoses so that patients with suspected monogenic kidney stone disease gain access to an expanded range of services and enrollment in clinical trials and registries.

Hair-straightening cosmetics containing glyoxylic acid induce crystalline nephropathy

We recently reported the case of a patient who experienced three consecutive episodes of acute kidney injury, all of them following a "Brazilian" hair-straightening treatment. The cream used for the straightening procedure contained glyoxylic acid. To examine possible underlying mechanisms causing kidney injury, four groups of mice were exposed to topical application of (i) the straightening product, (ii) a cream containing 10% glyoxylic acid, (iii) a cream containing 10% glycolic acid or (iv) a control cream. Application of glycolic acid slightly increased urine oxalate excretion, while glyoxylic acid and the straightening product dramatically increased urine oxalate excretion and caused calcium oxalate nephropathy after transcutaneous absorption. Thus, glyoxylic acid was presumptively absorbed through the skin, metabolized to oxalate and promoted crystallization of calcium oxalate in urine. Hence, cosmetic products containing glyoxylic acid may induce acute kidney injury and should be discontinued. Further studies are needed to investigate the metabolism of glycolic acid and glyoxylic acid following topical application.

Recurrent symptomatic urolithiasis in a patient with cystic fibrosis.

A 6-month-old girl, previously diagnosed with cystic fibrosis (CF), was admitted to hospital for nephrolithiasis. Her parents were first-degree cousins. The patient underwent endoscopic stone management. Despite no family history of stones and medical treatment with potassium citrate, the patient developed recurrent renal stones and atypical urinary tract infections during follow-up. Basic investigations were all normal. Due to consanguinity and early presentation of nephrolithiasis, metabolic causes such as cystinuria and hyperoxaluria were considered. Cystinuria was excluded due to normal cystine levels. High urinary oxalate excretion was found as expected due to absorptive (secondary) hyperoxaluria in CF patients. An early stone burden in the patient with a history of medical treatment and consanguinity led us to perform a genetic testing. Genetic testing revealed a missense homozygous variant in exon 1 of the AGXT gene. The patient was diagnosed with primary hyperoxaluria type 1. Two rare life-threatening genetic diseases were found together in the same child.

#190 Long-term treatment with lumasiran: final results from the phase 2 open-label extension study

