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GS-441524 is an adenosine nucleoside antiviral demonstrating significant efficacy in the treatment of feline infectious peritonitis (FIP), an otherwise fatal illness, resulting from infection with feline coronavirus. However, following the emergence of COVID-19, veterinary development was halted, and Gilead pursued clinical development of a GS-441524 pro-drug, resulting in the approval of Remdesivir under an FDA emergency use authorization. Despite lack of regulatory approval, GS-441524 is available without a prescription through various unlicensed online distributors and is commonly purchased by pet owners for the treatment of FIP. Herein, we report data obtained from the analytical characterization of two feline renal calculi, demonstrating the propensity for GS-441524 to cause renal toxicity through drug-induced crystal nephropathy in vivo. As definitive diagnosis of drug-induced crystal nephropathy requires confirmation of the lithogenic material to accurately attribute a mechanism of toxicity, renal stone composition and crystalline matrix were characterized using ultra-performance liquid chromatography photodiode array detection (UPLC-PDA), ultra-performance liquid chromatography mass spectrometry (LCMS), nuclear magnetic resonance (NMR) spectroscopy, X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). This work serves to provide the first analytical confirmation of GS-441524-induced crystal nephropathy in an effort to support toxicologic identification of adverse renal effects caused by administration of GS-441524 or any pro-drug thereof., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Plastic pollution is a growing concern. It can form smaller particles called microplastics (<5 mm). Microplastics can break down into even smaller pieces called nanoplastics (<1 μm). These minute particles can infiltrate human cells and tissues, with their health impacts still largely undetermined. On average, a liter of bottled water includes about 240,000 tiny pieces of plastic. The purpose of this study was to evaluate the association between the use of bottled plastic water (BW) and several health outcomes. Utilizing data from the Italian National Institute of Statistics' "Aspects of Daily Life" survey (N = 45,597), we employed logistic regression to explore the correlation between BW consumption and the prevalence of various chronic diseases, including hypertension, gastric/duodenal ulcers, and kidney stones. Adjustments were made for covariates such as education, age, gender, and economic resources. Our analysis indicated a statistically significant association between BW consumption and increased risk of hypertension (Odds ratio [OR] = 1.05, 95% confidence interval [CI] 1.00-1.11), diabetes (OR = 1.09, 95% CI 1.01-1.18), gastric/duodenal ulcers (OR = 1.21, 95% CI 1.07-1.38), and kidney stones (OR = 1.17, 95% CI 1.03-1.32). The consumption of BW is associated with heightened risk for certain health conditions. Policymakers and healthcare providers should consider implementing targeted prevention strategies and awareness campaigns.

Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Purpose: Heavy metal exposure can cause impaired or reduced pathology in the kidneys, lungs, liver, and other vital organs. However, the relationship between heavy metal exposure and kidney stones has not been determined. The goal of this research was to determine the association between heavy metal exposure and kidney stones in a population of American adults in general., Materials and Methods: We evaluated 29,201 individuals (≥20 years) from the National Health and Nutrition Examination Survey (NHANES). The association between heavy metal exposure and kidney stones was verified by multiple logistic regression and restricted cubic spline (RCS) regression. Dose-response curves were generated to analyze the relationship between heavy metal concentrations and the occurrence of kidney stones. Moreover, we used propensity score matching (PSM) to exclude the effect of confounding variables., Results: After a rigorous enrollment screening process, we included 8518 participants. Logistic regression showed that urinary cadmium (U-Cd) and urinary cobalt (U-Co) concentrations were significantly different in the kidney stone group before PSM ( p   <   0.001). Dose-response curves revealed that the occurrence of kidney stones increased significantly with increasing U-Cd and U-Co concentrations. After adjustment for covariates, only biomarkers of U-Co were linked to the occurrence of kidney stones. When the lowest quartile was used as a reference, the 95% confidence intervals (95% CIs) for kidney stones across the other quartiles were 1.015 (0.767-1.344), 1.409 (1.059-1.875), and 2.013 (1.505-2.693) for U-Cos ( p   <   0.001)., Conclusion: In the U.S. population, high U-Co levels are positively correlated with the potential risk of kidney stones.

Drug-induced nephrolithiasis represents only 1%-2% of stone cases. Here we focus on drugs capable of crystallizing and forming stone, specifically phenazopyridine (Pyridium/Azo). This is a case of a patient who presented with a stone conglomerate in the right proximal ureter and underwent definitive treatment. Interestingly, the stone had a purple hue with FTIR spectroscopy showing stone composition of calcium oxalate (monohydrate and dihydrate) and a material resembling phenazopyridine. We retrospectively learned that she used multiple extended courses of phenazopyridine over 3 months.

C-C chemokine receptor type 2 (CCR2) is a monocyte chemokine associated with oxidative stress and inflammation. Kidney stones (KS) are composed of calcium oxalate (CaOx), which trigger renal oxidative stress and inflammatory. This study aims to evaluate the effects of CCR2 on KS in vivo and in vitro. Eight-week-old male C57BL/6J mice were intraperitoneally injected with glyoxylate (GOX) daily to establish a KS model, and along with CCR2 antagonist (INCB3344) treatment on days 2, 4, and 6. The results showed that CCR2 antagonist reduced renal injury markers (blood urea nitrogen and serum creatinine), alleviated renal tubular injury and CaOx crystal deposition. CCR2 antagonist also decreased CCR2 expression induced by GOX treatment and increased Nrf2 expression. GOX treatment promoted malondialdehyde (MDA) production, decreased glutathione (GSH) content, and inhibited catalase (CAT) and superoxide dismutase (SOD) activity, however, CCR2 antagonist attenuated the above effects of GOX. CCR2 antagonist had inhibitory effects on GOX-induced inflammatory cytokine expression (IL1B, IL6 and MCP1), and inhibited apoptosis by increasing Bcl-2 expression and decreasing Bax and cleaved-caspase 3 expression. In vitro experiments were performed by co-culture model of CaOx-induced damaged HK-2 cells and macrophage-like THP-1 cells. CCR2 antagonist inhibited CaOx-induced THP-1 cell M1 polarization by decreasing the TNF-α, IL6 and iNOS levels, and further alleviated CaOx-induced oxidative stress damage, inflammatory response and apoptosis of HK-2 cells. The study suggests that CCR2 antagonist may be resistant to CaOx crystals-induced oxidative stress and inflammation by inhibiting macrophage M1 polarization.

