Hydroxycitric acid prevents hyperoxaluric-induced nephrolithiasis and oxidative stress via activation of the Nrf2/Keap1 signaling pathway.

Nephrolithiasis is a common and frequently-occurring disease in the urinary system with high recurrence. The present study aimed to explore the protective effect and underlying mechanism of hydroxycitric acid (HCA) in hyperoxaluria-induced nephrolithiasis in vitro and in vivo. Crystal deposition and pathophysiological injury in rat models of glyoxylate-induced nephrolithiasis were examined using H&E staining. Cell models of nephrolithiasis were established by oxalate-treated renal tubular epithelial cells. The levels of oxidative stress indexes were determined by ELISA kits. Cell proliferation in vivo and in vitro was evaluated using a cell counting kit-8 (CCK-8) assay and Ki-67 cell proliferation detection kit. Cell apoptosis was measured by flow cytometry and TUNEL staining. The protein levels were examined by western blotting. Our results showed that HCA administration significantly reduced crystal deposition and kidney injury induced by glyoxylate. HCA also alleviated oxidative stress via upregulating the antioxidant enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and reducing the malondialdehyde (MDA) content. Moreover, HCA treatment promoted cell proliferation and inhibited apoptosis of renal tubular epithelial cells exposed to hyperoxaluria. Of note, Nrf2 activator dimethyl fumarate (DMF) exerted the same beneficial effects as HCA in nephrolithiasis. Mechanistically, HCA prevented crystal deposition and oxidative stress induced by hyperoxaluria through targeting the Nrf2/Keap1 antioxidant defense pathway, while knockdown of Nrf2 significantly abrogated these effects. Taken together, HCA exhibited antioxidation and anti-apoptosis activities in nephrolithiasis induced by hyperoxaluria via activating Nrf2/Keap1 pathway, suggesting that it may be an effective therapeutic agent for the prevention and treatment of nephrolithiasis.

Acetate attenuates hyperoxaluria-induced kidney injury by inhibiting macrophage infiltration via the miR-493-3p/MIF axis.

Hyperoxaluria is well known to cause renal injury and end-stage kidney disease. Previous studies suggested that acetate treatment may improve the renal function in hyperoxaluria rat model. However, its underlying mechanisms remain largely unknown. Using an ethylene glycol (EG)-induced hyperoxaluria rat model, we find the oral administration of 5% acetate reduced the elevated serum creatinine, urea, and protected against hyperoxaluria-induced renal injury and fibrosis with less infiltrated macrophages in the kidney. Treatment of acetate in renal tubular epithelial cells in vitro decrease the macrophages recruitment which might have reduced the oxalate-induced renal tubular cells injury. Mechanism dissection suggests that acetate enhanced acetylation of Histone H3 in renal tubular cells and promoted expression of miR-493-3p by increasing H3K9 and H3K27 acetylation at its promoter region. The miR-493-3p can suppress the expression of macrophage migration inhibitory factor (MIF), thus inhibiting the macrophages recruitment and reduced oxalate-induced renal tubular cells injury. Importantly, results from the in vivo rat model also demonstrate that the effects of acetate against renal injury were weakened after blocking the miR-493-3p by antagomir treatment. Together, these results suggest that acetate treatment ameliorates the hyperoxaluria-induced renal injury via inhibiting macrophages infiltration with change of the miR-493-3p/MIF signals. Acetate could be a new therapeutic approach for the treatment of oxalate nephropathy.

Oxalate homeostasis.

Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.

Nephro-protective effect of Daphnetin in hyperoxaluria-induced rat renal injury via alterations of the gut microbiota.