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder in which hepatic oxalate overproduction can lead to kidney failure and life-threatening systemic disease. Lumasiran, an RNA interference (RNAi) therapeutic indicated for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels, reduces hepatic oxalate production by degrading the mRNA encoding glycolate oxidase. Patients with PH1 who completed a Phase 1/2 study were eligible to enroll in a Phase 2 open-label extension (OLE) study (NCT03350451) within 12 months of completing the Phase 1/2 study. Method Patients enrolled in the 54-month Phase 2 OLE had previously met eligibility criteria for the Phase 1/2 study, including: age 6 to 64 years, PH1 confirmed by genetic criteria, 24-hour (24 h) UOx excretion >0.7 mmol/1.73 m2/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2, and a stable pyridoxine (vitamin B6) regimen for patients taking vitamin B6. In the Phase 2 OLE, patients were to initiate subcutaneous lumasiran 1.0 mg/kg once monthly (qM), 3.0 mg/kg qM, or 3.0 mg/kg every 3 months (q3M) based on their dose/regimen in the Phase 1/2 study. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were change in 24 h UOx corrected for body surface area (BSA) over time, change in 24 h UOx:creatinine ratio (UOx:Cr) over time, and change in estimated glomerular filtration rate (eGFR) over time. Change over time in POx and plasma glycolate, incidence of anti-drug antibodies (ADAs), and rates of kidney stone AEs were also assessed. Results All 20 patients (median age 11.5 years; 65% female) who completed the Phase 1/2 study entered the Phase 2 OLE (Table 1). Most patients (65%) were taking vitamin B6 at baseline. All patients transitioned to the 3.0 mg/kg q3M dose/regimen by month (M) 21, and all patients completed the study. Six patients transitioned to commercially available lumasiran prior to M54 but on or after M45. The most common treatment-related AEs were injection-site reactions (ISRs) with 13 events in 8 patients (40%); all ISRs were graded mild. Of all lumasiran doses administered during the OLE, 3% (13 of 427 total doses of lumasiran) were associated with ISRs. Other than ISRs, the only treatment-related AEs affecting >1 patient were increases in bilirubin (N=3 patients; 15%); all events resolved without lumasiran dosing changes. Severe AEs were reported by 2 patients (10%); serious AEs were reported by 7 patients (35%). No deaths occurred. No severe or serious AEs were related to treatment, and no patients discontinued lumasiran or withdrew due to AEs. Lumasiran treatment led to a substantial reduction in 24 h UOx relative to the Phase 1/2 study-derived baseline (Fig. 1A). At M54, the mean absolute change from baseline in 24 h UOx was −1.5 mmol/24 h/1.73 m2 and the mean percent change was −68%. From M42 through M54, 24 h UOx was ≤1.5×ULN in ≥89% of patients. At M54, the mean percent change from baseline in 24 h UOx:Cr was −77%. Mean eGFR was generally stable over time (Fig. 1B). Mean absolute change from baseline in eGFR at M54 was −1.6 mL/min/1.73 m2. Lumasiran treatment also led to reductions in POx from baseline, and mean post-baseline POx values remained within the normal range through M54. Mean plasma glycolate levels were elevated at the start of the Phase 2 OLE due to persistence of the treatment effect from the Phase 1/2 study. After treatment resumed, levels increased and then plateaued. One patient (5%) had an ADA positive result at M6 but no ADA-related AEs; subsequent tests were negative through M48. Overall, the kidney stone AE rate was low during the Phase 2 OLE (0.17/person-year (PY]); by comparison, the rate of symptomatic kidney stones was 0.45/PY during the 12 months prior to the Phase 1/2 study and the kidney stone AE rate was 0.90/PY during the Phase 1/2 study. Conclusion In the longest follow-up reported to date, lumasiran treatment was well tolerated in patients with PH1 in the Phase 2 OLE. The most common treatment-related AEs were mild, transient ISRs; no severe or serious AEs were treatment related. Mean 24 h UOx reductions were sustained over more than 4.5 years of treatment. Mean eGFR was stable over time.

#1846 Oxalate nephropathy in diabetic kidney disease: another factor to take into account?

Abstract Background and Aims Patients with diabetes mellitus (DM) have an increased urinary excretion of oxalate. Around 40% of patients with oxalate nephropathy have DM. The aim of this study was to describe the prevalence of tubular deposits of calcium oxalate (CaOx) crystals in patients with diabetic kidney disease (DKD) and investigate its association with renal survival. Method We performed an observational retrospective study that included patients with DKD in renal biopsies performed at our centre between January 1999 and December 2021. We revised the biopsy specimens for the presence of intratubular CaOx crystals. We excluded patients with a histological findings of non-diabetic kidney disease and those lost to follow-up. Renal survival was defined as a state free from developing end-stage kidney disease (ESKD) requiring renal replacement therapy. Results The study included 87 patients with a mean age of 63.1 ± 13 years, 73.5% were male, and 88.5% had type 2 DM (11.5% type 1 DM). Baseline GFR at the moment of kidney biopsy was 38.5 ± 23 ml/min, and baseline median proteinuria was 3.46 (1.35-5.70) g/day. We found intratubular CaOx deposits in 11 biopsies (12.6%). These findings were only found in patients with type 2 DM (14.3% vs 0%), and was more frequently present in patients with a history of renal stones (33.3% vs 11.1%). There were no differences in baseline GFR, proteinuria or vintage of DM between patients with intratubular CaOx deposits and those with no signs of oxalte nephropathy. CaOx deposition was not associated with other histological lesions such as percentage of glomerular sclerosis, grade of interstitial fibrosis and/or tubular atrophy, interstitial inflammation, arterial hyalinosis or arteriosclerosis. After a median follow-up of 41 months, 49.4% of patients developed ESKD while 26.4% died without progressing to ESKD. The patients who progressed to ESKD had a higher baseline serum creatinine (2.56 ± 1.45 vs 1.98 ± 1.07 ml/min, p = 0.037) and lower serum albumin (3.08 ± 0.70 vs 3.57 ± 0.74 g/dl, p = 0.003). In the regression analysis there was no association between intratubular CaOx deposits and progression to ESKD (OR = 2.96, 95% CI 0.73-12.03). In the adjusted model, no histological lesions were associated with renal survival. In the survival analysis, the presence of intratubular CaOx deposits was not associated with neither renal nor patient survival. Conclusion Oxalate nephropathy, defined as the presence of intratubular CaOx deposits in kidney biopsies, may be found in patients with DKD. In our cohort, 14.3% of type 2 DM patients with DKD had concomitant oxalate nephropathy. Its presence was not associated with a worse renal or patient survival.

