Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. METHODS: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months). RESULTS: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). CONCLUSIONS: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

Purslane-induced oxalate nephropathy: case report and literature review.

BACKGROUND: The 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 PRESENTATION: We 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. CONCLUSIONS: Our 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.

Future treatments for hyperoxaluria.

PURPOSE OF REVIEW: The review of potential therapies in the treatment of hyperoxaluria is timely, given the current excitement with clinical trials and the mounting evidence of the importance of oxalate in both kidney stone and chronic kidney disease. RECENT FINDINGS: Given the significant contribution of both endogenous and dietary oxalate to urinary oxalate excretions, it is not surprising therapeutic targets are being studied in both pathways. This article covers the existing data on endogenous and dietary oxalate and the current targets in these pathways. SUMMARY: In the near future, there will likely be therapies targeting both endogenous and dietary oxalate, especially in subsets of kidney stone formers.

"Green Smoothie Cleanse" Causing Acute Oxalate Nephropathy.

Oxalate nephropathy is an uncommon condition that causes acute kidney injury with the potential for progression to end-stage renal disease. Diagnosis is based on the kidney biopsy findings of abundant polarizable calcium oxalate crystals in the epithelium and lumen of renal tubules. We report a case of acute oxalate nephropathy in a 65-year-old woman, temporally associated with the consumption of an oxalate-rich green smoothie juice "cleanse" prepared from juicing oxalate-rich green leafy vegetables and fruits. Predisposing factors included a remote history of gastric bypass and recent prolonged antibiotic therapy. She had normal kidney function before using the cleanse and developed acute kidney injury that progressed to end-stage renal disease. Consumption of such juice cleanses increases oxalate absorption, causing hyperoxaluria and acute oxalate nephropathy in patients with predisposing risk factors. Given the increasing popularity of juice cleanses, it is important that both patients and physicians have greater awareness of the potential for acute oxalate nephropathy in susceptible individuals with risk factors such as chronic kidney disease, gastric bypass, and antibiotic use.

Vitamin C-induced oxalate nephropathy in a renal transplant patient related to excessive ingestion of cashew pseudofruit (Anacardium occidentale L.): a case report.

BACKGROUND: Ingestion of vitamin C is generally regarded as harmless. Oxalate nephropathy is an infrequent condition and is characterized by oxalate deposition in the renal tubules, in some cases resulting in acute kidney injury. It can be caused by overproduction of oxalate in genetic disorders and, more frequently, as a secondary phenomenon provoked by ingestion of oxalate or substances that can be transformed into oxalate in the patient. CASE PRESENTATION: We present a case of acute oxalate nephropathy in a 59-year-old black male with type 2 diabetes mellitus, who received a kidney transplant 11 years prior. He ingested a large amount of cashew pseudofruit ("cashew apple") during 1 month and developed acute kidney injury. His previous blood creatinine was 2.0 mg/dL, which increased to 7.2 mg/d; he required hemodialysis. He was subsequently discharged without need for dialysis; 3 months later his blood creatinine stabilized at 3.6 mg/dL. CONCLUSIONS: This pseudofruit is rich in ascorbic acid (vitamin C) and poor in oxalate. Urinary oxalate excretion begins to increase when amounts of ascorbic acid above bodily requirements are ingested, and may provoke acute oxalate nephropathy. The patient's oxalate acute nephropathy, in this case, was attributed to excessive vitamin C ingestion from the cashew pseudofruit associated with decreased renal function.

N-acetylcysteine protects against star fruit-induced acute kidney injury.

BACKGROUND: Star fruit (SF) is a popular fruit, commonly cultivated in many tropical countries, that contains large amount of oxalate. Acute oxalate nephropathy and direct renal tubular damage through release of free radicals are the main mechanisms involved in SF-induced acute kidney injury (AKI). The aim of this study was to evaluate the protective effect of N-acetylcysteine (NAC) on SF-induced nephrotoxicity due to its potent antioxidant effect. MATERIALS AND METHODS: Male Wistar rats received SF juice (4 mL/100 g body weight) by gavage after a 12 h fasting and water deprivation. Fasting and water deprivation continued for 6 h thereafter to warrant juice absorption. Thereafter, animals were allocated to three experimental groups: SF (n = 6): received tap water; SF + NAC (n = 6): received NAC (4.8 g/L) in drinking water for 48 h after gavage; and Sham (n = 6): no interventions. After 48 h, inulin clearance studies were performed to determine glomerular filtration rate. In a second series of experiment, rats were housed in metabolic cages for additional assessments. RESULTS: SF rats showed markedly reduced inulin clearance associated with hyperoxaluria, renal tubular damage, increased oxidative stress and inflammation. NAC treatment ameliorated all these alterations. Under polarized light microscopy, SF rats exhibited intense calcium oxalate birefringence crystals deposition, dilation of renal tubules and tubular epithelial degeneration, which were attenuate by NAC therapy. CONCLUSIONS: Our data show that therapeutic NAC attenuates renal dysfunction in a model of acute oxalate nephropathy following SF ingestion by reducing oxidative stress, oxaluria, and inflammation. This might represent a novel indication of NAC for the treatment of SF-induced AKI.

