Nephrolithiasis in two patients on iron chelation therapy: A case report.

Drug-induced nephrolithiasis can arise from insoluble components within medications or crystallization of metabolites due to changes in metabolism and urinary pH. The connection between drugs utilized for iron chelation therapy (ICT) and nephrolithiasis is not well understood. In this report, we describe two pediatric patients diagnosed with nephrolithiasis while undergoing treatment with the chelating agents deferasirox, deferiprone, and deferoxamine for iron overload secondary to repeat blood transfusion.

Effect of Carnosine on the Activity of Matrix Metalloproteinase-2 and Oxidative Stress in the Kidneys in Experimental Urate Nephrolithiasis.

The effect of carnosine on MMP-2 activity and oxidative stress in the kidneys in experimental urate nephrolithiasis was studied. Urate nephrolithiasis was modeled in Wistar rats by intragastric administration of a mixture of oxonic and uric acids. Carnosine was administered intragastrically through a tube in a dose of 15 mg/kg. In rats treated with carnosine, the concentration of MMP-2 in the urine decreased by 3.7 times, and the excretion of MMP-2 with urine decreased by 4.3 times. In the homogenate of the kidneys from rats treated with carnosine, the concentration of TBA-reactive substances decreased by 5 times and the concentration of MMP-2 decreased by 12.7%. After treatment with carnosine, the number of histologically confirmed cases of urate nephrolithiasis decreased by 2 times, while the mean size of urate deposits decreased by 2.7 times. Thus, carnosine inhibits MMP-2 and reduces the intensity of oxidative stress in the kidneys, which prevents the development of urate nephrolithiasis.

A pilot dynamic analysis of formative factors of nephrolithiasis related to metabolic syndrome: evidence in a rat model.

INTRODUCTION AND OBJECTIVE: To examine the dynamic changes in the formative factors of nephrolithiasis and the final micromorphological changes in an obesity-initiated metabolic syndrome (MS) rat model. METHODS: Forty five-week-old male Sprague-Dawley (SD) rats were randomly divided into four groups: the regular diet group (RD), high-fat diet group (HFD), regular diet with drug (ethylene glycol and ammonium chloride) group (RDD), and high-fat diet with drug group (HFDD). A dynamic assessment of MS components (body weight (BW), body length (BL), Lee's index (LI), blood glucose (BG), total cholesterol (TC), and triglycerides (TGs)) and stone-forming factors (urinary pH, urinary calcium, and urinary oxalate acid) was carried out. In addition, the levels of oxidative stress (OS) markers (CAT, SOD, TAC, GSH-PX, and MDA) were measured, and histological analysis was carried out at the end of 16 weeks. RESULTS: MS-related parameters, such as BW, LI, BG, TC, and TG, were significantly higher in HFD-fed rats than in RD-fed rats (p < 0.001). In the HFDD group, significantly lower urinary pH, hyperoxaluria, and hypocalciuria were noted in the dynamic assessment of stone-forming factors (p < 0.001). CAT, TAC, and MDA were notably changed in the HFD-fed groups, particularly the HFDD rats. Histological analysis showed that the renal tubules of HFDD rats had the highest scores for both inflammation and renal crystallization deposition (p < 0.05). CONCLUSIONS: Our results suggest that male SD rats with MS are prone to developing nephrolithiasis. Validation in an in vivo model may lead to an understanding of the underlying pathophysiological mechanisms of action of MS-related nephrolithiasis in humans.Key messagesMale SD rats with metabolic syndrome are more prone to developing calcium oxalate nephrolithiasis after treatment with ethylene glycol and ammonium chloride compared to control lean rats.MS-related nephrolithiasis in rats induced by ethylene glycol and ammonium chloride is mainly related to increased hyperoxaluria and inflammation and decreased antioxidant levels.High-fat diet-fed SD rats treated with ethylene glycol and ammonium chloride are a stable and valid in vivo model for understanding the potential mechanism of action of MS-related nephrolithiasis.