Background: Proton pump inhibitors (PPIs) are widely used throughout the world as an effective gastrointestinal drug. Nevertheless, according to the existing literature, PPIs can reduce the excretion of magnesium, calcium and other components in urine, which may promote the formation of kidney stones. We used the National Health and Nutrition Examination Survey (NHANES) database to further investigate the association between the use of PPIs and the prevalence of kidney stones., Methods: We performed a cross-sectional analysis using data from 2007 to 2018 NHANES. PPIs use information of 29,910 participants was obtained by using prescription medications in the preceding month, and kidney stones were presented by a standard questionnaire. Multiple regression analysis and stratified analysis were used to estimate the association between PPIs use and kidney stones after an adjustment for potential confounders., Results: The multiple logistic regression indicated that the PPIs exposure group (P1) had a significantly higher risk of nephrolithiasis than the PPIs non-exposure group (P0) in Model 3 (OR 1.24, 95% CI 1.10-1.39, P < 0.001). The stratified analyses indicated there were significant statistical differences between PPIs use and kidney stones among females (OR 1.36, 95% CI 1.15-1.62, P < 0.001), non-Hispanic whites (OR 1.27, 95% CI 1.09-1.48, P = 0.002), individuals with an education level than 11th grade (OR 1.41, 95% CI 1.13-1.76, P = 0.002) and individuals with an annual family income of $0 to $19,999 (OR 1.32, 95% CI 1.06-1.65, P = 0.014) and $20,000 to $44,999 (OR 1.25, 95% CI 1.02-1.54, P = 0.033) in Model 3., Conclusions: Our study revealed that PPIs use is associated with a higher prevalence of kidney stones for the US population, primarily among women, non-Hispanic whites, individuals with low education levels and individuals with low household income levels. Further studies are required to confirm our findings., (© 2024. The Author(s).)

Purpose: This study aimed to evaluate the effect of Ziziphus jujuba (Z. jujuba) leaf hydroalcoholic extract on the prevention/treatment of kidney stones., Materials and Methods: Thirty-six male Wistar rats were randomly divided into six groups: control, Sham (kidney stone induction (KSI) by ethylene glycol 1% + ammonium chloride 0.25% through drinking water for 28 days), Prevention groups 1, 2 (KSI and Z. jujuba leaf (250 and 500 mg/kg, respectively) through gavage for 28 days), and Treatment groups 1, 2 (KSI and Z. jujuba leaf (250 and 500 mg/kg, respectively) from the 15th day). On the 29th day, the rats' 24-hour urine was assessed, the animals were weighed, and blood samples were taken. Finally, after nephrectomy and weighing the kidneys, tissue sections were prepared to examine the number of calcium oxalate crystals and tissue changes., Results: The results indicated a significant increase in kidney weight and index, tissue changes, and the number of calcium oxalate crystals in the Sham group compared to the control; using Z. jujuba leaf considerably reduced them in experimental groups compared to the Sham. Body weight decreased in the Sham and experimental groups (except the prevention 2 group) compared to the control, while this observed reduction was lower in all experimental groups compared to the Sham. The mean urinary calcium, uric acid, creatinine, and serum creatinine in Sham and experimental groups (except the prevention 2 group) indicated a substantial increase compared to the control and decreased significantly in all experimental groups compared to the Sham., Conclusion: Hydroalcoholic extract of Z. jujuba leaf is effective in the reduction of calcium oxalate crystals forming, and its most effective dose was 500mg/kg.

Few studies have examined the relationship between lipid metabolism and kidney stone formation, particularly the role of key lipid regulatory factors in kidney stone formation. We evaluated the effect of the lipid regulatory factor-peroxisome proliferator-activated receptor alpha on the formation of renal stones in mice by injecting them with glyoxylate followed by treatment with either a peroxisome proliferator-activated receptor alpha agonist fenofibrate or an antagonist GW6471 (GW). Liquid chromatography coupled with trapped ion mobility spectrometry-quadrupole-time-of-flight mass spectrometry-based lipidomics was used to determine the lipid profile in the mouse kidneys. Histological and biochemical analyses showed that the mice injected with glyoxylate exhibited crystal precipitation and renal dysfunction. Crystallization decreased significantly in the fenofibrate group, whereas it increased significantly in the GW group. A total of 184 lipids, including fatty acyls, glycerolipids, glycerophospholipids, and sphingolipids differed significantly between the mice in the model and control groups. Peroxisome proliferator-activated receptor alpha activity negatively correlated with glyoxylate-induced kidney stone formation in mice, which may be related to improved fatty acid oxidation, maintenance of ceramide/complex sphingolipids cycle balance, and alleviation of disorder in phospholipid metabolism., (© 2023 Wiley-VCH GmbH.)

Objective: To assess the association of different sedentary behaviors and glucosamine use with the risk of kidney stones and examine the modification of genetic risk of kidney stones on this association., Methods: 473,225 participants free of kidney stones at baseline from the UK Biobank were included. Total sedentary time was calculated as the sum of the duration of TV-watching, driving, and non-occupational computer using. The primary outcome was new-onset kidney stones., Results: During a median follow-up of 12.0 years, 5528 cases of kidney stones were documented. All major sedentary behaviors and total sedentary time were significantly positively related to the risk of kidney stones (All P for trend<0.05). Participants with total sedentary time ≥ 3.5 h/day had a significantly higher risk of new-onset kidney stones (vs. <3.5 h/day [tertile 1]; HR, 1.18; 95%CI,1.10-1.27). Compared with non-users, participants who regularly used glucosamine had a significantly lower risk of new-onset kidney stones in those with total sedentary time < 3.5 h/day (HR, 0.72; 95%CI,0.59-0.86), but not in those with total sedentary time ≥ 3.5 h/day (HR, 0.99; 95%CI,0.91-1.08; P-interaction = 0.001). Among participants with total sedentary time < 3.5 h/day, there was a dose-response relationship of glucosamine use with new-onset kidney stones (P for trend<0.001). Genetic risks of kidney stones did not significantly modify the association., Conclusions: TV-watching, driving and non-occupational computer using were all positively associated with the risk of new-onset kidney stones. Glucosamine use was associated with a lower risk of new-onset kidney stones in participants with total sedentary time < 3.5 h/day, following a dose-response relationship., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Currently, there is limited research on the specific relationship between N, N-diethyl-m-toluamide (DEET) exposure and the odds of kidney stones. We aimed to investigate the relationship between DEET exposure and the prevalence of kidney stones., Methods: We included 7,567 qualified participants in our research from the 2007-2016 NHANES survey. We carried out three logistic regression models to explore the potential association between DEET exposure and the odds of kidney stones. Spline smoothing with generalized additive models (GAM) was utilized to assess the non-linear relationship and restricted cubic spline (RCS) curves was to determine the dose-response association. Multivariate regression models were used to conduct stratified analysis and sensitivity analysis., Results: Baseline characteristics of study participants presented the distribution of covariables. Regression analysis revealed that the odds of kidney stones were positively associated with the main metabolites of 3-diethyl-carbamoyl benzoic acid (DCBA) (log2) (OR = 1.05, 95% CI 1.02 to 1.08). The fourth quartile of urine DCBA showed a greater risk of kidney stones in the fully adjusted model (OR = 1.36, 95% CI 1.08 to 1.72). Another DEET metabolite of N, N-diethyl-3-hydroxymethylbenzamide (DHMB) was used to confirm the accuracy and stability of the results. The spline smoothing curve represented two main DEET metabolites had similar no-linear relationships and a positive trend with kidney stones proportion. RCS implied that the incidence of kidney stones rose with increasing levels of DEET exposure. High-risk groups on kidney stones were exhibited by stratified analysis under DEET exposure., Conclusion: Our study suggests that DEET exposure is positively associated with odds of kidney stones. Further investigation into the underlying processes of this association is required to guide the prevention and treatment of kidney stones., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wei, He, Wei, Huang, Xiong, Deng, Chen, Li and Zhang.)