It is well proved that hyperoxaluria induces the renal injury and finally causes the end stage kidney disease. Daphnetin (coumarin derivative) already confirmed renal protective effect in renal model, but hyperoxaluria protective effect still unexplore. The objective of this research was to scrutinize the renal protective effect of daphnetin against ethylene glycol (GC)-induced hyperoxaluria via altering the gut microbiota. GC (1% v/v) was used for the induction of hyperoxaluria in the rats and the rats were received the oral administration of daphnetin (5, 10 and 15 mg/kg). The body and renal weight were assessed. Urine, renal, inflammatory cytokines, antioxidant, inflammatory parameters, and gut microbiota were appraised. Daphnetin effectually improved the body weight and reduced the renal weight. Its also remarkably boosted the magnesium, calcium, citrate level and suppressed the level of uric acid and oxalate formation. Daphnetin significantly (p < .001) ameliorate the level of urinary kidney injury molecule 1 (KIM-1), blood urea nitrogen (BUN), urea, serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL) and uric acid along with inflammatory cytokines and inflammatory mediators. Daphnetin considerably repressed the malonaldehyde (MDA) level, protein carbonyl and improved the level of glutathione reductase (GR), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT). Daphnetin treatment considerably altered the microbial composition of different bacteria at phylum, genus and family level. Daphnetin significantly suppressed the Firmicutes relative abundance and boosted the Bacteroidetes relative abundance. Our result clearly indicated that daphnetin remarkably ameliorates the GC induced hyperoxaluria in rats via altering the oxidative stress, inflammatory reaction and gut microbiota. PRACTICAL APPLICATION: Nephrotoxicity is a serious health disease worldwide. We induce the renal toxicity in the experimental rats using the ethylene glycol and scrutinized the renal protective effect of daphnetin. Daphnetin considerably suppress the renal, urine parameters. For estimation the underlying mechanism, we estimated the gut microbiota in all group rats. Daphnetin remarkably altered the level of gut microbiota and suggesting the renal protective effect.

Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis.

Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitute two-thirds of all kidney stones. SLC26A3 (DRA, downregulated in adenoma) is an anion exchanger of chloride, bicarbonate, and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by approximately 70% reduced urine oxalate excretion in knockout mice. We previously identified a small-molecule SLC26A3 inhibitor (DRAinh-A270) that selectively inhibited SLC26A3-mediated chloride/bicarbonate exchange (IC50 ~ 35 nM) and, as found here, oxalate/chloride exchange (IC50 ~ 60 nM). In colonic closed loops in mice, luminal DRAinh-A270 inhibited oxalate absorption by 70%. Following oral sodium oxalate loading in mice, DRAinh-A270 largely prevented the 2.5-fold increase in urine oxalate/creatinine ratio. In a mouse model of oxalate nephropathy produced by a high-oxalate low-calcium diet, vehicle-treated mice developed marked hyperoxaluria with elevated serum creatinine, renal calcium oxalate crystal deposition, and renal injury, which were largely prevented by DRAinh-A270 (10 mg/kg twice daily). DRAinh-A270 administered over 7 days to healthy mice did not show significant toxicity. Our findings support a major role of SLC26A3 in intestinal oxalate absorption and suggest the therapeutic utility of SLC26A3 inhibition for treatment of hyperoxaluria and prevention of calcium oxalate nephrolithiasis.

Successfully treated bronchopulmonary oxalosis caused by Aspergillus tubingensis in a non-neutropenic patient: A case report and review of the literature.

Pulmonary oxalosis can be fatal, and Aspergillus tubingensis is commonly resistant to azoles in Japan. We report a case of bronchopulmonary oxalosis caused by A. tubingensis in a non-neutropenic patient who was successfully treated with voriconazole monotherapy. The susceptibility of the isolates to voriconazole and the effective elimination of contagious necrotic tissue by expectoration seemed to be two major factors contributing to the patient's survival. According to the literature review, pulmonary oxalosis is associated with a high mortality rate over a short term. An exploration of detailed information about the genomic characteristics and drug susceptibility of Aspergillus isolates is important for the development of treatment strategies for this life-threatening disease.

Prospective Randomized Evaluation of Idiopathic Hyperoxaluria Treatments.