Glycine suppresses kidney calcium oxalate crystal depositions via regulating urinary excretions of oxalate and citrate.

An abnormal urine composition is a key reason for kidney stone formation, but little is known about the roles of small metabolites in the urine during kidney stone formation. Here, we found urine glycine in patients with kidney calcium oxalate (CaOx) stone was significantly lower than that in healthy people via 1 H NMR spectra detection, and investigated the role and underlying mechanism of glycine in the regulation of CaOx stone formation. Our results showed that glycine could significantly attenuate ethylene glycol-induced CaOx crystal depositions in rat kidney via decreasing urine oxalate and increasing urine citrate. Mechanism studies revealed that glycine could decrease urine oxalate through downregulating Slc26a6 expression, whereas increase urine citrate via inhibiting Nadc1 expression. Moreover, glycine decreased the protein expression of both Slc26a6 and Nadc1 via increasing the expression of miRNA-411-3p, which directly bound to the 3'-untranslated regions of Slc26a6 and Nadc1 messenger RNAs, in vitro and in vivo. Together, our results revealed a novel role of glycine in the regulation of kidney CaOx crystal formation and provided a potential target for the treatment of kidney CaOx stone.

Atorvastatin inhibits renal inflammatory response induced by calcium oxalate crystals via inhibiting the activation of TLR4/NF-κB and NLRP3 inflammasome.

This study aimed to investigate the renal protective effect of atorvastatin (ATV) on the kidney inflammation induced by calcium oxalate (CaOx) crystals. A cell model of cell-crystal interactions and a rat model of CaOx kidney stone were established. The expressions of TLR4, NF-κB, NLRP3, and cleaved caspase-1 in cells and rat kidney tissues were detected using Western blot, immunohistochemical, and/or immunofluorescence. The concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS) in cells, and lactic acid dehydrogenase (LDH) in the culture medium were measured. The secreted levels of interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were examined by ELISA. The serum levels of creatinine (CRE) and blood urea nitrogen (BUN) were measured. von Kossa staining was used for the evaluation of renal lens deposition. The CaOx model group showed significantly decreased SOD level; increased concentrations of MDA; ROS and LDH; elevated expressions of TLR4, NF-κB, NLRP3, and cleaved caspase-1; and the elevated release of IL-1ß, IL-18, IL-6, and TNF- α as compared to the control group. The treatment with ATV significantly inhibited the formation of CaOx kidney stone by increasing the level of SOD; downregulating MDA, ROS, and LDH; inhibiting the expressions of TLR4, NF-κB, NLRP3 and cleaved caspase-1; and blocking the secretion of inflammatory cytokines. In addition, the serum levels of CRE and BUN, and the intrarenal crystal deposition were also significantly decreased in ATV-treated rats. In summary, oxidative stress, TLR4/NF-κB, and NLRP3 inflammasome pathways are involved in renal inflammatory responses induced by CaOx crystals. ATV treatment significantly suppressed oxidative stress, inhibited the activation of TLR4/NF-κB and NLRP3 inflammasome pathways, and decreased the release of inflammatory mediators, thereby ameliorating CaOx crystal-induced damage and crystal deposition in HK-2 cells and rat kidney tissues.

Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila.

