Dynamic change and preventive role of stress response via Keap1-Nrf2 during renal crystal formation.

Oxidative stress is a major risk factor for calcium oxalate nephrolithiasis. Reports suggest that oxidative stress response is induced in animals and humans with kidney stones. Keap1, Nrf2, and HO-1 are known as oxidative stress mediators. However, the association between oxidative stress response and stone formation is unclear. In this study, we analyzed oxidative stress response from the acute to the crystal formation phase when crystal formation was applied to renal crystal mice model and bioimaging mice and investigated the effect on crystal formation. In renal tissues, after glyoxylate administration, HO-1 increased for up to 6 h and returned to baseline at 24 h. This was observed following each daily dose until five days after the crystallization phase; however, the range of increase was attenuated. The possibility that Nrf2 activity influenced the number of crystals was considered in the experiment. Crystal formation increased in Nrf2-deficient mice and could be reduced by Nrf2 activators. In conclusion, the oxidative stress response via the Keap1-Nrf2 pathway may contribute to crystal formation. Particularly, this pathway may be a prospective target for drug development to prevent and cure nephrolithiasis.

Butyric acid inhibits oxidative stress and inflammation injury in calcium oxalate nephrolithiasis by targeting CYP2C9.

This study investigates the mechanism by which butyric acid can protect against calcium oxalate (CaOx) nephrolithiasis. To do so, a rat model was used with 0.75% ethylene glycol administration to induce CaOx crystal formation. Histological and von Kossa staining revealed calcium deposits and renal injury, while dihydroethidium fluorescence staining was used to detect reactive oxygen species (ROS) levels. Flow cytometry and TUNEL assays were used to assess apoptosis, respectively. Treatment with sodium butyrate (NaB) was found to partially reverse the oxidative stress, inflammation, and apoptosis associated with CaOx crystallization in the kidney. In addition, in HK-2 cells, NaB reversed the decreased cell viability, increased ROS levels and apoptosis damage caused by oxalate exposure. Network pharmacology was employed to predict the target genes of butyric acid, CYP2C9. Subsequently, NaB was found to significantly reduce CYP2C9 levels in vivo and in vitro, and inhibition of CYP2C9 by Sulfaphenazole (a specific CYP2C9 inhibitor), was able to reduce ROS levels, inflammation injury, and apoptosis in oxalate-induced HK-2 cells. Collectively, these findings suggest that butyric acid may inhibit oxidative stress and reduce inflammation injury in CaOx nephrolithiasis by suppressing CYP2C9.

Empagliflozin and Decreased Risk of Nephrolithiasis: A Potential New Role for SGLT2 Inhibition?

CONTEXT: Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists. OBJECTIVE: We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. METHODS: We pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study. RESULTS: The median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104), yielding annual incidence rates of 1.01 vs 0.63 events/100 patient-years in the 2 respective groups. The IRR was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin. In the sensitivity analysis, the results were similar (IRR, 0.62 [95% CI, 0.45-0.85]). CONCLUSION: Compared with placebo, empagliflozin therapy was associated with an approximate 40% reduced risk of urinary tract stone events in T2D patients. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine. Dedicated randomized prospective clinical trials are warranted to confirm these initial observations in patients with and without T2D.

Probiotics in the Prevention of the Calcium Oxalate Urolithiasis.

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical activity) in all developed countries. Some 80% of all kidney stones cases are oxalate urolithiasis, which is also characterized by the highest risk of recurrence. Frequent relapses of nephrolithiasis contribute to severe complications and high treatment costs. Unfortunately, there is no known effective way to prevent urolithiasis at present. In cases of diet-related urolithiasis, dietary changes may prevent recurrence. However, in some patients, the condition is unrelated to diet; in such cases, there is evidence to support the use of stone-related medications. Interestingly, a growing body of evidence indicates the potential of the microbiome to reduce the risk of developing renal colic. Previous studies have primarily focused on the use of Oxalobacterformigenes in patients with urolithiasis. Unfortunately, this bacterium is not an ideal probiotic due to its antibiotic sensitivity and low pH. Therefore, subsequent studies sought to find bacteria which are capable of oxalate degradation, focusing on well-known probiotics including Lactobacillus and Bifidobacterium strains, Eubacterium lentum, Enterococcus faecalis, and Escherichia coli.