Purpose: Calcium oxalate (CaOx) stone formation is influenced by urinary oxalate excretion. Stone formers with elevated urinary oxalate are commonly prescribed a low-oxalate diet or oral supplementation with vitamin B6 and magnesium to reduce urinary oxalate excretion. This study aims to compare the effects of dietary modification vs supplementation vs a combination of both on urinary oxalate. Materials and Methods: We enrolled patients with a documented history of CaOx stones and newly diagnosed idiopathic hyperoxaluria. Patients were randomized into three treatment groups: low oxalate diet (D), supplementation with 25 mg vitamin B6 and 400 mg magnesium oxide (S), or both low oxalate diet and B6/magnesium supplementation (DS). Baseline and 3-month postintervention 24-hour urine tests were obtained. The primary endpoint was change in 24-hour urinary oxalate (Ox24) at 12 weeks. Secondary endpoints included changes in other 24-hour urine parameters, compliance rates, and adverse effect rates. Results: In total, 164 patients were recruited and 62, 47, and 55 were enrolled into the D, S, and DS groups, respectively. Of these, 99 patients completed the study (56.5% of the D, 72.3% of the S, and 54.6% of the DS groups, respectively). Significant differences were noted in median percent reduction in Ox24 values (-31.1% vs -16.0% vs -23.9%, p = 0.007) in the D, S, and DS groups, respectively. Furthermore, the percentages of patients within each treatment arm who realized a decrease in Ox24 were also found to be significantly different: D = 91.4% vs. S = 67.6% vs DS = 86.7%, p = 0.027. No significant adverse events were observed in any of the study arms. Conclusion: Low oxalate diet is more effective than B6/magnesium supplementation at lowering urinary oxalate in idiopathic hyperoxaluric stone formers. Combination therapy did not produce greater reductions in urinary oxalate than either of the monotherapy arms suggesting it is of little clinical utility. Further study with long-term longitudinal follow-up is required to determine if these treatment strategies reduce recurrent stone events in this population.

Protective Effects of Quercetin on Oxidative Stress-Induced Tubular Epithelial Damage in the Experimental Rat Hyperoxaluria Model.

Background and Objectives: The most common kidney stones are calcium stones and calcium oxalate (CaOx) stones are the most common type of calcium stones. Hyperoxaluria is an essential risk factor for the formation of these stones. Quercetin is a polyphenol with antioxidant, anti-inflammatory, and many other physiological effects. The aim of this study was to investigate the protective effect of quercetin in hyperoxaluria-induced nephrolithiasis. Materials and Methods: Male Wistar-Albino rats weighing 250-300 g (n = 24) were randomized into three groups: Control (n = 8), ethylene glycol (EG) (n = 8), and EG + quercetin (n = 8). One percent EG-water solution was given to all rats except for the control group as drinking water for five weeks. Quercetin-water solution was given to the EG + quercetin group by oral gavage at a dose of 10 mg/kg/day. Malondialdehyde (MDA), catalase (CAT), urea, calcium, and oxalate levels were analyzed in blood and urine samples. Histopathological assessments and immunohistochemical analyses for oxidative stress and inflammation indicators p38 mitogen-activated protein kinase (p38-MAPK) and nuclear factor kappa B (NF-kB) were performed on renal tissues. Results: The MDA levels were significantly lower in the quercetin-treated group than in the EG-treated group (p = 0.001). Although CAT levels were higher in the quercetin-treated group than the EG-administered group, they were not significantly different between these groups. The expression of p38 MAPK was significantly less in the quercetin-treated group than the EG group (p < 0.004). There was no statistically significant difference between the quercetin and EG groups in terms of NF-kB expression. Conclusions: We conclude that hyperoxaluria activated the signaling pathways, which facilitate the oxidative processes leading to oxalate stone formation in the kidneys. Our findings indicated that quercetin reduced damage due to hyperoxaluria. These results imply that quercetin can be considered a therapeutic agent for decreasing oxalate stone formation, especially in patients with recurrent stones due to hyperoxaluria.