An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.

Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 inflammasome, CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (IL)-1ß and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1ß-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.

Oxalate at physiological urine concentrations induces oxidative injury in renal epithelial cells: effect of α-tocopherol and ascorbic acid.

OBJECTIVES: To test our hypothesis that physiological levels of urinary oxalate induce oxidative renal cell injury, as studies to date have shown that oxalate causes oxidative injury only at supra-physiological levels. To study the combined effect of α-tocopherol and ascorbic acid against oxalate-induced oxidative injury, as oxalate-induced oxidative cell injury is known to promote initial attachment of calcium oxalate crystals to injured renal tubules and subsequent development of kidney stones. MATERIALS AND METHODS: Cultures of normal (antioxidant-undepleted) and antioxidant-depleted LLC-PK1 cells were exposed to oxalate at human physiological urine concentrations. After exposure, markers of oxidative stress and cell injury were measured in the cells and media, respectively. In addition, we also evaluated the combined effects of α-tocopherol and ascorbic acid on oxalate-induced oxidative cell injury. RESULTS: Exposure of renal cells to oxalate at urinary physiological levels increased the oxidative cell injury as assessed by increased lactate dehydrogenase (LDH) leakage and increased lipid hydroperoxide in the renal cells; however, this effect was not seen until 24 h after oxalate exposure, at which point the injury was milder. On the other hand, when cellular reduced glutathione (GSH) and catalase were depleted in renal epithelial cells with pharmacological inhibitors, the physiological levels of urinary oxalate caused significant oxidative cell injury at 24 h, and remarkably, when additional endogenous antioxidants were depleted, the oxalate at the upper limit of normal 24 h urine caused a significant amount of cell injury in a shorter period of time, which was comparable to that seen in cells exposed to higher levels of oxalate. Exposure of LLC-PK1 cells to oxalate resulted in increased levels of H2 O2 and lipid hydroperoxide, correlating with increased release of cell injury markers, including LDH, alkaline phosphate, and γ-glutamyl transpeptidase from renal tubular epithelial cells. Oxalate exposure decreased the activity and protein expression of superoxide dismutase and glutathione peroxidase in a time-dependent manner. LLC-PK1 cells treated with oxalate and either α-tocopherol or ascorbic acid alone exhibited a significant decrease in oxidative cell injury and restored endogenous renal antioxidants towards normal levels, and interestingly, combined treatment with α-tocopherol and ascorbic was more efficient at preventing oxalate-induced toxicity than treatment with either agent alone. CONCLUSION: To our knowledge this is the first study to show that oxalate alone at human physiological urine concentrations (in the absence of calcium oxalate crystal formation), induced oxidative renal injury in renal epithelial cells when endogenous antioxidants are depleted. Our data further suggests that a combination of α-tocopherol and ascorbic acid may be more effective than each individual agent in reducing oxalate-induced oxidative renal injury and subsequent calcium oxalate crystal deposition in recurrent stone formers.

Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys.

OBJECTIVES: Polymorphism of the gene for matrix GLA protein (MGP), a calcification inhibitor, is associated with nephrolithiasis. However, experimental investigations of MGP role in stone pathogenesis are limited. We determined the effect of renal epithelial exposure to oxalate (Ox), calcium oxalate (CaOx) monohydrate (COM) or hydroxyapatite (HA) crystal on the expression of MGP. METHODS: MDCK cells in culture were exposed to 0.3, 0.5 or 1 mM Ox and 33, 66 or 133-150 µg/cm(2) of COM/HA for 3-72 h. MGP expression and production were determined by Western blotting and densitometric analysis. Enzyme-linked immunosorbent assay was performed to determine MGP release into the medium. Hyperoxaluria was induced in male Sprague-Dawley rats by feeding hydroxyl-L-proline. Immunohistochemistry was performed to detect renal MGP expression. RESULTS: Exposure to Ox and crystals led to time- and concentration-dependent increase in expression of MGP in MDCK cells. Cellular response was quicker to crystal exposure than to the Ox, expression being significantly higher after 3-h exposure to COM or HA crystals and more than 6 h of exposure to Ox. MGP expression was increased in kidneys of hyperoxaluric rats particularly in renal peritubular vessels. CONCLUSION: We demonstrate increased expression of MGP in renal tubular epithelial cells exposed to Ox or CaOx crystals as well as the HA crystals. The most significant finding of this study is the increased staining seen in renal peritubular vessels of the hyperoxaluric rats, indicating involvement of renal endothelial cells in the synthesis of MGP.