Hydroxycitrate prevents calcium oxalate crystallization and kidney injury in a nephrolithiasis rat model.

Hydroxycitrate (HCA) is a derivative of citric acid, and previous studies of HCA have revealed its ability to inhibit the formation of calcium oxalate crystals in vitro. To date, there has been little evidence proving that HCA has the same effectiveness in vivo. The present study was designed to investigate the ameliorating effect of HCA on calcium oxalate deposition and renal impairment in a male rat model. Male Sprague-Dawley rats were randomly divided into four groups: a control group, a model group (glyoxalic acid), a CA group (glyoxalic acid + CA), and an HCA group (glyoxalic acid + HCA). Kidney stone formation was induced by injection of glyoxalic acid (60 mg/kg). The results showed that serum and urinary parameters were significantly improved by HCA treatment. In addition, differences in the formation of calcium oxalate crystals between groups were observed, and HCA was superior to CA in inhibiting crystal accumulation. The ultrastructure of renal tubules and glomeruli occurred in the model group, and the above lesions were significantly reduced in the HCA group. Both OPN and SOD expression levels were promoted by HCA, while CA only promoted OPN. In this article, we provided data on whether HCA affected kidney stones and the expression levels of OPN and SOD in a male rat model.

Impact on urinary oxalate levels with use of ezetimibe.

Background: Calcium oxalate stones are the most common cause of nephrolithiasis in the United States. Smaller studies of <15 patients investigating ezetimibe, a selective cholesterol absorption inhibitor, have suggested increased urine oxalate levels with use of the drug. We attempt to better define this relationship of ezetimibe on urinary oxalate using a larger patient sample analysing multiple urine collections on and off treatment. Materials and Methods: We retrospectively reviewed all consecutive patients from 01/2018 through 04/2019 evaluated for nephrolithiasis with use of ezetimibe documented in their medical record at Mayo Clinic Florida. Primary outcomes included increase in urinary oxalate with use of ezetimibe and reduction in urinary oxalate with discontinuation of medication. Results: Of 57 reviewed patients, 30 (53%) met inclusion criteria yielding 117 24-h urine measurements either on ezetimibe (72 measurements) or off ezetimibe (41 measurements). The mean urinary oxalate level off ezetimibe was 39.86 mg versus 40.45 mg with ezetimibe. After adjusting for age and sex, the estimated difference was 1.239 mg (95% CI, -4.856 to 7.335 mg; p = 0.93). A subset of six patients with urinary oxalate values both on and off ezetimibe showed a difference in 24-h urinary oxalate levels ranged from -16.40 to 14.95 mg (mean difference = 0.93 mg; median difference = 3.84 mg). Conclusion: Use of ezetimibe does not provide clear evidence of a difference in urinary oxalate levels.

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: A meta-analysis and systematic review.

To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) for investigating the effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition. PubMed, Web of Science, Embase, EBSCO, and Cochrane Library databases (updated November 2020) were searched for studies with the following keywords: diet, fluid, recurrent, prevention, randomized controlled trials, and nephrolithiasis. The search strategy and study selection process was conducted by following the PRISMA statement. Six RCTs were identified for satisfying the inclusion criteria and enrolled in this meta-analysis. Our result showed that low protein with or without high fiber diet intervention does not decrease the recurrence of stone upon comparing with control groups (RR = 2.32, 95% CI = 0.42-12.85; P = 0.34) with significant heterogeneity among the studies (I2 = 81%, P = 0.02). But normal-calcium, low protein, low-salt diet had recurrences did reduced the recurrence compared to normal-calcium diet. And the fluid intake has a positive effect on prevention of recurrent stone formation (RR = 0.39, 95% CI = 0.19-0.80; P = 0.01) with insignificant heterogeneity among the studies (I2 = 9%, P = 0.30). The different components of urine at baseline were reported in four studies. Upon reviewing the low protein with or without high fiber dietary therapy groups, it was found that there were no obvious changes in the 24-hour urine sodium, calcium, citrate, urea, and sulfate. In conclusion, our study shows that the only low protein with or without fiber does not affect recurrence, but low Na, normal Ca diet has a marked effect on reducing recurrence of calcium stone. And fluid intake shows a significant reduction in the recurrence of calcium stone.