Nedosiran Dramatically Reduces Serum Oxalate in Dialysis-Dependent Primary Hyperoxaluria 1: A Compassionate Use Case Report.

Primary hyperoxaluria 1 (PH1) is a devastating condition involving recurrent urolithiasis, early end-stage renal disease and multisystemic deposition of calcium oxalate crystals. Treatment options for PH1 are limited, inevitably requiring transplantation, usually combined kidney and liver transplant. Here we report successful compassionate use of Nedosiran, an RNA interference targeting lactate dehydrogenase, in an index patient. Monthly Nedosiran injections led to dramatically decreased plasma oxalate levels, decreased frequency of weekly hemodialysis sessions from 6 to 3, and deferral of combined kidney and liver transplant. Nedosiran represents a novel and impactful potential therapeutic for PH1 patients with end-stage renal disease.

Antiurolithic effects of medicinal plants: results of in vivo studies in rat models of calcium oxalate nephrolithiasis-a systematic review.

Urolithiasis is one of the oldest diseases affecting humans, while plants are one of our oldest companions providing food, shelter, and medicine. In spite of substantial progress in understanding the pathophysiological mechanisms, treatment options are still limited, often expensive for common people in most parts of the world. As a result, there is a great interest in herbal remedies for the treatment of urinary stone disease as an alternative or adjunct therapy. Numerous in vivo and in vitro studies have been carried out to understand the efficacy of herbs in reducing stone formation. We adopted PRISMA guidelines and systematically reviewed PubMed/Medline for the literature, reporting results of various herbal products on in vivo models of nephrolithiasis/urolithiasis. The Medical Subject Heading Terms (Mesh term) "Urolithiasis" was used with Boolean operator "AND" and other related Mesh Unique terms to search all the available records (July 2019). A total of 163 original articles on in vivo experiments were retrieved from PubMed indexed with the (MeshTerm) "Urolithiasis" AND "Complementary Therapies/Alternative Medicine, "Urolithiasis" AND "Plant Extracts" and "Urolithiasis" AND "Traditional Medicine". Most of the studies used ethylene glycol (EG) to induce hyperoxaluria and nephrolithiasis in rats. A variety of extraction methods including aqueous, alcoholic, hydro-alcoholic of various plant parts ranging from root bark to fruits and seeds, or a combination thereof, were utilized. All the investigations did not study all aspects of nephrolithiasis making it difficult to compare the efficacy of various treatments. Changes in the lithogenic factors and a reduction in calcium oxalate (CaOx) crystal deposition in the kidneys were, however, considered favorable outcomes of the various treatments. Less than 10% of the studies examined antioxidant and diuretic activities of the herbal treatments and concluded that their antiurolithic activities were a result of antioxidant, anti-inflammatory, and/or diuretic effects of the treatments.

Renoprotective effect of tectorigenin glycosides isolated from Iris spuria L. (Zeal) against hyperoxaluria and hyperglycemia in NRK-49Fcells.

Oxidative stress has been identified as an underlying factor in the development of insulin resistance, ß-cell dysfunction, impaired glucose tolerance and type 2 diabetes mellitus and it also play major role in kidney stone formation. The present study is aimed to elucidate the in vitro nephroprotective activity of two isoflavonoid glycosides, tectorigenin 7-O-ß-D-glucosyl-(1→6)-ß-D-glucoside (1) and tectorigenin 7-O-ß-D-glucosyl-4'-O-ß-D-glucoside (2) isolated from the n-BuOH fraction of Iris spuria L. (Zeal) rhizome MeOH extract against oxalate and high glucose-induced oxidative stress in NRK-49F cells. The results revealed that compounds 1 and 2 significantly increased the antioxidant enzyme activities and decreased MDA levels in both oxalate and high glucose stress. Treatment with these phytochemicals effectively down-regulated expression of crystal modulator genes and pro-fibrotic genes in oxalate and high glucose-mediated stress respectively. This study indicates cytoprotective, antioxidant, anti-urolithic and anti-diabetic effects of compounds 1 and 2 against oxalate and high glucose stress.[Figure: see text].