Chaga mushroom-induced oxalate nephropathy.

Chaga mushrooms have been used in folk and botanical medicine as a remedy for cancer, gastritis, ulcers, and tuberculosis of the bones. A 72-year-old Japanese female had been diagnosed with liver cancer 1 year prior to presenting at our department. She underwent hepatectomy of the left lobe 3 months later. Chaga mushroom powder (4 - 5 teaspoons per day) had been ingested for the past 6 months for liver cancer. Renal function decreased and hemodialysis was initiated. Renal biopsy specimens showed diffuse tubular atrophy and interstitial fibrosis. Oxalate crystals were detected in the tubular lumina and urinary sediment and oxalate nephropathy was diagnosed. Chaga mushrooms contain extremely high oxalate concentrations. This is the first report of a case of oxalate nephropathy associated with ingestion of Chaga mushrooms.

Hippuric acid in 24 h urine collections as a biomarker of fruits and vegetables intake in kidney stone formers.

This work aimed to underline the prospects of hippuric acid, a product of the metabolism of polyphenols, as a new biomarker of fruits and vegetables intake associated with lithogenic risk. Biochemical parameters of lithogenic risk and hippuric acid were measured in the 24 h urine collections of a cohort of 696 Italian kidney stone formers divided into two subgroups according to their different dietary habits. The link between lithogenic risk parameters and hippuric acid was assessed and this compound was revealed as a valuable biomarker of fruits and vegetables intake in kidney stone formers. A cut-off value of urinary excretion of hippuric acid, 300 mg/24 h, was set as the threshold of discrimination between low and high intake of fruits and vegetables for these patients. These results highlight the importance of monitoring of the excretion hippuric acid in urine to address proper dietary guidelines for the management of stone former patients.

Short-term alteration of nitrogen supply prior to harvest affects quality in hydroponic-cultivated spinach (Spinacia oleracea).

BACKGROUND: Quality-associated problems, such as excessive in planta accumulation of oxalate, often arise in soillessly cultivated spinach (Spinacia oleracea). Maintaining a higher level of ammonium (NH4⁺) compared to nitrate (NO3⁻) during the growth period can effectively decrease the oxalate content in hydroponically cultivated vegetables. However, long-term exposure to high concentrations of NH4⁺ induces toxicity in plants, and thus decreases the biomass production. Short-term application of NH4⁺ before harvesting in soilless cultivation may provide an alternative strategy to decrease oxalate accumulation in spinach, and minimise the yield reduction caused by NH4⁺ toxicity. RESULT: The plants were pre-cultured in 8 mmol L⁻¹ NO3⁻ nutrient solution. Next, 6 days before harvest, the plants were transferred to a nutrient solution containing 4 mmol L⁻¹ NO3⁻ and 4 mmol L⁻¹ NH4⁺. This new mix clearly reduced oxalate accumulation, increased levels of several antioxidant compounds, and enhanced antioxidant capacity in the edible parts of spinach plants, but it did not affect biomass production. However, when the 8 mmol L⁻¹ NO3⁻ was shifted to either nitrogen-free, 4 mmol L⁻¹ NH4⁺ or 8 mmol L⁻¹ NH4⁺ treatments, although some of the quality indexes were improved, yields were significantly reduced. CONCLUSIONS: Short-term alteration of nitrogen supply prior to harvest significantly affects quality and biomass of spinach plants, and we strongly recommend to simultaneously use NO3⁻ and NH4⁺ in hydroponic cultivation, which improves vegetable quality without decreasing biomass production.

Unveiling potential adverse events associated with escitalopram oxalate: A real-world analysis based FDA adverse event reporting system database.

OBJECTIVE: The study aimed to conduct a multidimensional evaluation of potential adverse events (AEs) of escitalopram oxalate based on the FDA adverse event reporting system (FAERS) database. METHODS: This study utilized the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-poisson shrinker (MGPS) to mine and analyze data from the FAERS database from the first quarter of 2004 to the second quarter of 2023. RESULTS: There was a total of 19,854 AE reports related to escitalopram oxalate, extracting 625 preferred terms (PTs), and covering 27 system organ classes (SOCs). The results showed that the number of reports by females was significantly higher than males, accounting for 57.68%. The reporting number was higher in 2018 and 2019, accounting for 9.50% and 10.18% of the total reports, respectively. The main reporters were consumers and other health professionals, accounting for 26.99% and 26.75% respectively. The majority of the reports were primarily from the United States. Newly emerging AE signals such as intentional overdose (n = 691, ROR 8.51, PRR 8.45, IC 3.05, Empirical Bayesian Geometric Mean (EBGM) 8.35), suicide attempt (n = 665, ROR 8.58, PRR 8.52, IC 3.06, EBGM 8.42), serum serotonin (n = 5, ROR 1044.78, PRR 1044.71, IC 2.56, EBGM 392.39), anti-actin antibody positive (n = 5, ROR 626.87, PRR 626.83, IC 2.56, EBGM 313.91), among others, were not mentioned in the drug's label. CONCLUSION: While escitalopram oxalate has clear benefits in the treatment of depression and other mental health disorders, the presence of AEs also suggests risks associated with its use. Particularly concerning are risks of suicide and changes in serum serotonin levels.