Nephrolithiasis is one of the most common kidney diseases, with poorly understood pathophysiology, but experimental study has been hindered by lack of experimentally tractable models. Drosophila melanogaster is a useful model organism for renal diseases because of genetic and functional similarities of Malpighian (renal) tubules with the human kidney. Here, we demonstrated function of the sex-determining region Y protein-interacting protein-1 (Sip1) gene, an ortholog of human Na+/H+ exchanger regulatory factor (NHERF1), in Drosophila Malpighian tubules and its impact on nephrolithiasis. Abundant birefringent calculi were observed in Sip1 mutant flies, and the phenotype was also observed in renal stellate cell-specific RNA interference Sip1 knockdown in otherwise normal flies, confirming a renal etiology. This phenotype was abolished in rosy mutant flies (which model human xanthinuria) and by the xanthine oxidase inhibitor allopurinol, suggesting that the calculi were of uric acid. This was confirmed by direct biochemical assay for urate. Stones rapidly dissolved when the tubule was bathed in alkaline media, suggesting that Sip1 knockdown was acidifying the tubule. SIP1 was shown to collocate with Na+/H+ exchanger isoform 2 (NHE2) and with moesin in stellate cells. Knockdown of NHE2 specifically to the stellate cells also increased renal uric acid stone formation, and so a model was developed in which SIP1 normally regulates NHE2 activity and luminal pH, ultimately leading to uric acid stone formation. Drosophila renal tubules may thus offer a useful model for urate nephrolithiasis.

Antibiotic Use and Risk of Incident Kidney Stones in Female Nurses.

RATIONALE & OBJECTIVE: The intestinal microbiome may affect urinary stone disease by modulating the amount of oxalate absorbed from the intestine and subsequently excreted in urine. This study sought to explore the association between antibiotics, which alter the intestinal microbiota, and risk for urinary stone disease. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 5,010 women in the Nurses' Health Study (NHS) I and II who had collected 24-hour urine samples. EXPOSURES: Use of antibiotics during the age range of 40 to 49 (NHS II), 40 to 59 (NHS I), and 20 to 39 years (both cohorts). OUTCOMES: Incident symptomatic urinary stone disease; urine composition. ANALYTICAL APPROACH: Cause-specific hazards regression adjusted for age, body mass index, comorbid conditions, thiazide use, and dietary factors. Follow-up was censored at the time of asymptomatic kidney stones, cancer, or death. RESULTS: Cumulative use of antibiotics for a total of 2 or more months during the age range of 40 to 49 years (NHS II) and 40 to 59 years (NHS II) was associated with significantly higher risk for developing incident stones compared with no use (pooled HR, 1.48; 95% CI, 1.12-1.96). Similar results were found for the period of 20 to 39 years (pooled HR, 1.36; 95% CI, 1.00-1.84). Results were unchanged after excluding participants who reported urinary tract infection with their stone event or as the most common reason for antibiotic use. Urine composition was generally similar across antibiotic groups except for marginally lower urine pH and citrate values among those taking antibiotics for 2 or more months. LIMITATIONS: Observational design; lack of information for type of antibiotic used; relatively large span of time between antibiotic use and urine collection. CONCLUSIONS: Use of antibiotics for more than 2 months in early adulthood and middle age is associated with higher risk for urinary stone disease in later life.

Association of sirtuin 1 gene polymorphisms with nephrolithiasis in Eastern chinese population.

Sirtuin 1 (SIRT1), an NAD+-dependent deacylase, has been identified to be associated with renal tubular inflammatory conditions and metabolic disorders, which are risk factors of nephrolithiasis. To further confirm the role of the SIRT1 in kidney stone formation, the expression of SIRT1 was analyzed based on a mouse model and the genetic polymorphisms of SIRT1 gene was compared between patients with kidney stones and controls. The calcium oxalate (CaOx) crystal-induced renal injury model was established to analyzed the expression of SIRT1 in the kidney tissue of both wild-type and ApoE(-/-) mice. And a total of 430 Eastern Chinese subjects (215 patients with nephrolithiasis and 215 age- and gender-matched controls) were recruited for the present study to investigate the associations between 6 common single nucleotide polymorphisms (SNPs) (i.e., rs10509291, rs3740051, rs932658, rs33957861, rs3818292 and rs1467568) in the SIRT1 gene and the incidence of kidney stones. Pairwise linkage disequilibrium and the haplotypes of the 6 SNPs were also analyzed. The genotypes of SIRT1 gene polymorphisms were analyzed by a Snapshot assay. Reduced expression of SIRT1 was observed in the kidney of the mice in the crystal group, revealing the potential role of SIRT1 in the nephrolithiasis. However, we did not find a significant association between the 6 SNPs of the SIRT1 gene and kidney stone formation in the Eastern Chinese population.