Objective: Several studies have suggested a potential link between use of proton pump inhibitors (PPIs) and the risk of kidney stones, attributed to alterations in urine mineral levels. Our study aimed to investigate the association between PPI use and kidney stones in US adults., Design: Cross-sectional study., Setting: National Health and Nutrition Examination Survey (2007-2018)., Participants: 27 075 individuals with complete information on PPI use and history of kidney stones were included in this study., Outcomes and Analyses: Non-linear analysis, logistic regression analysis and subgroup analysis were conducted to estimate the relationship between PPI use and the occurrence and recurrence of kidney stones, after adjusting for potential confounding factors., Results: Multivariable logistic regression analysis revealed a significant association between PPI use and kidney stones (OR 1.31, 95% CI 1.07 to 1.60), with a 4% increase in the prevalence of kidney stones for each additional year of PPI use (p<0.001). Similarly, PPI use was significantly associated with recurrent kidney stones (OR 1.49, 95% CI 1.04 to 2.13), with a 7% increase in the recurrence of kidney stones for each additional year of PPI use (p<0.001). Furthermore, these associations remained significant even after conducting propensity score matching analysis on a subset of PPI users and non-users (all p≤0.001). Subgroup analyses showed that the effects of PPI use on kidney stones differed by age, sex, race and body mass index., Conclusions: This study indicated that long-term use of PPI was associated with a higher risk of both the presence and recurrence of kidney stones., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Calcium oxalate (CaOx) stones are the most prevalent type of kidney stones. CaOx crystals can stimulate reactive oxygen species (ROS) generation and induce renal oxidative stress to promote stone formation. Intracellular Ca 2+ is an important signaling molecule, and an elevation of cytoplasmic Ca 2+ levels could trigger oxidative stress. Our previous study has revealed that upregulation of Ang II/AT1R promoted renal oxidative stress during CaOx exposure. IP3/IP3R/Ca 2+ signaling pathway activated via Ang II/AT1R is involved in several diseases, but its role in stone formation has not been reported. Herein, we focus on the role of AT1R/IP3/IP3R-mediated Ca 2+ release in CaOx crystals-induced oxidative stress and explore whether inhibition of this pathway could alleviate renal oxidative stress. NRK-52E cells were exposed to CaOx crystals pretreated with AT1R inhibitor losartan or IP3R inhibitor 2-APB, and glyoxylic acid monohydrate-induced CaOx stone-forming rats were treated with losartan or 2-APB. The intracellular Ca 2+ levels, ROS levels, oxidative stress indexes, and the gene expression of this pathway were detected. Our results showed that CaOx crystals activated AT1R to promote IP3/IP3R-mediated Ca 2+ release, leading to increased cytoplasmic Ca 2+ levels. The Ca 2+ elevation was able to stimulate NOX2 and NOX4 to generate ROS, induce oxidative stress, and upregulate the expression of stone-related proteins. 2-APB and losartan reversed the referred effects, reduced CaOx crystals deposition and alleviated tissue injury in the rat kidneys. In summary, our results indicated that CaOx crystals promoted renal oxidative stress by activating the AT1R/IP3/IP3R/Ca 2+ pathway. Inhibition of AT1R/IP3/IP3R-mediated Ca 2+ release protected against CaOx crystals-induced renal oxidative stress. 2-APB and losartan might be promising preventive and therapeutic agents for the treatment of kidney stone disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Assessing the effects of heavy metals (HMs) on kidney stone is often limited to analyzing individual metal exposures, with studies on the effects of exposure to mixtures of HMs being scarce. To comprehensively evaluate the relationship between exposure to mixed HMs and kidney stones, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2016, which included 7809 adults. We used multiple statistical methods, including multiple logistic regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp) and bayesian kernel machine regression (BKMR), to assess the association between single HM and mixed exposure to HMs and kidney stones. Firstly, in single exposure analysis, urinary cadmium (Cd) and cobalt (Co) demonstrated a positive association with the risk of kidney stones. Secondly, various other approaches consistently revealed that mixed exposure to HMs exhibited a positive association with kidney stone risk, primarily driven by Cd, Co, and barium (Ba) in urine, with these associations being particularly notable among the elderly population. Finally, both BKMR and survey-weighted generalized linear models consistently demonstrated a significant synergistic effect between urinary Co and urinary uranium (Ur) in elevating the risk of kidney stones. Overall, this study provides new epidemiological evidence that mixed exposure to HMs is associated with an increased risk of kidney stones. Further prospectively designed studies are needed to confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD., Materials and Methods: We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups., Results: KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756)., Conclusion: Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking., Trial Registration: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058)., (© 2023. The Author(s).)

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

Background: The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration. This study was performed to explore the association between urinary cadmium and kidney stone., Materials and Methods: Data from the National Health and Nutrition Examination Survey (2011-2020) were included and further analyzed. Urinary cadmium was stratified into quartiles with quartile 1 (Q1: 0.025-0.104 μg/L) and quartile 4 (Q4: 0.435-7.581 μg/L). Further weighted logistic regression was adopted to evaluate the association between urinary cadmium and kidney stone. A subgroup analysis was used to verify the findings. The non-linear association was examined using the restricted cubic spline (RCS) regression., Results: A total of 9,056 adults aged 20 years and above were included in this study. In the fully adjusted model, an increased risk of kidney stones was identified for quartile 2 (OR = 1.40, 95% CI = 1.06-1.84, P < 0.05), quartile 3 (OR = 1.18, 95% CI = 0.88-1.59, P > 0.05), and quartile 4 (OR = 1.54, 95% CI = 1.10-2.06, P < 0.05). A similar association was found between continuous cadmium increase and OR of kidney stones in the fully adjusted model (OR = 1.13, 95% CI = 1.01-1.26, P < 0.05). The RCS also indicated a non-linear association between urinary cadmium concentration and kidney stone risk ( P for non-linear < 0.001)., Conclusion: In summary, cadmium exposure is identified as a risk factor for kidney stones in this study. Their non-linear association makes demands on early intervention for the cadmium-exposed population. Medical interventions for kidney stone prevention should take cadmium exposure into account., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ye, Chen, Luo, Xu, Fan and Wang.)