#2827 Beyond the scale: unveiling the kidney stone risk after bariatric surgery

Abstract Background and Aims Nephrolithiasis is a prevalent condition, with calcium oxalate being the primary component found in kidney stones. Both obesity and gastric bypass surgery pose as risk factors for nephrolithiasis. Malabsorptive bariatric procedures alter 24-hour urine profiles, leading to increased urinary oxalate and reduced urinary citrate levels. This study aims to evaluate the risk factors for calcium oxalate lithiasis in a population after gastric bypass surgery at our center. Method We performed a monocentric retrospective study to evaluate hyperoxaluria and urinary lithiasis in patients who underwent gastric bypass surgery between 2020 and 2021. We assessed urinary oxalate excretion, urinary citrate excretion, and urinary sodium excretion between 4 and 28 months after surgery. To confirm the adequacy of the collection, a comparison was made with the expected urinary creatinine value (20 to 25 mg/kg ideal weight for men and 15 to 20 mg/kg ideal weight for women). We developed a risk score: citraturia < 288 mg/24 h (1 point); oxaluria > 45 mg/L (1 point) and natriuresis > 97.75 mmol/24 h (1 point). Patients were classified as without risk (0 points), at low risk (1 point), at high risk (2 points), and at very high risk (3 points). Additionally, the patients’ historical incidence of lithiasis was examined, both preoperatively and postoperatively, using clinical records. Post-surgery assessments included imaging evidence of lithiasis (when available) or clinical episodes of renal colic. Results Fifty-six patients underwent a 24-hour urine collection. Twenty-two were excluded due to incomplete urine collection, determined by the expected urinary creatinine value and a time lapse exceeding 28 months between surgery and analytical assessment. The median time elapsed between surgery and analytical evaluation was 9.5 months [IQR 6.3 - 12] months. A total of 34 patients were included in the study, 8.8% were male and the median age of the patients was 51.5 [IQR 42.3–57.8] years. The median body mass index decreased from 43.1 [IQR 39.7–46.3] kg/m2 before to 31.8 [IQR 28.6–35.7] kg/m2 six months after surgery. The low risk for calcium oxalate lithiasis in the examined patient sample was 52.9% (n = 18); high risk 20.6% (n = 7), no risk 26.5% (n = 9) and very high risk 0%. We detected 3 (8.8%) patients with concentration hyperoxaluria, 20 (58.8%) patients with natriuresis > 97.75 mmol/24 h and 8 (23.5%) patients with reduced urinary citrate levels. All patients exhibited normal kidney function. The median follow-up duration was 27 months. Out of the total number of patients, only 3 reported renal colic episodes, and imaging evidence of lithiasis was found in just 2 of them before surgery. Among those with a risk score > 0, only 1 had a history of lithiasis. Throughout the follow-up period, none of the patients experienced new lithiasis post-surgery. Regarding the limitations of our study, we highlight the relatively brief duration of follow-up, which may pose challenges in comprehensively evaluating outcomes such as lithiasis. Additionally, the absence of imaging screening represents a notable constraint, impeding the comprehensive assessment of patients with asymptomatic lithiasis. Conclusion This study concludes that within the bariatric surgery population, a specific subgroup is at an elevated risk for renal lithiasis. Recognizing this subgroup promptly and instituting heightened preventive measures may prove advantageous within this demographic.

Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1: Results from a Phase III Clinical Trial

Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx). ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged≥6 years with PH1 and estimated glomerular filtration rate (eGFR)≥30 ml/min per 1.73 m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month36. Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions. In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract.

Lumasiran treatment in pediatric patients with PH1: real-world data within a compassionate use program in Italy.