Impact of Phyllantus niruri and Lactobacillus amylovorus SGL 14 in a mouse model of dietary hyperoxaluria.

Hyperoxaluria is a pathological condition which affects long-term health of kidneys. The present study evaluates the impact of the combination of Lactobacillus amylovorus SGL 14 and the plant extract Phyllantus niruri (namely Phyllantin 14™) on dietary hyperoxaluria. Safety and efficacy of Phyllantin 14 have been evaluated in vivo. Mice C57BL6 fed a high-oxalate diet were compared to mice fed the same diet administered with Phyllantin 14 by gavage for 6 weeks. Control mice were fed a standard diet without oxalate. No adverse effects were associated to Phyllantin 14 supplementation, supporting its safety. Mice fed a high-oxalate diet developed significant hyperoxaluria and those administered with Phyllantin 14 showed a reduced level of urinary oxalate and a lower oxalate-to-creatinine ratio. Soluble and insoluble caecal oxalate were significantly lower in treated group, a finding in agreement with the colonisation study, i.e. mice were colonised with SGL 14 after 3 weeks. Microbiota analysis demonstrated that both oxalate diet and Phyllantin 14 can differently modulate the microbiota. In conclusion, our findings suggest that Phyllantin 14 supplementation represents a potential supportive approach for reducing urinary oxalate and/or for enhancing the efficacy of existing treatments.

Lessons from rodent gastric bypass model of enteric hyperoxaluria.

PURPOSE OF REVIEW: The aim of the article is to review studies on bone health and oxalate metabolism/therapeutics in the obese rodent model of Roux-en-Y gastric bypass (RYGB) and examine pathways to decrease procedural morbidity. RECENT FINDINGS: Compared with controls, RYGB rodents have up to 40-fold more fat in their stool (steatorrhea) which positively correlates to increased urinary oxalate. These unabsorbed intestinal fatty acids bind calcium and prevent gut calcium oxalate formation, increasing soluble luminal oxalate availability and absorption (enteric hyperoxaluria). When intraluminal fecal fat exceeded about 175 mg/24 h in our model, more paracellular and transcellular oxalate transport across the distal colon occurred. Increasing dietary calcium and colonization with Oxalobacter formigenes reduced hyperoxaluria, whereas vitamin B6 supplementation did not. RYGB animals, when severely calcium deficient, had bone mineral density loss that could not be rescued with vitamin D supplementation. SUMMARY: The findings of hyperoxaluria, steatorrhea, and decreased bone mineral density are seen in both human and rodent RYGB. Our model suggests that a low-fat, low-oxalate diet combined with calcium supplementation can decrease urinary oxalate and improve skeletal bone health. Our model is a useful tool to study renal and bone RYGB effects. Studies of longer duration are required to further evaluate mechanisms of disease and durability of therapeutics.

Stiripentol identifies a therapeutic target to reduce oxaluria.

PURPOSE OF REVIEW: Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly primary hyperoxaluria type I and II, threatening renal function. Ethylene glycol poisoning may induce the precipitation of calcium oxalate crystals in renal tubules, leading to acute renal failure. In both cases, oxalate results from glyoxylate transformation to oxalate in the liver, by lactate dehydrogenase (LDH) enzymes, especially the LDH-5 isoenzyme. The purpose of the review is to highlight LDH as a potential therapeutic target according to recent publications. RECENT FINDINGS: Genetic therapy targeting LDH metabolism decreases urine oxalate excretion in rodents. Stiripentol is an antiepileptic drug that has been shown recently to inhibit neuronal LDH-5 isoenzyme. Stiripentol was hypothesized to reduce hepatic oxalate production and urine oxalate excretion. In vitro, stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol oral administration decreases urine oxalate excretion in rats and protects renal function and renal tissue against ethylene glycol intoxication and chronic calcium oxalate crystalline nephropathy. SUMMARY: The use of stiripentol in-vitro and in-vivo highlights that targeting hepatic LDH by pharmacological or genetic tools may decrease oxalate synthesis, deserving clinical studies.