Protective potential of Angelica sinensis polysaccharide extract against ethylene glycol-induced calcium oxalate urolithiasis.

PURPOSE: To evaluate a Angelica sinensis polysaccharide aqueous extract as a preventive agent in experimentally induced urolithiasis using in- vitro and vivo models. MATERIAL AND METHODS: Angelica sinensis polysaccharide was investigated in vitro to determine its antilithiatic effects on the formation and morphology of calcium oxalate (CaOx) crystals and was analyzed in vivo to determine its ability to prevent CaOx urolithiasis in rats subjected to ethylene glycol-induced urolithiasis. Potassium citrate administration was used in the positive control group. The urolithiasis-related biochemical parameters were evaluated in the rats urine, serum and kidney homogenates. Kidney sections were subjected to histopathological and immunohistochemical analyses, and urolithiasis-related phospho-c-Jun NH2-terminal protein kinase and kidney injury molecule-1proteins were evaluated by Western blot analyses. RESULTS: Angelica sinensis polysaccharide exhibited concentration-dependent inhibition of CaOx crystal formation. The in vitro assay revealed significant inhibition of crystal formation (6.99 ± 1.07) in the group treated with 4.0 mg/mL Angelica sinensis polysaccharide extract compared with the control group (58.38 ± 5.63; p < .05). In vivo, after treatment with ethylene glycol for 28 days, urinary oxidative stress, oxalate, creatinine, urea and urolithiasis-related protein were significantly increased (p < .05), except for serum oxidative stress (p > .05). The rats administered the extract of Angelica sinensis polysaccharide showed significantly decreased pathological change and CaOx deposition (p < .05) compared with the urolithiatic rats. Significantly reduced levels of urinary oxidative stress, oxalate, creatinine, urea and urolithiasis-related protein were observed in the Angelica sinensis polysaccharide treatment groups (p < .05) compared with the nephrolithic rats. CONCLUSION: The results presented here suggest that Angelica sinensis polysaccharide has the potential to inhibit CaOx crystallization in vitro and may present anti-urolithiatic effects in vivo.

Nephrolithiasis against type 2 diabetes mellitus: on the effect of hypoglycemic therapy on lithogenesis.

AIM: To study the effects of oral hypoglycemic agents that can affect the probability of recurrence of nephrolithiasis. MATERIALS AND METHODS: The article is based on the results of examination and treatment of 315 patients suffering from recurrent nephroli-thiasis and medically compensated type 2 diabetes mellitus treated at the N.A. Lopatkin Institute of Urology and Interventional Radio-logy - the branch of the SMRC of Radiology, Ministry of Health of Russia and D.D. Pletnev City Hospital Moscow Healthcare -Department in 2012-2017. The patients were divided into three groups according to the applied tool antidiabetic: metformin, glibenclamide, canagliflozin. The control group consisted of patients receiving insulin therapy. RESULTS: The propensity of Metformin to reduce the pH of urine, which has a negative impact in the conditions of urate nephrolithiasis, which is most common in the population of patients with type 2 diabetes mellitus. Glibenclamide, on the contrary, somewhat latches urine. But changes in the reaction of urine under the influence of the drug do not go beyond normal values and are not clinically significant. Canagliflozin increases diuresis due to medication induced glycosuria and stimulates renal excretion of uric acid and its salts. However canagliflozin does not cause significant shifts in the pH of urine that may somewhat negates the increased risk of recurrence of urate stone formation in the background of the uricosuric effect of the drug. CONCLUSION: Drug therapy of type 2 diabetes mellitus significantly affects the properties of urine from patients with nephrolithiasis.