Purpose: The association between menopause, postmenopausal hormone therapy, and kidney stone disease has long been a topic of discussion and is still unclear. Moreover, most previous research has focused on Caucasians. Therefore, we aimed to explore this issue in an Asian population., Methods: In this cross-sectional study, we enrolled female participants aged between 30 and 70 years from the Taiwan Biobank. The presence of kidney stone disease (KSD) was defined through a self-reported questionnaire. The participants were divided into two groups according to the presence of menopause; premenopausal and postmenopausal groups. The associations among menopause, postmenopausal hormone therapy, and KSD were examined using binary logistic regression models., Results: A total of 17,460 women with available information were recruited, including 5976 in the premenopausal group and 11,484 in the postmenopausal group. Compared to the premenopausal group, the postmenopausal group had a significantly higher prevalence of KSD (3% vs. 6%). The odds ratio for KSD was higher in the postmenopausal group than in the premenopausal group (odds ratio = 1.50; 95% confidence interval = 1.17-1.92) after adjusting for confounders. We also examined associations between the type of menopause (natural and surgical) and KSD, and found that both types of menopause were associated with KSD in age-adjusted and multivariable models. Compared with those who had never received postmenopausal hormone therapy, those who had received postmenopausal hormone therapy were not associated with a higher risk of KSD., Conclusions: Our study suggests that natural and surgical menopause were associated with KSD. However, we found no association between the postmenopausal hormone therapy and KSD in the postmenopausal women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Kidney stone disease is increasingly common in the general population, with a high recurrence rate after stone removal. It has been proven that caffeine consumption can reduce the risk of diseases, such as stroke and dementia. However, the effect of caffeine intake on the incidence of kidney stones has not been determined. This systematic review and meta-analysis were performed to evaluate the association of caffeine intake with the risk of incident kidney stones., Methods: PubMed, Web of Science, Scopus, Cochrane and Google Scholar were searched using terms related to coffee, caffeine and kidney stones to find eligible articles up to December 2021. Articles with clear diagnostic criteria for kidney stone disease and the exact intake dose of caffeine were included. The incidence of kidney stone disease was the main outcome. Summarized risk estimates and 95% CIs for the highest and lowest categories of caffeine intake were calculated using a random effects model., Results: Seven studies were included in the final meta-analysis, with 9707 cases of kidney stones and a total of 772,290 cohort members. Compared with the lowest category of caffeine intake, the pooled relative risk (RR) was 0.68 ([95% CI 0.61-0.75], I 2  = 57%) for the highest category of caffeine intake. Subgroup analyses showed that caffeine intake had an inverse relationship with the incidence of kidney stones in all subgroups., Conclusion: This study suggests that a higher caffeine intake may be associated with a lower risk of incident kidney stones., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

In the present study, we characterized the probiotic properties of two commercially available bacterial strains, Lactobacillus paragasseri UBLG-36 and Lacticaseibacillus paracasei UBLPC-87, and evaluated their ability to degrade oxalate in vitro and in a hyperoxaluria-induced nephrolithiasis rat model. UBLG-36 harboring two oxalate catabolizing genes, oxalyl coenzyme A decarboxylase (oxc) and formyl coenzyme A transferase (frc), was previously shown to degrade oxalate in vitro effectively. Here, we show that UBLPC-87, lacking both oxc and frc, could still degrade oxalate in vitro. Both these strains harbored several potential putative probiotic genes that may have conferred them the ability to survive in low pH and 0.3% bile, resist antibiotic stress, show antagonistic activity against pathogenic bacteria, and adhere to epithelial cell surfaces. We further evaluated if UBLG-36 and UBLPC-87 could degrade oxalate in vivo and prevent hyperoxaluria-induced nephrolithiasis in rats. We observed that rats treated with 4.5% sodium oxalate (NaOx) developed hyperoxaluria and renal stones. However, when pre-treated with UBLG-36 or UBLPC-87 before administering 4.5% NaOx, the rats were protected against several pathophysiological manifestations of hyperoxaluria. Compared to the hyperoxaluric rats, the probiotic pre-treated rats showed reduced urinary excretion of oxalate and urea (p < 0.05), decreased serum blood urea nitrogen and creatinine (p < 0.05), alleviated stone formation and renal histological damage, and an overall decrease in renal tissue oxalate and calcium content (p < 0.05). Taken together, both UBLG-36 and UBLPC-87 are effective oxalate catabolizing probiotics capable of preventing hyperoxaluria and alleviating renal damage associated with nephrolithiasis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Proton pump inhibitors (PPIs) are widely prescribed medications that have effects on both enteric and urinary solute handling with an unknown effect on risk of nephrolithiasis. Our objectives were to examine the association between PPI exposure and incident nephrolithiasis and to determine its effect on 24H urine chemistry. We performed a single-center retrospective study on patients diagnosed with gastroesophageal reflux disease (GERD) without a history of kidney stones. Exposure to PPIs was abstracted, and then subsequent kidney stone diagnoses were identified. Multivariable Cox models with time-varying covariates were used to estimate the hazard of PPI use on incident nephrolithiasis. We used multivariable linear regression to analyze a subset of patients who went through 24-h urine analysis. We identified n = 55,765 PPI-naïve GERD patients without prior kidney stone diagnoses of whom 40,866 (73.2%) were exposed to PPI over a median of 3 year follow up. On multivariable analysis, PPI use was associated with higher risk of incident kidney stone diagnoses (HR 1.19, 95% CI 1.06-1.34). Among 593 patients with GERD with 24-H urine data, the PPI-exposed group (n = 307) had significantly lower mean urinary citrate (mean 3.0 vs 3.4 mmol, p = 0.029) and urinary magnesium (mean 3.6 vs 4.3 mmol, p < 0.001) on multivariable analyses. Exposure to PPIs is associated with an increased risk of kidney stones among patients with GERD. Hypomagnesemia and hypocitraturia associated with PPI exposure may contribute to kidney stone risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The prevention role of Lactiplantibacillus plantarum against the formation of kidney stones has been increasingly recognized; its mechanism, however, has mainly been focused on inhibiting the inflammation in the colon in the gastrointestinal (GI) system, and the intestinal metabolites from microflora have not been revealed fully with regarding to the stone formation. In this study, we investigated the effect of L. plantarum J-15 on kidney stone formation in renal calcium oxalate (CaOx) rats induced by ethylene glycol and monitored the changes of intestinal microflora and their metabolites detected by 16S rRNA sequencing and widely targeted analysis, followed by the evaluation of the intestinal barrier function and inflammation levels in the colon, blood and kidney. The results showed that L. plantarum J-15 effectively reduced renal crystallization and urinary oxalic acid. Ten microbial genera, including anti-inflammatory and SCFAs-related Faecalibaculum, were enriched in the J-15 treatment group. There are 136 metabolites from 11 categories significantly different in the J-15 supplementation group compared with CaOx model rats, most of which were enriched in the amino acid metabolic and secondary bile acid pathways. The expression of intestinal tight junction protein Occludin and the concentration of pro-inflammatory cytokines and prostaglandin were decreased in the intestine, which further reduced the translocated lipopolysaccharide and inflammation levels in the blood upon J-15 treatment. Thus, the inflammation and injury in the kidney might be alleviated by downregulating TLR4/NF-κB/COX-2 signaling pathway. It suggested that L. plantarum J-15 might reduce kidney stone formation by restoring intestinal microflora and metabolic disorder, protecting intestinal barrier function, and alleviating inflammation. This finding provides new insights into the therapies for renal stones., (© 2022 Federation of American Societies for Experimental Biology.)