[Tea polyphenol protects against HK-2 cell injury induced by oxalate and calcium oxalate monohydrate crystals].

OBJECTIVE: To test whether the antioxidants tea polyphenol (TP) can provide protection against oxalate and calcium oxalate monohydrate (COM) crystals toxicity in HK-2 cells. METHODS: Four groups were chosen for the study: Negative control group, positive control group (COM+oxalate), TP group (TP+COM+oxalate), VitE group (vitamin E+COM+oxalate). HK-2 cells were exposed for 4, 8, 12 and 24 h. The viability of the cells was assessed by MTT. The cellular injury was assessed by the concentration of lactate dehydrogenase (LDH), hydrogen peroxide and viability of Na+/K+ ATP enzyme. The peroxidation level was assessed by malondialdehyde (MDA) content and viability of superoxide dismutase (SOD). The morphological changes of HK-2 cells after being exposed for 4 and 12 h in each group were observed by transmission electron microscope (TEM). RESULTS: The effects of TP and vitamin E on oxalate and COM exposed cells were tested. The HK-2 cells exposed to oxalate and COM showed a significant reduction in viability of cells, Na+/K+ ATPase and SOD. LDH release, MDA content and concentration of H2O2 were significantly increased. In TP group, the addition of TP significantly increased viability of cells, activity of Na+/K+ ATPase and SOD while LDH release, MDA content and concentration of H2O2 were significant decreased compared with the positive control group. In the Vitamn E group, compared with the positive control group, viability of cells, and activity of Na+/K+ ATPase were not significantly changed and after addition of vitamin E, SOD activity was restored, LDH release, MDA content and concentration of H2O2 were significant decreased compared with the positive control group. The morphological changes of HK-2 cells were observed by TEM in the positive control group, TP group and VitE group. In the VitE and TP groups, the amount of the cells with vacuoles formed in kytoplasms, mitochondria swelling, karyotheca dissolved and nucleolus disappearing were less than in the positive group. The morphological changes in the TP group were less than in the VitE group. CONCLUSION: TP and vitamin E administration may prevent oxalate and COM mediated peroxidative injury and restore intracellular antioxidant enzyme activity. The protection rendered by TP was greater than that of vitamin E.

The preventive effects of Ulva lactuca aqueous extract, ulvan polysaccharides and atorvastatin on ethylene glycol-induced hyperoxaluria.

OBJECTIVE: Kidney stones are a common complication of hyperoxaluria. The aim of this study is to investigate the protective and preventive effects of Ulva lactuca aqueous extract, ulvan polysaccharides and atorvastatin on ethylene glycol-induced hyperoxaluria. MATERIALS AND METHODS: Male Wistar rats between 110 and 145 g in weight were used in the study, Ulva lactuca aqueous extract and polysaccharides were prepared. The male albino rats were supplemented with 0.75 percent ethylene glycol (v/v) in their drinking water for six weeks to induce hyperoxaluria. Ulvan infusions (100 mg/kg body weight), ulvan polysaccharides (100 mg/kg body weight), and atorvastatin (two milligrams/kg body weight) to treat hyperoxaluric rats for four weeks (every other day) were used. Weight loss, serum creatinine, serum urea, serum uric acid, serum oxalate, kidney oxalate, kidney lipid peroxidation, and kidney DNA fragmentation and kidney histopathological studies were done. RESULTS: Weight loss, rise of serum creatinine, serum urea, serum uric acid, serum oxalate, kidney oxalate, kidney lipid peroxidation, and kidney DNA fragmentation were all shown to be prevented by the addition of atorvastatin, polysaccharides, or aqueous extract, respectively. Catalase (CAT) activity, glutathione peroxidase (GPX) activity, glutathione-S-transferase (GST) activity, and histopathological perturbations were all significantly reduced by the medicines that were studied. CONCLUSIONS: Hyperoxaluria caused by ethylene glycol may be prevented by a combination of Ulva lactuca aqueous extract, ulvan polysaccharides, and atorvastatin. A reduction in renal oxidative stress and an improvement of the antioxidant defense system may be responsible for these protective benefits. However, Ulva lactuca infusion and ulvan polysaccharides need to be studied further in humans, in order to determine their efficacy and safety.