Primary hyperoxaluria (PH) is a rare, severe genetic disorder, characterized by increased urinary excretion of calcium oxalate, which is responsible for kidney damage and systemic clinical manifestations. Since the year 2020, a new molecule, lumasiran, based on RNA interference (RNAi) technology, has been added to the traditional therapeutic approach. The aim of this analysis was to define the baseline characteristics of a PH1 pediatric population treated with lumasiran in a compassionate-use program setting, and to evaluate the medium-term efficacy of this drug in the routine clinical setting. A retrospective observational analysis was conducted in nine pediatric patients (male:female 5:4; median age at lumasiran start 1.9 years, range 0-14.1). Data concerning oxalate concentration in plasma and urine, kidney stones events, ultrasound and kidney function were collected during the study period (follow-up, mean±standard deviation: 15.3±5 months). In this analysis, a reduction in the urinary oxalate to creatinine ratio (reduction range within the sixth month of treatment from 25.8% to 69.6%, median 51.2%) as well as plasma oxalate concentration under the limit of supersaturation of oxalate in all the patients. Only one patient presented new stone events; kidney ultrasonographic findings related to nephrocalcinosis remained stable in eight out of nine patients. Glomerular filtration rate remained stable during treatment. No adverse events related to lumasiran were noted. Data from this analysis support the efficacy and safety of lumasiran in a pediatric clinical setting, especially if administrated in early life.

Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

PurposeTo investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease.MethodsThis study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed.ResultsThe incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0–25.1) ng/mL; T1: 7.1 (1.8–19.9) ng/mL; T2: 5.9 (2.0–20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3–2.5) ng/mL; T1: 0.3 (0.3–1.1) ng/mL; T2: 0.5 (0.3–1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis.Conclusionsour data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.

Urinary oxalate excretion is increased in calcium oxalate nephrolithiasis patients and associated with increased urinary capacity of calcium oxalate crystallization

Urinary oxalate excretion is increased in calcium oxalate nephrolithiasis patients and associated with increased urinary capacity of calcium oxalate crystallization

Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3

Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH. In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months. Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m2) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to<0.60 mmol/24h;≥ULN to<1.3× ULN) 24-hour Uox excretion. All participants experienced≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs. Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing.

Therapeutic effects of probiotics and herbal medications on oxalate nephrolithiasis: a mini systematic review.

The majority of all kidney stone cases are oxalate urolithiasis with a high risk of recurrence. Beside its widespread occurrence, kidney stones are characterized by severe complications and high treatment costs. Probiotics and herbal medications could be forthcoming therapeutic interventions in the management of oxalate kidney stones. The PubMed/MEDLINE database was searched for keywords "Oxalobacter formigenes" AND "Oxalate" OR "oxalate degradation" AND "Lactobacillus" OR "Bifidobacterium" OR "recombinant Lactobacillus" OR "Bacillus subtilis", and "urolithiasis" AND "herbal extract". The search returned 253 results, 38 of which were included in the review. Most of the oxalate-degrading probiotics belong to the Oxalobacter formigenes, Lactobacillus, Bifidobacterium, and Bacillus genus with a minimum dosage of 107 CFU in the form of capsules, sachets, and lyophilized powder. Oxalate concentration in media was 5-50mM with an incubation time ranging from 24h to 14 days. The majority of the studies suggested that probiotic supplementation might be useful for reducing urinary excretion of oxalate and urea and alleviation of stone formation. Different herbal extracts were used on murine models of nephrolithiasis (induced by 0.5-3% ethylene glycol) with reduction of renal inflammation and urinary parameters, and calcium oxalate crystals. Several strains of probiotics and herbal extracts confer protective effects against kidney stone/nephrolithiasis, indicating their promising nature for being considered as elements of preventive / adjuvant therapeutic strategies.

Lumasiran: A Review in Primary Hyperoxaluria Type 1.

Lumasiran (Oxlumo®), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥6 years with PH1; this effect was sustained for ≥36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged <6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.

Intestinal Oxalate Absorption, Enteric Hyperoxaluria, and Risk of Urinary Stone Formation in Patients with Crohn's Disease.