Vitexin exerts protective effects against calcium oxalate crystal-induced kidney pyroptosis in vivo and in vitro.

BACKGROUND: Nephrolithiasis is a common urinary disease with a high recurrence rate of secondary stone formation. Several mechanisms are involved in the onset and recurrence of nephrolithiasis, e.g., oxidative stress, inflammation, apoptosis, and epithelial-mesenchymal transition (EMT). Vitexin, a flavonoid monomer derived from medicinal plants that exert many biological effects including anti-inflammatory and anticancer effects, has not been investigated in nephrolithiasis studies. Moreover, pyroptosis, a form of programmed cell death resulting from inflammasome-associated caspase activation, has not been studied in mice with nephrolithiasis. PURPOSE: We aimed to investigate the protective effect and underlying mechanisms of vitexin in nephrolithiasis, and the related role of pyroptosis in vivo and in vitro. METHODS: Mouse models of nephrolithiasis were established via intraperitoneal injection of glyoxylate, and cell models of tubular epithelial cells and macrophages were established using calcium oxalate monohydrate (COM). Crystal deposition and kidney tissue injury were evaluated by hematoxylin and eosin, and von Kossa staining. Renal oxidative stress indexes including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), were analyzed. The renal expression of interleukin-1 beta (IL-1ß), gasdermin D (GSDMD), osteopontin (OPN), CD44, and monocyte chemotactic protein 1 (MCP-1), and EMT-related proteins in renal tubular epithelial cells was assessed. Cell viability and the apoptosis ratio were evaluated. RESULTS: In vivo, vitexin alleviated crystal deposition and kidney tissue injury, and decreased the level of MDA, and increased the levels of SOD, GSH, and CAT. Vitexin also reduced the levels of the pyroptosis-related proteins GSDMD, NLRP3, cleaved caspase-1, and mature IL-1ß, which were elevated in mice with nephrolithiasis, and repressed apoptosis and the expression of OPN and CD44. Moreover, vitexin mitigated F4/80-positive macrophage infiltration and MCP-1 expression in the kidneys. Furthermore, an in vitro study showed that vitexin increased the viability of HK-2 cells and THP-1-derived macrophages, which was impaired by treatment with COM crystals, decreased the medium lactate dehydrogenase (LDH) level, and inhibited the expression of pyroptosis-related proteins in HK-2 cells and macrophages. Vitexin repressed EMT of HK-2 cells, with increased expression of pan-cytokeratin (Pan-ck) and decreased expression of Vimentin and alpha-smooth muscle actin (α-SMA), and downregulated the Wnt/ß-catenin pathway. Moreover, vitexin suppressed tumor necrosis factor-α (TNF-α) and IL-1ß mRNA expression, which was upregulated by COM in macrophages. CONCLUSION: Vitexin exerts protective effects against nephrolithiasis by inhibiting pyroptosis activation, apoptosis, EMT, and macrophage infiltration. In addition, GSDMD-related pyroptosis mediates nephrolithiasis.

Kaempferol alleviates calcium oxalate crystal-induced renal injury and crystal deposition via regulation of the AR/NOX2 signaling pathway.