Oxalate exposure to human renal epithelial cells triggers a vicious cycle of oxidative stress leading to cellular injury and deposition of calcium oxalate crystals on the injured cells. This results in further oxidative damage causing inflammation and loss of cell-cell adhesion factors, ultimately leading to irreparable kidney damage. However, these events can be attenuated or prevented by plants rich in antioxidants used in the traditional system of medicine for treatment of kidney stones. To delineate the mechanism by which Bergenia ligulata extract exerts its cytoprotective role in oxalate-induced injury we designed this study. Our results revealed that oxalate-injured HK2 cells cotreated with ethanolic extract of Bergenia ligulata displayed increased viability, reduced oxidative stress due to lowered production of intracellular reactive oxygen species (ROS) and decreased apoptosis. We also observed lowered markers of inflammation, along with increased expression of epithelial marker E-cadherin and decreased expression of mesenchymal markers Vimentin, F-actin, Transforming growth factor beta 1 (TGF-β1) and EMT-related proteins in renal tubular epithelial cells through immunocytochemistry, real-time PCR and western blotting. Our findings collectively suggest that by reducing oxidative stress, modulating crystal structure and preventing crystal-cell adhesion, B. ligulata inhibits the EMT pathway by downregulating the various mediators and thereby exerts its cytoprotective effect., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the association between kidney stones and risk of subsequent opioid misuse., Methods: The Healthcare Cost and Utilization Project's (HCUP) inpatient, ambulatory, and emergency department databases from 4 states were queried to identify associations with a primary diagnosis code related to kidney stones followed by a diagnosis of opioid abuse, dependence, or overdose between 2005, and 2015. Logistic regression was performed to determine the strength and significance of the relationship between number of primary kidney stone episodes and subsequent diagnosis of opioid misuse., Results: The final cohort included 783,929 patients across 4 states. On multivariable analysis the number of primary stone encounters (PSE) was strongly associated with the risk of developing an opioid-related disorder (ORD) when adjusting for relevant covariates (odds ratio 1.3). Patients seen in the emergency department (OR 1.4) and those treated in Iowa (OR 2.9) were at higher risk for ORD than those seen in different contexts or states. Younger age increased the strength of this association. Higher income (OR 0.7) and non-white race (OR 0.7) reduced the risk of ORD, while a diagnosis of chronic pain (OR 3.5) increased risk., Conclusion: Risk of subsequent diagnosis of ORD is increased in patients who have multiple episodes of care related to kidney stones., Competing Interests: DECLARATION OF COMPETING INTEREST The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Background: Environmental lead (Pb) and cadmium (Cd) pollution has been considered a risk factor in the etiology of kidney stones. However, the association between Pb and Cd exposure and kidney stone incidence has yet to be determined., Objectives: This study aimed to determine a possible the association between kidney stones with Pb and Cd exposure (alone or combined) in a non-occupational population., Methods: Pb and Cd contaminations in soil-plant system were determined by flame atomic absorption spectrophotometry. Health risk assessment of dietary Pb or Cd intake from rice and vegetables were calculated. Kidney stones were diagnosed with urinary tract ultrasonography. Urinary cadmium (UCd) and blood lead (BPb) levels were determined by graphite-furnace atomic absorption spectrometry. Multivariate logistic regression models were constructed., Results: The hazard indexes (HI) of Pb and Cd were 7.91 and 7.31. The odds ratio (OR) was 2.83 (95 %CI:1.38-5.77) in males with high BPb (BPb ≥ 100 μg/L), compared with those with low BPb (BPb＜100 μg/L). Compared to those with low BPb and low UCd (BPb＜100 μg/L and UCd＜2 μg/g creatinine), the ORs were 2.58 (95 % CI:1.17-5.70) and 3.43 (95 % CI:1.21-9.16) in females and males with high BPb and high UCd (BPb ≥100 μg/L and UCd ≥2 μg/g creatinine), respectively. The OR was 3.16 (95 % CI:1.26-7.88) in males with high BPb and low UCd (BPb ≥ 100 μg/L and UCd ＜2 μg/g creatinine), compared to those with low BPb and low UCd., Conclusions: Kidney stones incidence was increased by high Pb exposure in males, and by Pb and Cd co-exposure in males and females., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Defective permeability barrier is considered to be an incentive of hyperuricemia, however, the link between them has not been proven. Here, we evaluated the potential preventive effects of Lactiplantibacillus plantarum N-1 (LPN1) on gut microbiota and intestinal barrier function in rats with hyperoxaluria-induced kidney stones. Male rats were supplied with 1% ethylene glycol (EG) dissolved in drinking water for 4 weeks to develop hyperoxaluria, and some of them were administered with LPN1 for 4 weeks before EG treatment as a preventive intervention. We found that EG not only resulted hyperoxaluria and kidney stone formation, but also promoted the intestinal inflammation, elevated intestinal permeability, and gut microbiota disorders. Supplementation of LPN1 inhibited the renal crystalline deposits through reducing urinary oxalic acid and renal osteopontin and CD44 expression and improved EG-induced intestinal inflammation and barrier function by decreasing the serum LPS and TLR4/NF-κB signaling and up-regulating tight junction Claudin-2 in the colon, as well as increasing the production of short-chain fatty acid (SCFAs) and the abundance of beneficial SCFAs-producing bacteria, mainly from the families of Lachnospiraceae and Ruminococcaceae. Probiotic LPN1 could prevent EG-induced hyperoxaluria by regulating gut microbiota and enhancing intestinal barrier function., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Calcium oxalate (CaOx) stones are the most common type of kidney stones and are associated with high recurrence, short chain fatty acids (SCFAs), and inflammation. However, it remains uncertain whether SCFAs affect the formation of CaOx stones through immunomodulation. We first performed mass cytometry (CyTOF) and RNA sequencing on kidney immune cells with glyoxylate-induced CaOx crystals (to elucidate the landscape of the associated immune cell population) and explored the role of SCFAs in renal CaOx stone formation through immunomodulation. We identified 29 distinct immune cell subtypes in kidneys with CaOx crystals, where CX3CR1 + CD24 - macrophages significantly decreased and GR1 + neutrophils significantly increased. In accordance with the CyTOF data, RNA sequencing showed that most genes involved were related to monocytes and neutrophils. SCFAs reduced kidney CaOx crystals by increasing the frequency of CX3CR1 + CD24 - macrophages and decreasing GR1 + neutrophil infiltration in kidneys with CaOx crystals, which was dependent on the gut microbiota. GPR43 knockdown by transduction with adeno-associated virus inhibited the alleviation of crystal formation and immunomodulatory effects in the kidney, due to SCFAs. Moreover, CX3CR1 + CD24 - macrophages regulated GR1 + neutrophils via GPR43. Our results demonstrated a unique trilateral relationship among SCFAs, immune cells, and the kidneys during CaOx formation. These findings suggest that future immunotherapies may be used to prevent kidney stones using SCFAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jin, Jian, Chen, Ma, Ma, Liu, Gong, Xiang, Zhu, Shu, Qi, Li and Wang.)

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., (© 2021 Wiley Periodicals LLC.)