A Drosophila genetic model of nephrolithiasis: transcriptional changes in response to diet induced stone formation.

BACKGROUND: Urolithiasis is a significant healthcare issue but the pathophysiology of stone disease remains poorly understood. Drosophila Malpighian tubules were known to share similar physiological function to human renal tubules. We have used Drosophila as a genetic model to study the transcriptional response to stone formation secondary to dietary manipulation. METHODS: Wild-type male flies were raised on standard medium supplemented with lithogenic agents: control, sodium oxalate (NaOx) and ethylene glycol (EG). At 2 weeks, Malpighian tubules were dissected under polarized microscope to visualize crystals. The parallel group was dissected for RNA extraction and subsequent next-generation RNA sequencing. RESULTS: Crystal formation was visualized in 20%(±2.2) of flies on control diet, 73%(±3.6) on NaOx diet and 84%(±2.2) on EG diet. Differentially expressed genes were identified in flies fed with NaOx and EG diet comparing with the control group. Fifty-eight genes were differentially expressed (FDR <0.05, p < 0.05) in NaOx diet and 20 genes in EG diet. The molecular function of differentially expressed genes were assessed. Among these, Nervana 3, Eaat1 (Excitatory amino acid transporter 1), CG7912, CG5404, CG3036 worked as ion transmembrane transporters, which were possibly involved in stone pathogenesis. CONCLUSIONS: We have shown that by dietary modification, stone formation can be manipulated and visualized in Drosophila Malpighian tubules. This genetic model could be potentially used to identify the candidate genes that influence stone risk hence providing more insight to the pathogenesis of human stone disease.

[Comparative estimation of antilithogenic activity of porcine kidney derived biomedical substance and sodium citrate in experimental urolithiasis].

AIM: to compare the anti-lithogenic activity of biomedical substance derived from freeze-dried porcine kidney and sodium citrate. MATERIALS AND METHODS: The experiments were conducted on Wistar rats divided into three groups of 15 animals each: control group (disease control), comparison group (sodium citrate treatment) and experimental group (treatment with biomedical substance from porcine kidneys). Experimental urolithiasis was modeled using the ethylene glycol model. On every 7th day of the 6 week experiment testing was done calcium and oxalate urine concentration and the activity of marker enzymes of renal epithelial damage: lactate dehydrogenase (LDH), -glutamyl transferase (GGT), and N-acetyl--D-glucosaminidase (NAG). At the end of the experiment, a part of the rats were decapitated and the renal tissue was tested for the oxidant status indicators of (renal thiobarbiturate reactive product content, TBRP, and total prooxidant activity, TPA) and antioxidant enzyme activities: glutathione peroxidase (GPO), superoxide dismutase (SOD) and catalase (CAT). To measure the number and size of calcium deposits formed in the renal papillary area, the Koss histochemical method was used. RESULTS: The experimental findings showed developing oxalate nephrolithiasis in the control group, as indicated by urinary supersaturation of oxalate ion, increased activity of marker enzymes, oxidative stress and the formation of numerous calcium deposits in the renal papillary area. In the comparison group, the 3-week use of sodium citrate contributed to a significant decrease in nephrolithiasis: a 3 to 4-fold decrease in the activity of marker enzymes in the urine, a 3.8-fold increase in the concentration of TBRP, normalization of GPO activity; the number and size of urinary calcium deposits decreased by 3.4 and 1.9 times, respectively. In the experimental group, using biomedical substance led to an even greater therapeutic effect. LDH activity and concentration of TPRP showed 1.9 times and by 26.2% greater decrease than in the comparison group, respectively, SOD and CAT activity almost doubled, there were 3.6 times fewer calcium deposits in the field of view and their mean size was 1.7 times smaller than in the comparison group. CONCLUSION: The study findings showed that the porcine kidney derived biomedical substance provide significantly greater antilithogenic effect than sodium citrate.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.