Rosiglitazone Suppresses Calcium Oxalate Crystal Binding and Oxalate-Induced Oxidative Stress in Renal Epithelial Cells by Promoting PPAR-γ Activation and Subsequent Regulation of TGF-ß1 and HGF Expression.

Peroxisome proliferator-activated receptor- (PPAR-) γ is a ligand-dependent transcription factor, and it has become evident that PPAR-γ agonists have renoprotective effects, but their influence and mechanism during the development of calcium oxalate (CaOx) nephrolithiasis remain unknown. Rosiglitazone (RSG) was used as a representative PPAR-γ agonist in our experiments. The expression of transforming growth factor-ß1 (TGF-ß1), hepatocyte growth factor (HGF), c-Met, p-Met, PPAR-γ, p-PPAR-γ (Ser112), Smad2, Smad3, pSmad2/3, and Smad7 was examined in oxalate-treated Madin-Darby canine kidney (MDCK) cells and a stone-forming rat model. A CCK-8 assay was used to evaluate the effects of RSG on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were monitored, and lipid peroxidation in renal tissue was detected according to superoxide dismutase and malondialdehyde levels. Moreover, the location and extent of CaOx crystal deposition were evaluated by Pizzolato staining. Our results showed that, both in vitro and in vivo, oxalate impaired PPAR-γ expression and phosphorylation, and then accumulative ROS production was observed, accompanied by enhanced TGF-ß1 and reduced HGF. These phenomena could be reversed by the addition of RSG. RSG also promoted cell viability and proliferation and decreased oxidative stress damage and CaOx crystal deposition. However, these protective effects of RSG were abrogated by the PPAR-γ-specific inhibitor GW9662. Our results revealed that the reduction of PPAR-γ activity played a critical role in oxalate-induced ROS damage and CaOx stone formation. RSG can regulate TGF-ß1 and HGF/c-Met through PPAR-γ to exert antioxidant effects against hyperoxaluria and alleviate crystal deposition. Therefore, PPAR-γ agonists may be expected to be a novel therapy for nephrolithiasis, and this effect is related to PPAR-γ-dependent suppression of oxidative stress.

ALLN-177, oral enzyme therapy for hyperoxaluria.

PURPOSE: To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS: Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3 × day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS: The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI - 23.71, - 4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (- 2.8; 95% CI - 4.9, - 0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION: ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria. TRIAL REGISTRATION: Clinicaltrials.gov NCT02289755.

Protective effect of pentoxifylline on oxidative renal cell injury associated with renal crystal formation in a hyperoxaluric rat model.

The aim of the study is to investigate the effects of pentoxifylline (PTX) on the renal tubular cell injury and stone formation in a hyperoxaluric rat model induced by ethylene glycol and its possible underlying mechanisms. The study was performed with 30 male Wistar rats and randomized into three groups of teen. The sham-control (group 1) received only drinking water orally. The EG/untreated (group 2) received drinking water containing 0.75% EG for 4 weeks orally. The EG/PTX treated (group 3) received drinking water containing 0.75% EG for 4 weeks orally and PTX. Urine and blood were collected to determine some parameters. The kidneys were also removed for histological examination. Serum and urinary parameters were significantly improved in the EG/PTX treated. In the EG/PTX-treated group, the MDA, TOS and MPO activity reduced and the TAS, SOD, CAT and GSH-Px activities were increased markedly compared with the group 2. In urine of the group 2 rats, a large number of CaOx crystals were displayed and most tubules that contained crystals were dilated and showed degeneration, necrosis, and desquamation of the lining epithelium. Only few CaOx crystals were r in EG/PTX-treated animal's urine. Mild tissue damage was observed in PTX-treated rats. iNOS expression was significantly elevated in the group 2. In contrast, in the EG/PTX-treated group, eNOS expression in renal tubular epithelial cells was increased. Current study indicates that PTX may partially reduce renal tubular injury resulting from hyperoxaluria-induced oxidative and nitrosative stress.