Cell injury is a necessary and critical event during CaOx kidney stone formation. Sirt1 exerts a number of pleiotropic effects, protecting against renal cell injury. This study aims to explore the relationship between Sirt1 and CaOx kidney stone formation and the underlying mechanism. Sirt1 expression in renal tissues or HK-2 cells was detected by Western blot, immunohistochemistry and immunofluorescence. Apoptosis in renal tissues was examined by TUNEL staining. Renal pathological changes and the crystals deposition were detected by hematoxylin-eosin and Von Kossa staining. Crystal-cell adhesion and cell injury in HK-2 cells were assessed by atomic absorption spectrometry and flow cytometry, respectively. Sirt1 expression in nephrolithiasis patients was downregulated and the level of apoptosis was increased. Further study found that Sirt1 expression was decreased in both in vivo and in vitro models. Interestingly, the levels of cell injury were elevated in vivo and in vitro models. Suppressing Sirt1 expression promoted COM-induced crystal-cell adhesion and exacerbated cell injury. In contrast, increasing the expression of Sirt1 by lentivirus transfection in vitro and resveratrol administration in vivo, alleviated crystal deposition and cell damage. Our findings suggest that Sirt1 could inhibit kidney stone formation, at least in part, through attenuating CaOx -induced cell injury., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Drug-induced urolithiasis falls into two categories: drug-induced and metabolically-induced. Certain antimicrobials are associated with each; sulfonamides are associated with drug- or metabolite-containing calculi when taken in large doses over a long period of time. Trimethoprim-sulfamethoxazole, a member of the sulfonamide family, is a rare cause of drug-induced calculi. Cases of sulfonamide urolithiasis occurring in patients with known stone disease have rarely been reported., Case Presentation: We report a case of a patient with a brief history of recurrent calcium oxalate nephrolithiasis requiring 2 ureteroscopic procedures whose existing 6 mm lower pole renal stone more than quadrupled in size to form a 4 cm renal staghorn after 4 months of high-dose treatment for Nocardia pneumonia with trimethoprim-sulfamethoxazole. After ureteroscopy with laser lithotripsy and basketing of fragments, the stone was found to be predominantly composed of N 4 -acetyl-sulfamethoxazole, a metabolite of sulfamethoxazole., Conclusion: Stones composed of sulfamethoxazole or its metabolites are rare but have known associated risk factors that should be considered when prescribing this antibiotic. This case report illustrates additional risk factors for consideration, including pre-existing urinary calculi that may serve as a nidus for sulfamethoxazole deposition, and reviews treatment and prevention methods., (© 2021. The Author(s).)

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data., Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression., Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019., Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years., Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity., Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years)., Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD., Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Mentha piperita L., a well-known traditional herb, constitutes essential oil as one of its important constituent, used for its flavor, aroma and therapeutic applications. Based on the antioxidant, antispasmodic and nephroprotective potential, the essential oil of Mentha piperita was evaluated for its preventive and curative effects against ethylene glycol induced urolithiasis. Peppermint oil (Mp.Eo) was evaluated for its antioxidant potential by DPPH method. Urolithiasis was developed in male rats by the administration of ammonium chloride and ethylene glycol in drinking water. Different doses of Mp.Eo (10, 30 and 50 mg/kg) and cystone, the standard antiurolithic drug (500 mg/kg), were given along with stone-inducing regimen in prophylactic model and after intoxication for the next fourteen days in curative model. Urine and serum were analyzed for various biochemical parameters. One representative kidney from each group was studied for changes in histological parameters. Mp.Eo was found to be effective against urolithiasis-associated changes including crystalluria, polyuria and acidic urine. Mp.Eo also neutralized the altered levels of urinary uric acid, magnesium, total protein, serum creatinine and serum BUN. The data obtained from the present study demonstrated the therapeutic importance of peppermint oil against urolithiasis.

Cranberry is a popular ingredient in dietary supplements in the U. S. and is commonly used for preventing urinary tract infections. Because of its popularity in dietary supplements, the U. S. Pharmacopeial Convention has developed quality standards for cranberry ingredients. The purpose of this review was to determine if there are safety issues that should preclude the admission of cranberry ingredients from the development of U. S. Pharmacopeial Convention quality standards. Based on the totality of the data, the U. S. Pharmacopeial Convention concluded that cranberry ingredients are not known to be associated with serious risks to human health when consumed properly in dietary supplements and therefore were admitted for standard development. Although published clinical and animal data indicated that cranberry is not associated with serious adverse effects, interactions with warfarin and kidney stone formation were identified as potential risks. Studies have reported contradictory data regarding the role of cranberry in kidney stone formation, with some reports suggesting cranberry is associated with a reduced risk of kidney stones. Interactions with warfarin were not associated with moderate intakes of cranberry juice (240 - 480 mL). Some reports suggested that the potential for warfarin interactions requires excessive intakes of cranberry juice (1 - 2 L/day) or cranberry extracts (3000 mg/day). Cases of warfarin interactions with cranberry have mostly involved patients with serious illnesses and/or individuals taking concomitant medications. Based on these findings, the U. S. Pharmacopeial Convention concluded that the use of cautionary labeling statements regarding interactions with warfarin or kidney stone formation is not necessary in the development of quality standards for cranberry ingredients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment., Methods: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12)., Results: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred., Conclusion: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks., Trial Registration: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Urinary tract stones are one of the most common diseases in the urinary tract. Lack of kidney stone treatment causes irreparable damages to the kidneys, which has many harmful effects. Date palm pits are recommended in traditional medicine as an effective drug in the treatment of kidney stones. The aim of this study was to investigate the effect of aqueous extract of date palm pits on kidney stones induced by ethylene glycol in male rats., Methods: In this study, 40 rats were classified into five groups (n = 8), including the healthy group receiving normal water, the negative control group, the therapeutic groups with doses of 150 mg/kg and 300 mg/kg, and the prevention group with a dose of 300 mg/kg. In order to induce kidney stones, ethylene glycolated water (1%) was used as drinking water in the studied groups. Blood and urine of rats were collected on days 14 and 28 of the study to assess urinary parameters of calcium, creatinine, uric acid and phosphorus, and serum parameters of blood urea nitrogen, creatinine, uric acid, calcium, and phosphorus. Also, the kidneys of rats were removed from the body on day 28 of the study and were given to a pathologist for examination., Results: Results of serum parameters shows that the use of date palm pits extract in the treatment and prevention groups with a dose of 300 mg/kg significantly (P < .05) has reduced the levels of blood urea nitrogen, uric acid, calcium, creatinine and phosphorus. Also, the results of urinary parameters show that the use of the extract caused a significant decrease (P < .05) in creatinine, uric acid and calcium in the prevention group and a significant decrease (P < .05) in creatinine and uric acid in the therapeutic group with a dose of 300 mg/kg. Pathological results show a decrease in the number and size of calcium oxalate crystals in renal tubules in the treatment and prevention groups in a dose-dependent manner., Conclusion: The results of this study showed that the use of aqueous extract of date palm pits has been effective in the treatment and prevention of kidney stones induced by ethylene glycol in rats.

The aim of this study is to investigate whether the filtration barrier is affected by experimental kidney stone formation. Thirty-two rats divided into 4 equally groups (n = 8) at random. Group I control; Group II 1% ethylene glycol; Group III 1% Ethylene glycol + 0.25% Ammonium chloride; Group IV 1% Ethylene glycol + 0.5% Ammonium chloride group. Tissues applied hematoxylin-eosin, periodic-acid-Schiff, Pizzolato's staining. Immunohistochemically stained with integrin α3β1, type IV collagen, laminin, nephrin, CD2-associated protein (CD2AP) and podocin to show the filtration barrier structure. The TUNEL method was used for apoptosis. The amount of calcium, magnesium, creatinine and uric acid in urine and blood samples, also urine microprotein determined. Stones were formed in all experimental groups. Urine calcium, creatinine, uric acid levels decreased, magnesium levels were not changed. No statistically significant change was observed in blood serum results and TUNEL analysis. Immunohistochemical results showed an increase in nephrin, podocin, CD2AP, laminin and a decrease in integrin α3β1 and type IV collagen. Consequently, there is an increase in the expression densities of the proteins incorporated in the structure to prevent loss of functionality in the cellular part supporting the structure against a weakening of the basement membrane structure in the glomerular structure in which urine is filtered.