Nephrotoxicity of Natural Products.

BACKGROUND: The manufacture and sale of natural products constitute a multi-billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. SUMMARY: This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. KEY MESSAGES: The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education.

Prospective study of nephrolithiasis occurrence in children receiving cefotriaxone.

AIM: Ceftriaxone is a commonly used antibiotic among the paediatric population. Various reports have associated high doses of Ceftriaxone with the development of nephrolithiasis; our aim was to test this association with a 5 day course of treatment. METHODS: Our study group consisted of 120 patients divided into two groups. The first group included 60 patients who underwent treatment with Ceftriaxone therapy that was started empirically and continued for 5 days at the dose of 80 mg/kg per day. The second group (60 patients) who received treatment with other antibiotics (other than Ceftriaxone), as recommended by hospital protocols. Patients with urinary tract infections (UTI) were excluded as UTI may be a predisposing cause for nephrolithiasis. Baseline and follow up after 5 days were done with; abdominal ultrasound, serum urea, creatinine, serum calcium, 24 h urinary calcium and urinary calcium/ creatinine ratio. Extended metabolic tests were done for cases that developed nephrolithiasis. RESULTS: Five cases out of the 60 patients treated with Ceftriaxone developed calculi; that were small and were eliminated spontaneously in four cases at mean duration of 3 weeks. In these cases renal ultrasonography examinations were normal prior to treatment; and none of them had metabolic disturbances or risk factors leading to stone formation. By multiple regression analysis, only age was related to nephrolithiasis formation being higher in the group that has developed stones. CONCLUSION: Only patients who underwent Ceftriaxone therapy have developed renal stones, even with a short course of therapy (5 days), and in the absence of a known predisposing cause for nephrolithiasis. We have thus concluded that Ceftriaxone by itself maybe a predisposing factor for nephrolithiasis.

Acetazolamide-Induced Nephrolithiasis in Idiopathic Intracranial Hypertension Patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure of unknown cause. Acetazolamide is widely used as the initial treatment option; however, previously published evidence suggests that this drug may also increase the risk of nephrolithiasis. The purpose of this study was to examine daily acetazolamide use and its relationship to nephrolithiasis and compare clinical presentation of IIH between those with and without nephrolithiasis. METHODS: We conducted a case-control study using patient data collected by the Intracranial Hypertension Registry. A total of 670 patients were identified as potential study participants, 19 meeting the case definition of developing a stone during acetazolamide treatment for IIH. From the remaining pool of eligible participants, 40 controls were randomly selected. Two-sampled t tests, Fisher exact testing, and exact logistic regression were used to examine differences between cases and controls and to ascertain associations with IIH clinical features and mean daily acetazolamide dosage. RESULTS: Among all eligible patients, 19 (2.8%) developed a stone during acetazolamide treatment for IIH. Among these patients, 17 (89.5%) developed a stone within 1.5 years of initial acetazolamide treatment. Daily acetazolamide use was not significantly related to stone development (odds ratio = 0.95; 95% confidence intervals: 0.86-1.05). Additionally, the relationship between the clinical presentation of IIH at the time of diagnosis (signs and symptoms) and stone development did not reach statistical significance (P > 0.05). CONCLUSIONS: Our results demonstrate that: 1) stone formation during acetazolamide treatment is a relatively infrequent occurrence within the IIH population; 2) among patients who develop a stone, formation is likely to occur within the first year and half; 3) there is no evidence to support the association between acetazolamide daily dosage and stone development; and 4) no unique IIH disease features at the time of diagnosis are associated with stone development. Treatment with acetazolamide should be administered to IIH patients with caution and closely monitored for stone development especially within the first year and a half of treatment.

Phenotype standardization for drug-induced kidney disease.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition.

The selective NADPH oxidase inhibitor apocynin has potential prophylactic effects on melamine-related nephrolithiasis in vitro and in vivo.