BACKGROUND: Calcium oxalate (CaOx) crystal deposition and crystal-induced renal tubular epithelial cell injury have been found to fundamentally contribute to the formation of CaOx nephrolithiasis. PURPOSE: In the current work, we aim to study the role and mechanism of kaempferol in CaOx crystal kidney deposition and crystal-induced renal injury. STUDY DESIGN: Mice models and HK-2 cells were used to investigate the effect of kaempferol in CaOx crystal-induced renal injury and crystal deposition in the kidney and its underlying mechanism by a series of experiments. METHODS: CaOx crystal deposition in mice renal tubulars and tubular damage were evaluated. And crystal adhesion to HK-2 cells, as well as cellular injury were identified. Furthermore, the effect of kaempferol on the expression of androgen receptor (AR) in renal tubular epithelial cells was assessed. The interaction between AR and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and the intrinsic molecular mechanism of how AR regulated NOX2 in HK-2 cells were dissected. Additionally, several different assays were applied to analyze the expression levels of various related genes in this study. RESULTS: It was revealed that kaempferol reduced CaOx crystal deposition in renal tubulars and crystal adhesion to HK-2 cells. Meanwhile, the results of in vivo and in vitro experiments corroborated that crystal-associated cellular injury, oxidative stress, inflammation and over-expression of OPN and CD44 in the kidney were ameliorated by kaempferol. Moreover, kaempferol functioned on inhibiting the expression of AR in renal tubular epithelial cells, and AR was able to up-regulate the expression of NOX2 at the transcriptional level by directly binding to the promoter of NOX2. Kaempferol decreased crystal deposition and crystal-induced renal oxidative and inflammatory injury by the down-regulation of AR/NOX2 signaling pathway. CONCLUSION: Taken together, our study findings suggest that kaempferol has a suppressive effect on renal AR expression, which can attenuate CaOx crystal deposition and crystal-induced kidney injury through repressing oxidative stress and inflammation in the kidney by modulating the AR/NOX2 signaling pathway. It demonstrates that kaempferol may have preventive and therapeutic potential for CaOx nephrolithiasis.

Theaflavin protects against oxalate calcium-induced kidney oxidative stress injury via upregulation of SIRT1.

Renal tubular cell injury induced by calcium oxalate (CaOx) is a critical initial stage of kidney stone formation. Theaflavin (TF) has been known for its strong antioxidative capacity; however, the effect and molecular mechanism of TF against oxidative stress and injury caused by CaOx crystal exposure in kidneys remains unknown. To explore the potential function of TF on renal crystal deposition and its underlying mechanisms, experiments were conducted using a CaOx nephrocalcinosis mouse model established by glyoxylate intraperitoneal injection, and HK-2 cells were subjected to calcium oxalate monohydrate (COM) crystals, with or without the treatment of TF. We discovered that TF treatment remarkably protected against CaOx-induced kidney oxidative stress injury and reduced crystal deposition. Additionally, miR-128-3p expression was decreased and negatively correlated with SIRT1 level in mouse CaOx nephrocalcinosis model following TF treatment. Moreover, TF suppressed miR-128-3p expression and further abolished its inhibition on SIRT1 to attenuate oxidative stress in vitro. Mechanistically, TF interacted with miR-128-3p and suppressed its expression. In addition, miR-128-3p inhibited SIRT1 expression by directly binding its 3'-untranslated region (UTR). Furthermore, miR-128-3p activation partially reversed the acceerative effect of TF on SIRT1 expression. Taken together, TF exhibits a strong nephroprotective ability to suppress CaOx-induced kidney damage through the recovery of the antioxidant defense system regulated by miR-128-3p/SIRT1 axis. These findings provide novel insights for the prevention and treatment of renal calculus.

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.

Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis.

AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) may reduce nephrolithiasis risk by increasing urine flow. We aimed to investigate whether initiation of SGLT2I was associated with reduced nephrolithiasis risk. METHODS: We conducted an active-comparator new-user cohort study using the Danish health registries in the period 11 November 2012 to 31 December 2018. Individuals aged ≥40 years initiating SGLT2Is or glucagon-like peptide-1 receptor agonists (GLP1 RAs) were followed from treatment initiation until an inpatient or outpatient diagnosis of nephrolithiasis, death, emigration or end of study. New users of SGLT2Is were matched 1:1 on propensity scores to new users of GLP1 RAs. In supplementary analyses, risk of recurrent nephrolithiasis was assessed in individuals with a history of nephrolithiasis before treatment initiation. RESULTS: We identified 24,290 and 19,576 eligible users of SGLT2Is and GLP1 RAs, respectively. After matching, 12,325 patient pairs remained. The median age was 61 years and median follow-up was 2.0 years. The nephrolithiasis rate was 2.0 per 1000 person-years in SGLT2I initiators compared with 4.0 per 1000 person-years in GLP1 RA initiators, with a rate difference of -1.9 per 1000 person-years (95% CI -2.8, -1.0) and an HR of 0.51 (95% CI 0.37, 0.71). For recurrent nephrolithiasis (n = 731 patient pairs), the rate difference was -17 per 1000 person-years (95% CI -33, -1.5) and the HR was 0.68 (95% CI 0.48, 0.97). CONCLUSIONS/INTERPRETATION: Initiation of treatment with SGLT2Is was associated with a clinically significant reduced risk of incident and recurrent nephrolithiasis.