Nephrolithiasis is a common urologic manifestation of Crohn's disease. The purpose of this study was to investigate the clinical characteristics, intestinal oxalate absorption, and risk factors for urinary stone formation in these patients. In total, 27 patients with Crohn's disease and 27 healthy subjects were included in the present study. Anthropometric, clinical, and 24 h urinary parameters were determined, and the [13C2]oxalate absorption test was performed. Among all patients, 18 had undergone ileal resection, 9 of whom had a history of urinary stones. Compared to healthy controls, the urinary excretion values of calcium, magnesium, potassium, sulfate, creatinine, and citrate were significantly lower in patients with Crohn's disease. Intestinal oxalate absorption, the fractional and 24 h urinary oxalate excretion, and the risk of calcium oxalate stone formation were significantly higher in patients with urolithiasis than in patients without urolithiasis or in healthy controls. Regardless of the group, between 83% and 96% of the [13C2]oxalate was detected in the urine within the first 12 h after ingestion. The length of ileum resection correlated significantly with the intestinal absorption and urinary excretion of oxalate. These findings suggest that enteric hyperoxaluria can be attributed to the hyperabsorption of oxalate following extensive ileal resection. Oral supplementation of calcium and magnesium, as well as alkali citrate therapy, should be considered as treatment options for urolithiasis.

Twenty-four-hour urine oxalate and risk of chronic kidney disease.

To assess whether 24-h urine oxalate (UOx) excretion is a risk factor for incident chronic kidney disease (CKD). This longitudinal observational USA-based study included 426896 individuals aged ≥18years with no CKD at baseline and with at least one UOx, and at least 6months of baseline and 6months of follow-up data. Of these, 11239 (2.6%) had an underlying malabsorptive condition. Incident CKD, defined by relevant International Classification of Diseases codes, was identified from a multi-source data cloud containing individual-level healthcare claims and electronic medical records data. The association between categories of UOx and incident CKD was modeled using logistic regression adjusting for age, sex, race, body mass index, baseline urine calcium, urine citrate, urine volume, tobacco use, hypertension, diabetes, malabsorption and cardiovascular disease. Mean follow-up time was 38.9months (standard deviation 21.7). Compared with individuals with UOx <20mg/24h, the odds of developing incident CKD increased for UOx 20-29mg/24h [multivariable-adjusted odds ratio (MVOR) 1.14 (95% CI 1.07, 1.21)] through 80+mg/24h [MVOR 1.35 (1.21, 1.50)] and was statistically significant for each UOx category. A similar pattern was seen in the subgroup with a malabsorptive condition though the magnitudes of association were larger, with the odds of developing incident CKD increased for UOx 20-29mg/24h [MVOR 1.50 (1.03, 2.20)] through 80+mg/24h [MVOR 2.34 (1.50, 3.63)] as compared with UOx <20mg/24h. The risk of incident CKD increases with increasing 24-h UOx excretion. Future studies should examine whether reducing UOx diminishes the risk of developing CKD.

Risk Profile of Patients with Brushite Stone Disease and the Impact of Diet.

This study examined the profile of patients and the impact of diet on the risk of brushite stone formation under controlled, standardized conditions. Sixty-five patients with brushite nephrolithiasis were enrolled in the study. Metabolic, dietary, and 24 h urinary parameters were collected under the habitual, self-selected diet of the patients and the balanced mixed, standardized diet. The [13C2]oxalate absorption, ammonium chloride, and calcium loading tests were conducted. All patients had at least one abnormality on the usual diet, with hypercalciuria (84.6%), increased urine pH (61.5%), and hyperphosphaturia (43.1%) being the most common. Absorptive hypercalciuria was present in 32.1% and hyperabsorption of oxalate in 41.2%, while distal renal tubular acidosis (dRTA) was noted in 50% of brushite stone formers. The relative supersaturation of brushite did not differ between patients with and without dRTA. Among all recent brushite-containing calculi, 61.5% were mixed with calcium oxalate and/or carbonate apatite. The relative supersaturation of brushite, apatite, and calcium oxalate decreased significantly under the balanced diet, mainly due to the significant decline in urinary calcium, phosphate, and oxalate excretion. Dietary intervention was shown to be effective and should be an integral part of the treatment of brushite stone disease. Further research on the role of dRTA in brushite stone formation is needed.

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium

Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P= 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P< 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P= 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.