The objective of this study is to examine the effects of apocynin on melamine-cyanuric acid mixture (MCM)-induced nephrolithiasis in vitro and in vivo. For the in vitro experiments, changes in oxidative stress (OS) markers and the expression of osteopontin (OPN) and phospho-p38 (p-p38) were measured to assess the effects of apocynin treatment after MCM-induced crystallization in HK-2 cells, a human renal epithelial-derived cell line. For in vivo studies, the potential effects of apocynin in preventing and treating nephrolithiasis were analyzed with a MCM-induced nephrolithiasis rat model, and urea and creatinine levels were measured. Urinary 8-IP (a product of lipid peroxidation) and malondialdehyde levels and superoxide dismutase activity were assessed in the kidneys as markers of renal OS. The kidneys were removed, weighed, and subjected to histopathological examination. The urolithiasis-associated proteins p-p38 and OPN were evaluated by immunohistochemistry and Western blotting. Apocynin treatment prevented the MCM-induced changes in OS and in OPN and p-p38 expression in HK-2 cells. For in vivo experiments, the expression of OS markers, renal OPN, and p-p38 increased after MCM administration, and these increases were diminished by apocynin. In addition, apocynin prevented MCM-induced renal crystallization. Moreover, prophylactic apocynin treatment reduced MCM-induced nephrotoxicity. After therapeutic apocynin treatment in nephrolithic rats, OS decreased, but the other indicators did not improve significantly. Prophylactic apocynin administration reduced renal melamine-related-crystal deposition, potentially by modulating OS and thereby decreasing p-p38 and OPN expression.

Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats.

OBJECTIVE: In this study, anti-inflammatory effects of Royal Jelly were investigated by inducing renal inflammation in rats with the use of ethylene glycol. For this purpose, the calcium oxalate urolithiasis model was obtained by feeding rats with ethylene glycol in drinking water. MATERIALS AND METHODS: The rats were divided in five study groups. The 1st group was determined as the control group. The rats in the 2nd group received ethylene glycol (1%) in drinking water. The rats in the 3rd group were daily fed with Royal Jelly by using oral gavage. The 4th group was determined as the preventive group and the rats were fed with ethylene glycol (1%) in drinking water while receiving Royal Jelly via oral gavage. The 5th group was determined as the therapeutic group and received ethylene glycol in drinking water during the first 2 weeks of the study and Royal Jelly via oral gavage during the last 2 weeks of the study. RESULTS: At the end of the study, proinflammatory/anti-inflammatory cytokines, TNF-a, IL-1ß and IL-18 levels in blood and renal tissue samples from the rats used in the application were measured. CONCLUSION: The results have shown that ethylene glycol does induce inflammation and renal damage. This can cause the formation of reactive oxygen species. Royal Jelly is also considered to have anti-inflammatory effects due to its possible antiradical and antioxidative effects. It can have positive effects on both the prevention of urolithiasis and possible inflammation during the existing urolithiasis and support the medical treatment.

[Metabolic therapy of nephrolithiasis in two different rat models of kidney disease].

108 albino male rats were used in two experimental rat models reproducing urolithiasis for the assessment of metabolic drug medicine Remaxol nephroprotective effect upon the development of this disease. "Ethyleneglycol" model consisted of adding 1% ethylene glycol solution in drinking water for 37 days and "fructose-induced" one--of adding 10% fructose solution in drinking water for the same period. Therapy included a 10-day course of daily i.v. injections of Remaxol (14 ml/kg). Both experimental models were successful in producing urolithiasis with considerable disturbances in the structure and functioning of kidneys up to revealing microconcrement formation. The "ethyleneglycol" model proved to cause maximum changes while the "Fructose-induced" model--only moderate ones. Metabolic correction of these changes was successful in nephroprotection effectively normalizing kidney functions and the total protein concentration, eliminating hyperglycemia and reducing creatinine and urea blood plasma concentration in both rat experimental models.