Undertreatment of primary hyperparathyroidism in a privately insured US population: Decreasing utilization of parathyroidectomy despite expanding surgical guidelines.

BACKGROUND: Primary hyperparathyroidism is associated with substantial morbidity, including osteoporosis, nephrolithiasis, and chronic kidney disease. Parathyroidectomy can prevent these sequelae but is poorly utilized in many practice settings. METHODS: We performed a retrospective cohort study using the national Optum de-identified Clinformatics Data Mart Database. We identified patients aged ≥35 with a first observed primary hyperparathyroidism diagnosis from 2004 to 2016. Multivariable logistic regression was used to determine patient/provider characteristics associated with parathyroidectomy. RESULTS: Of 26,522 patients with primary hyperparathyroidism, 10,101 (38.1%) underwent parathyroidectomy. Of the 14,896 patients with any operative indication, 5,791 (38.9%) underwent parathyroidectomy. Over time, there was a decreasing trend in the rate of parathyroidectomy overall (2004: 54.4% to 2016: 32.4%, P < .001) and among groups with and without an operative indication. On multivariable analysis, increasing age and comorbidities were strongly, inversely associated with parathyroidectomy (age 75-84, odds ratio 0.50 [95% confidence interval 0.45-0.55]; age ≥85, odds ratio 0.21 [95% confidence interval 0.17-0.26] vs age 35-49; Charlson Comorbidity Index ≥2 vs 0 odds ratio 0.62 [95% confidence interval 0.58-0.66]). CONCLUSION: The majority of US privately insured patients with primary hyperparathyroidism are not treated with parathyroidectomy. Having an operative indication only modestly increases the likelihood of parathyroidectomy. Further research is needed to address barriers to treatment and the gap between guidelines and clinical care in primary hyperparathyroidism.

Nephroprotective and antilithiatic activities of Costus spicatus (Jacq.) Sw.: Ethnopharmacological investigation of a species from the Dourados region, Mato Grosso do Sul State, Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus spicatus (Jacq.) Sw., also known as "cana-do-brejo," is a species that is widely used in Brazilian traditional medicine for the treatment of kidney diseases. However, no studies have evaluated its nephroprotective and antilithiatic effects. AIM: To investigate nephroprotective and antilithiatic effects of C. spicatus in a preclinical model of acute kidney injury (AKI) and in vitro nephrolithiasis. MATERIALS AND METHODS: C. spicatus leaves were collected directly from the natural environment in the Dourados region, Mato Grosso do Sul State, Brazil. The ethanol-soluble fraction of C. spicatus (ESCS) was obtained by infusion. Phytochemical characterization was performed by liquid chromatography coupled to diode array detector and mass spectrometer (LC-DAD-MS). We assessed whether ESCS has acute or prolonged diuretic activity. The nephroprotective effects of ESCS were evaluated in a model of AKI that was induced by glycerol (10 ml/kg, intramuscularly) in Wistar rats. Different doses of ESCS (30, 100, and 300 mg/kg) were administered orally for 5 days before the induction of AKI. Urinary parameters were measured on days 1, 3, 5, and 7. Twenty-four hours after the last urine collection, blood samples were obtained for the biochemical analysis. Blood pressure levels, renal vascular reactivity, renal tissue redox status, and histopathological changes were measured. Antilithiatic effects were evaluated by in vitro crystallization. Calcium oxalate precipitation was induced by sodium oxalate in urine samples with ESCS at 0.05, 0.5, and 5 mg/ml. RESULTS: From LC-DAD-MS analyses, flavonoids, saponins and other phenolic compounds were determined in the composition of ESCS. Significant reductions of the excretion of urinary total protein, creatinine, sodium, and potassium were observed in the AKI group, with significant histopathological damage (swelling, vacuolization, necrosis, and inflammatory infiltration) in the proximal convoluted tubule. Treatment with ESCS exerted a significant nephroprotective effect by increasing the urinary excretion of total protein, urea, creatinine, sodium, potassium, calcium, and chloride. All of the groups that were treated with ESCS exhibited a reduction of histopathological lesions and significant modulation of the tissue redox state. We also observed a concentration-dependent effect of ESCS on the crystallization of urinary crystals, with reductions of the size and proportion of monohydrated crystals. CONCLUSION: The data suggest that C. spicatus has nephroprotective and antilithiatic effects, suggesting possible effectiveness in its traditional use.