The Effect of Calcium and Vitamin B6 Supplementation on Oxalate Excretion in a Rodent Gastric Bypass Model of Enteric Hyperoxaluria.

OBJECTIVE: To test the effect of calcium and vitamin B6 therapies on urinary oxalate excretion in a rodent model of enteric hyperoxaluria after Roux-en Y gastric bypass (RYGB) surgery. METHODS: Obese male Sprague-Dawley rats underwent sham (n = 7) or RYGB (n = 10). Animals were maintained on low oxalate (1.5%) and fat (10%; LOF), normal calcium (0.6 %) diet for 8 weeks and then completed a 2-phase crossover metabolic study. In the first 2-week phase, animals were fed a Low oxalate and fat (LOF), high calcium (2.4%; HC) diet. After a 2-week washout, rats were fed a LOF/normal calcium diet highly enriched with vitamin B6. Urine was collected before and after each intervention. Plasma pyridoxal 5'-phosphate (PLP) and metabolites were measured baseline and 11 weeks after sham or RYGB. RESULTS: Compared to baseline, sham animals on LOF/HC diet doubled their urinary calcium excretion but not oxalate. RYGB animals on LOF/HC diet decreased urinary oxalate excretion 28% (P = .001) without a significant rise in urinary calcium. Vitamin B6 supplementation decreased RYGB urinary oxalate by approximately 15% (P = .06), and serum PLP explained 63% of urinary oxalate variability. CONCLUSION: Based on the findings in this model, calcium supplementation appears to be a reasonable therapy to decrease urinary oxalate in RYGB patients who maintain a low fat and oxalate diet. Serum PLP had a fair correlation to urinary oxalate excretion and may be a useful screening tool in hyperoxaluric RYGB patients. Further experimental human studies after RYGB are necessary to determine whether these commonly employed supplements truly provide a benefit in enteric hyperoxaluria.

Designer probiotic Lactobacillus plantarum expressing oxalate decarboxylase developed using group II intron degrades intestinal oxalate in hyperoxaluric rats.

Increased intestinal absorption of oxalate causes hyperoxaluria, a major risk factor for kidney stone disease. Intestinal colonization of recombinant probiotic bacteria expressing oxalate-degrading gene (OxdC) is an effective therapeutic option for recurrent calcium oxalate (CaOx) stone disease. Therefore, we aimed to develop food-grade probiotic L. plantarum secreting OxdC using lactococcal group II intron, Ll.LtrB and evaluate its oxalate degradation ability in vivo. Male Wistar albino rats were divided into four groups. The rats of group I received normal rat chow and drinking water. Groups II, III and IV rats received 5% potassium oxalate containing diet for 28 days. Groups III and IV rats received L. plantarum and food-grade recombinant L. plantarum respectively from 15 to 28 days. Biochemical parameters and crystalluria were analysed in 24 h urine samples. At the end of experimental period, rats were sacrificed; intestine and kidneys were dissected out for colonization studies and histopathological analysis. Herein, we found that the administration of recombinant probiotics significantly reduced the urinary oxalate, calcium, urea, and creatinine levels in rats of group IV compared to group II. Furthermore, colonization studies indicated that recombinant probiotics have gastrointestinal transit and intestinal colonization ability similar to that of wild-type bacteria. In addition, gene expression studies revealed down-regulation of OPN and KIM-1 among group IV rats. Histopathological analysis showed less evidence of nephrocalcinosis in group IV rats. In conclusion, the study demonstrates that food-grade L. plantarum secreting OxdC is capable of degrading intestinal oxalate and thereby prevent CaOx stone formation in experimental rats.