Aims: Mineralization of crystalline particles and the formation of renal calculi contribute to the pathogenesis of crystal nephropathies. Several recent studies on the biology of crystal handling implicated intrarenal crystal deposition-induced necroinflammation in their pathogenesis. We hypothesized that 6,7-dihydroxycoumarin (DHC) inhibit intrarenal crystal cytotoxicity and necroinflammation, and ameliorate crystal-induced chronic kidney disease (CKD)., Main Methods: An unbiased high content screening coupled with fluorescence microscopy was used to identify compounds that inhibit CaOx crystal cytotoxicity. The ligand-protein interactions were identified using computational models e.g. molecular docking and molecular dynamics simulations. Furthermore, mice and rat models of oxalate-induced CKD were used for in-vivo studies. Renal injury, crystal deposition, and fibrosis were assessed by histology analysis. Western blots were used to quantify the protein expression. Data were expressed as boxplots and analyzed using one way ANOVA., Key Findings: An unbiased high-content screening in-vitro identified 6,7-DHC as a promising candidate. Further, 6,7-DHC protected human and mouse cells from calcium oxalate (CaOx) crystal-induced necroptosis in-vitro as well as mice and rats from oxalate-induced CKD in either preventive or therapeutic manner. Computational modeling demonstrated that 6,7-DHC interact with MLKL, the key protein in the necroptosis machinery, and inhibit its phosphorylation by ATP, which was evident in both in-vitro and in-vivo analyses., Significance: Together, our results indicate that 6,7-DHC possesses a novel pharmacological property as a MLKL inhibitor and could serve as a lead molecule for further development of coumarin-based novel MLKL inhibitors. Furthermore, our data identify 6,7-DHC as a novel therapeutic strategy to combat crystal nephropathies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The potential nephrotoxicity of polyfluoroalkyl chemicals (PFCs) have received extensive attention. However, the relationship between PFCs and the risk of kidney stones remain unclear. This study aimed to examine the level of PFCs in the US population and its relationship with the risk of kidney stones. We investigated the serum levels of six PFCs in 8453 adult participants (≥20 years) from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016, including perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHS), 2-(N-methyl-perfluorooctane sulfonamido) acetate (MPAH), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUA), and perfluorododecanoic acid (PFDO). Logistic regression model was used to evaluate the correlation between PFCs and kidney stones. Of the 8453 participants, 787 self-reported a history of kidney stones. After adjusting for gender, age, race, education, marital status, body mass index (BMI), hypertension, diabetes and estimated glomerular filtration rate (eGFR), we found that total PFCs and PFHS were positively correlated with the risk of kidney stones. Compared with the lowest tertile, the odds ratios with 95% confidence intervals (CI) with increasing tertiles were 1.30 (95% CI,1.08-1.59, p = 0.007) and 1.25 (95 CI%,1.00-1.52, p = 0.024) for total PFCs and 1.24 (95 CI%,1.03-1.51, p = 0.032), and 1.35 (95 CI,1.10-1.68, p = 0.005) for PFHS. Our study shows that total PFCs and PFHS were associated with an increased risk of kidney stones., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Proton pump inhibitors (PPIs) are widely prescribed and have effects on gut ion absorption and urinary ion concentrations. PPIs might therefore protect against or contribute to development of kidney stones. We investigated the association between PPI use and kidney stones., Methods: We performed a retrospective study using data from the Women's Veteran's Cohort Study, which comprised men and women, from October 1, 1999 through September 30, 2017. We collected data from 465,891 patients on PPI usage over time, demographics, laboratory results, comorbidities, and medication usage. Time-varying Cox proportional hazards and propensity matching analyses determined risk of PPI use and incident development of kidney stones. Use of histamine-2 receptor antagonists (H2RAs) was measured and levothyroxine use was a negative control exposure., Results: PPI use was associated with kidney stones in the unadjusted analysis, with PPI use as a time-varying variable (hazard ratio [HR], 1.74; 95% CI, 1.67-1.82), and persisted in the adjusted analysis (HR, 1.46; CI, 1.38-1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19-1.33). Increased dosage of PPI was associated with increased risk of kidney stones (HR, 1.11; CI, 1.09-1.14 for each increase in 30 defined daily doses over a 3-month period). H2RAs were also associated with increased risk (adjusted HR, 1.47; CI 1.31-1.64). We found no association, in adjusted analysis, of levothyroxine use with kidney stones (adjusted HR, 1.06; CI 0.94-1.21)., Conclusions: In a large cohort study of veterans, we found PPI use to be associated with a dose-dependent increase in risk of kidney stones. H2RA use also has an association with risk of kidney stones, so acid suppression might be an involved mechanism. The effect is small and should not change prescribing for most patients., (Published by Elsevier Inc.)

In recent years, the use of opioids in medical practice has come under significant scrutiny. This, in part, is owing to evidence of overprescription and overuse of opioid medications, as well as the unintended consequences and side effects for patients who take these medications. Here, we review the role of opioids and the responsible use of these medications with respect to kidney stone disease and surgical interventions for kidney stones., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A 78-year-old man had been undergoing treatment with Cefamezin for pyogenic spondylitis. Because of complication of a urinary tract infection, the medication was switched to ceftriaxone (CTRX) 2 g/day. On day 18 after starting CTRX, the patient began experiencing abdominal pain. Computed tomography (CT) and endoscopic ultrasound led to the identification of calculi in the gallbladder and extrahepatic bile duct with a peculiar formation. We suspected CTRX-associated pseudo-cholecystolithiasis and pseudo-choledocholithiasis, although CT performed at admission had shown no such findings. Therefore, CTRX was discontinued. By day 17 after CTRX cessation, both the pseudo-cholecystolithiasis and pseudo-choledocholithiasis had disappeared.

Purpose: The association between caffeine intake and the risk of recurrent kidney stones is unknown. We examined the association between caffeine intake and the risk of recurrent kidney stones in adults., Methods: Individuals with history of passing at least one kidney stone were included from 2007 to 2014 National Health and Nutrition Examination Survey. Recurrent kidney stones were defined using a standard questionnaire and structured dietary recalls were used to determine caffeine intake. The weighted logistic regression was used to assess the association between caffeine intake and the risk of recurrent kidney stones, and the non-linear relationship was explored with restricted cubic splines. Caffeine and dietary confounders (minerals and vitamins) were adjusted for total energy intake with residual model., Results: The multivariate-adjusted odds ratios (95% confidence intervals) of recurrent kidney stones for per-quartile increment in caffeine intake were 1.15 (1.01-1.31) overall, 1.11 (0.96-1.29) for white race individuals, 1.33 (1.09-1.63) for non-white race individuals, 1.15 (0.97-1.36) for men, 1.24 (1.01-1.53) for women, 1.54 (1.08-2.19) for non-overweight individuals, 1.11 (0.97-1.28) for overweight/obese individuals, 1.13 (0.99-1.29) for caffeine from coffee, and 0.90 (0.79-1.03) for caffeine from non-coffee sources. A linear relationship was found between caffeine intake and the risk of recurrent kidney stones overall and in subgroup analyses., Conclusion: Compared with those who reported passing only one kidney stone, caffeine intake was independently and linearly associated with a higher risk of recurrent kidney stones in adults, especially for women, individuals of non-white race and non-overweight subjects. The increased risk may arise from caffeine from coffee.