Fu-Fang-Jin-Qian-Cao herbal granules protect against the calcium oxalate-induced renal EMT by inhibiting the TGF-ß/smad pathway.

CONTEXT: Nephrolithiasis is a major public health problem worldwide and Fu-Fang-Jin-Qian-Cao granules (FFJQC) is a traditional Chinese herbal formula that is used to treat nephrolithiasis. The main component of nephrolithiasis is calcium oxalate (CaOx) and the epithelial-mesenchymal transition (EMT) shown to play a crucial role in CaOx-induced kidney injury. However, the mechanism underlying the therapeutic effect of FFJQC on the CaOx-induced renal EMT is unknown. OBJECTIVE: This study explores the therapeutic benefits and mechanism of FFJQC in oxalate-induced kidney injury. MATERIALS AND METHODS: 60 male C57BL/6 mice were used in this experiment and divided into 6 groups. A mouse kidney stone model was created by intraperitoneal injection of glyoxylate at a dose of 100 mg/kg for 6 days. The standardized FFJQC was used to treat mouse crystal kidney injury by gavage at 1.35 and 2.7 g/kg, respectively. Western blotting and immunostaining for E-cadherin, cytokeratin 18 (CK18), vimentin, smooth muscle α-actin (α-SMA) and transforming growth factor ß (TGF-ß)/Smad pathway were conducted on renal tissues. RESULTS: Following CaOx-induced kidney injury, the levels of E-cadherin and CK18 in kidney decreased, while vimentin and α-SMA levels increased. The FFJQC treatment increased the levels of E-cadherin and CK18 and decreased vimentin and α-SMA levels in varying degrees. What's more, the FFJQC reduced the expression of CaOx-induced fibrosis marker collagen II. CONCLUSION: FFJQC alleviated the CaOx-induced renal EMT and fibrosis by regulating TGF-ß/smad pathway. Therefore, the FFJQC is an important traditional Chinese medicine for the treatment of CaOx-induced renal injury and fibrosis.

Dietary and lifestyle factors for primary prevention of nephrolithiasis: a systematic review and meta-analysis.

BACKGROUND: Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis. METHODS: PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible. RESULTS: Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27-1.52), dietary sodium (1.38, 1.21-1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51-0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64-0.75), alcohol (0.69, 0.56-0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76-0.90), and potassium. Vitamin D (1.22, 1.01-1.49) and calcium (1.16, 1.00-1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk. CONCLUSIONS: Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.

Common and Rare Complications of Bariatric Surgery.

As the prevalence of obesity has increased, bariatric surgery has become more common because of its proven efficacy at promoting weight loss and improving weight-related medical comorbidities. Although generally successful, bariatric surgery may also lead to complications and negatively affect health. This article highlights some common and rare complications of bariatric surgery. Specifically, it discusses the risk of nutrient deficiencies (which is influenced by surgery type) and their downstream effects, including ill-effects on bone health. Rarer complications, such as postbypass hypoglycemia and alcohol use disorder, are also discussed.

[Nephrolithiasis: From mechanisms to preventive medical treatment]. / Lithiase rénale : des mécanismes au traitement médical préventif.

Renal lithiasis is a frequent pathology (prevalence ranging from 10 to 12% in France) and a recurrent condition. It is associated with chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, especially if it is associated with nephrocalcinosis and/or is part of a monogenic disease (1.6% of lithiasis in adults, including 1% of cystinuria). In order to understand the pathophysiology of the nephrolithiasis, the analysis of stones (morphological and by infrared spectrophotometry) as well as a minimal biological evaluation including crystalluria must be carried out. Calcium nephrolithiasis is the most common form (more than 80%). Its preventive medical treatment relies on simple hygienic dietetics: non-alkaline hyperdiuresis greater than 2liters/day, normalization of calcium intakes (1g/day to be distributed over the three meals), restriction of sodium intakes (6g/day) and of protein intakes (0.8-1g/kg of theoretical weight/day), and avoidance of foods rich in oxalate. If there is a hypercalciuria (greater than 0.1mmol/kg of theoretical weight/day with normal calcium intakes), its mechanism should be explored with an oral calcium load test. In the absence of primary hyperparathyroidism, thiazide diuretics can be prescribed, taking care to prevent hypokalemia and iatrogenic hypocitraturia. The treatment of uric acid lithiasis includes alkaline hyperdiuresis (urinary pH 6.2 to 6.8). Allopurinol is only justified if the urinary excretion of uric acid exceeds 4mmol/day. With a well-managed medical treatment, more than 80% of recurrent lithiasis can be stopped, making nephrolithiasis one of the kidney diseases the more accessible to the preventive medical treatment.

Immunotherapy for stone disease.

PURPOSE OF REVIEW: In addition to traditional risk factors such as low urine volume or hypercalciuria, emerging data suggest that calcium oxalate (CaOx), one of the most common mineral complexes in the urine, elicits a strong immunologic response. This review highlights those studies and projects how future therapies may be directed for kidney stone prevention. RECENT FINDINGS: Over the last 2 years, several groups have studied the response of the immune system to CaOx crystals using cell culture and animal models. Dominguez et al. found that CaOx crystals were recognized by monocytes through an lipopolysaccharide-mediated mechanism, leading to M1 'inflammatory' macrophage phenotype. Patel et al. proposed excessive oxalate-mediated reactive oxygen species within macrophage mitochondria may impair their ability to properly clear stones. Two other groups developed mouse models (an androgen receptor knock-out and an overexpression of Sirtuin 3 protein) and demonstrated increased renal anti-inflammatory macrophage differentiation and decreased CaOx deposition in experimental compared with controls. Anders et al. fed hyperoxaluric mice 1,3-butanediol, which blocks an inflammatory form of cell death called NLRP3 inflammasome and found less intrarenal oxidative damage and higher anti-inflammatory renal infiltrates in experimentals. Finally, monocytes exposed to CaOx crystals followed by hydroxyapatite had reduced inflammatory cytokine and chemokine production compared with those without hydroxyapatite, suggesting that Randall's plaque may play a role in dampening M1-mediatiated CaOx inflammation. SUMMARY: By modulating the immune response, immunotherapy could provide the means to prevent stone recurrences in certain individuals. The promotion of M2 over M1 macrophages and inhibition of inflammation could prevent the cascade that leads to CaOx nucleation. Future therapies may target the ability of macrophages to degrade CaOx crystals to prevent stones.

Prevention of recurrent urinary stone disease.

PURPOSE OF REVIEW: Urinary stone disease (USD) is increasing in prevalence and recurrence is common. In pediatrics, most stones are composed primarily of calcium with the highest incidence observed in adolescents. Given the morbidity associated with USD, an in depth review of current management strategies is of paramount importance to highlight the data supporting the recommended treatments and the knowledge gaps which still exist. RECENT FINDINGS: Several interventions for the management of recurrent calcium USD in children have been recommended based on primarily adult studies. These interventions include modification of diet and fluid intake in addition to the utilization of medications such as thiazide diuretics and citrates when supportive care is inadequate. Overall there is conflicting data in the adult literature which is further complicated by our attempts to extrapolate these data to children. SUMMARY: Based on the currently available literature the management of USD in pediatrics should be individualized to each patient and focused on the particular metabolic risk factors that are identified during the course of their evaluation. Several interventions may be required or trialed in a particular patient to show an effect. Well designed trials to assess the efficacy of each intervention in the pediatric population are needed.