Nutrients, vitamins, probiotics, and herbal products may be risk factors, or alternately, protect against the formation of urinary stones. The purpose of this review was to update knowledge of the role of nutraceuticals in renal stone formation. A systematic search of the relevant literature published in PubMed in the last ten years was conducted and a narrative review of the data from the included studies was done. Search screened 513 studies that were reduced to 34 after evaluation by title and abstract; other 38 studies were retrieved by references of the selected studies. Beverages high fluid intake confirmed protective effect; orange juice protective effect; apple or grapefruit juice not confirmed as risk factors; sugar-sweetened soda and punch increased risk of stone formation. Energy intake: very high energy intake increased risk factor for women (especially after menopause); dietary acid load increased risk at equal levels of energy intake. Macronutrients confirmed increased risk of high protein intake. Calcium and Oxalate: calcium intake protective effect; oxalate intake only modest increase of risk in men and older women. Metal cations zinc and iron intake no clear impact on the risk of stone formation, dietary copper increased risk; manganese intake reduced risk of stone formation. Fruits and Vegetables decreased risk. Vitamins B6 intake not associated to risk of stone formation; vitamin C intake increased risk in men; vitamin D or supplemental vitamin D intake not associated to increased risk in men and younger women, suggestion of a higher risk in older women; Probiotics Gut colonization with Oxalobacter formigenes associated to lower risk of stone formation, effect of oxalate-degraders probiotics on urinary oxalate equivocal. Herbal products efficacy of some herbal products demonstrated in some trials, more investigations needed to confirm their efficacy and safety.

Objective: To investigate the effect of α-lipoic acid (α-LA) in the prevention and treatment of ethylene glycol-induced calcium oxalate deposition in a rat model and preliminary exploration of the mechanism., Methods: Sixty male Wistar rats were divided randomly and equally into six groups including two α-LA prevention groups, two α-LA therapeutic groups, one controlled group and one intervention group. Besides controlled group, other group received 1% glycol solution and 2 ml 2% ammonium chloride for 4 weeks as a stone inducer. The prevention groups received 0.1 and 0.2 mg/kg body weight/day/rat α-LA as food supplement during inducing stone and therapeutic groups received 0.1 and 0.2 mg/kg body weight/day/rat α-LA for 4 weeks after 4 weeks stone inducing., Results: The volume of urine, the pH and magnesium levels in the preventive and therapeutic groups were higher in a dose-independent manner (p < 0.05), and urinary calcium was lower (p < 0.05). Antioxidant stress enzyme activity (glutathione, superoxide dismutase, catalase) in serum and kidney homogenates in the preventive and therapeutic groups underwent significant regeneration (p < 0.05) and malondialdehyde levels and the production of free radical moieties decreased. Pathological observation demonstrated that there was deformation due to renal tubular expansion in the control group, greater visible inflammatory cell infiltration into the interstitial spaces and partial destruction of the glomerular structures. α-lipoic acid improved the lesions to varying degrees. The extent of crystal deposition was lower in the preventive and therapeutic groups compared with the control group (p < 0.05)., Conclusion: The present study indicated that α-LA provides both preventive and therapeutic effects against the deposition of calcium oxalate crystals in rats.

Drug precipitation in the nephrons of the kidney can cause drug-induced crystal nephropathy (DICN). To aid mitigation of this risk in early drug discovery, we developed a physiologically based in silico model to predict DICN in rats, dogs, and humans. At a minimum, the likelihood of DICN is determined by the level of systemic exposure to the molecule, the molecule's physicochemical properties and the unique physiology of the kidney. Accordingly, the proposed model accounts for these properties in order to predict drug exposure relative to solubility along the nephron. Key physiological parameters of the kidney were codified in a manner consistent with previous reports. Quantitative structure-activity relationship models and in vitro assays were used to estimate drug-specific physicochemical inputs to the model. The proposed model was calibrated against urinary excretion data for 42 drugs, and the utility for DICN prediction is demonstrated through application to 20 additional drugs.

Context: There are concerns about the long-term safety of conventional therapy on renal health in patients with hypoparathyroidism. Careful audit of these would help comparisons with upcoming parathyroid hormone therapy., Objective: We investigated nephrocalcinosis, renal dysfunction, and calculi, their predictors and progression over long-term follow-up in patients with primary hypoparathyroidism (PH)., Design and Setting: An observational study at a tertiary care center was conducted., Participants and Methods: A total of 165 PH patients receiving conventional therapy were evaluated by radiographs, ultrasonography, and computed tomography. Their glomerular filtration rate (GFR) was measured by Tc-99m-diethylenetriamine penta-acetic acid clearance. Clinical characteristics, serum total calcium, phosphorus, creatinine, hypercalciuria, and fractional excretion of phosphorus (FEPh) at presentation and during follow-up were analyzed as possible predictors of renal complications. Controls were 165 apparently healthy individuals., Results: Nephrocalcinosis was present in 6.7% of PH patients but not in controls. Patients younger than 15 years at presentation and with higher serum calcium-phosphorus product were at higher risk. Nephrocalcinosis showed no significant association with cataract and intracranial calcification. Prevalence of renal calculi was comparable between hypoparathyroid patients and controls (5% vs 3.6%, P = .58). Fourteen percent of patients had a GFR less than 60 mL/min/1.73 m2. Increased FEPh during follow-up was the significant predictor of low GFR. Nephrocalcinosis developed in 9% of patients over 10 years of conventional therapy., Conclusion: A total of 6.7% of PH patients had nephrocalcinosis, and 14% showed renal dysfunction. Prevalence of renal calculi was similar in patients and controls. Nine percent of patients developed nephrocalcinosis over 10 years of conventional therapy., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Kidney stone disease (nephrolithiasis; urolithiasis) is a clinical entity with long-term course and recurrence, primarily affecting mature and ageing men, involving the formation and presence of urinary stones in the kidneys and urinary tract. The pathogenesis of this disorder is complex and still not fully understood. A rare, potentially modifiable, form of kidney stone disease takes the form of drug-induced urinary stones. The aim of the review was a brief description of the classification and pathophysiology of kidney stone disease, along with the short characteristics of drug-induced urinary stones. This type of stones is formed as a result of crystallisation in the kidneys and urinary tract of sparingly soluble drugs and their metabolites, or as a result of metabolic changes caused by drugs, predestinating the development of stones containing endogenous compounds., Conclusion: Conclusion: Therefore, during treatment with the use of drugs with high lithogenic potential, the safety of pharmacotherapy should be monitored in the context of its increased risk of developing urinary stones.