Osteogenic-Like Microenvironment of Renal Interstitium Induced by Osteomodulin Contributes to Randall's Plaque Formation.

Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study explores the role of osteogenic-like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic-like differentiation potential compared to chloride voltage-gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA-seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic-like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic-like fates, by which OMD induces osteogenic-like microenvironment of renal interstitium to participate in RP formation. We identify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

The impact of anxiety on the risk of kidney stone disease: Insights into eGFR-mediated effects.

BACKGROUND: Previous studies have linked kidney stone disease (KSD) with depression, but there are no reports on the relationship between anxiety and KSD, and the mechanism underlying the potential relationship remains unclear. METHODS: Associations of anxiety and incident KSD were assessed in the National Health and Nutrition Examination Survey (NHENES) using multivariate logistic regression. Two-sample bidirectional Mendelian randomization studies and a two-step two-sample MR was used to estimate the mediating factors that influence KSD risk. RESULTS: Examinations of NHANES data revealed that a rise in the frequency and intensity of anxiety were independently associated with incident KSD. In MR analysis, anxiety (uk-a-51 and uk-b-6519) were from the UK Biobank, with sample sizes of 328,717 and 450,765 respectively. KSD data were from the FinnGen, including 8597 cases and 333,128 controls. In the IVW analysis, genetically predicted anxieties (ukb-a-51 and ukb-b-6519) were found to be causally associated with a higher risk of KSD, with odds ratios of 6.18 (95 % CI 2.54-15.04) and 3.44 (95 % CI 1.67-7.08), respectively. There were no reverse causal effects. Further mediation analysis indicated that anxiety increases the risk of KSD by raising eGFR, through which 11.8 % of the effect of anxiety on KSD risk was mediated. LIMITATIONS: The research was confined to individuals of European heritage, and there could be specific genetic variances among diverse ethnicities. CONCLUSION: The current study suggests anxiety as an independent causal risk factor for KSD and unveils a new pathogenic mechanism, showing that anxiety raises eGFR, thereby increasing the risk of KSD.

A high-calcium environment induced ectopic calcification of renal interstitial fibroblasts via TFPI-2-DCHS1-ALP/ENPP1 axis to participate in Randall's plaque formation.

Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.

Both enantiomers of ß-aminoisobutyric acid BAIBA regulate Fgf23 via MRGPRD receptor by activating distinct signaling pathways in osteocytes.

With exercise, muscle and bone produce factors with beneficial effects on brain, fat, and other organs. Exercise in mice increased fibroblast growth factor 23 (FGF23), urine phosphate, and the muscle metabolite L-ß-aminoisobutyric acid (L-BAIBA), suggesting that L-BAIBA may play a role in phosphate metabolism. Here, we show that L-BAIBA increases in serum with exercise and elevates Fgf23 in osteocytes. The D enantiomer, described to be elevated with exercise in humans, can also induce Fgf23 but through a delayed, indirect process via sclerostin. The two enantiomers both signal through the same receptor, Mas-related G-protein-coupled receptor type D, but activate distinct signaling pathways; L-BAIBA increases Fgf23 through Gαs/cAMP/PKA/CBP/ß-catenin and Gαq/PKC/CREB, whereas D-BAIBA increases Fgf23 indirectly through sclerostin via Gαi/NF-κB. In vivo, both enantiomers increased Fgf23 in bone in parallel with elevated urinary phosphate excretion. Thus, exercise-induced increases in BAIBA and FGF23 work together to maintain phosphate homeostasis.

Metabolic Syndrome and the Risk of Kidney Stones: a Large-scale Cohort Study from 487,860 UK Biobank participants.

OBJECTIVE: While some studies have suggested an association between metabolic syndrome and kidney stones, the quality and level of evidence in these studies vary. Whether some individual characteristics and clustering of metabolic syndrome traits increase the risk of kidney stones has not been examined in a large-scale prospective cohort. MATERIALS: We conducted a retrospective analysis of data from a prospective cohort of 487,860 UK Biobank participants who were free from kidney stones at baseline. The presence of metabolic syndrome was based on five criteria: abdominal obesity, high triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, high blood pressure (HBP), and type 2 diabetes mellitus (T2DM). Cox proportional hazards regression models were used to evaluate the association between metabolic syndrome and risk of kidney stones. RESULTS: After an average follow-up period of 12.6 years, a total of 5,213 of the 487,860 participants included in the UK Biobank study developed kidney stones. The partial traits of metabolic syndrome, including waist circumference (HR: 1.15, 95% CI: 1.10-1.20), HDL cholesterol (0.66, 0.55-0.79), HBP (1.11, 1.03-1.19) and T2DM (1.14, 1.04-1.21), were independently associated with the occurrence of kidney stones. The clustering of metabolic syndrome is significantly associated with kidney stone formation, and as the number of metabolic syndrome traits increases, the risk of kidney stones gradually increases. CONCLUSION: Metabolic syndrome is a significant and independent risk factor for the development of kidney stones. This association suggests that kidney stones may represent a systemic disorder influenced by the interplay of various metabolic risk factors.

Proton pump inhibitors use is associated with a higher prevalence of kidney stones: NHANES 2007-2018.

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.

Exposure to per- and polyfluoroalkyl substance and metabolic syndrome: A nationally representative cross-sectional study from NHANES, 2003-2018.

Per- and polyfluoroalkyl substances(PFAS) are widespread organic pollutants with endocrine-disrupting effects on human health, but the association of PFAS exposure with metabolic syndrome remains conflicting. National Health and Nutrition Examination Survey(NHANES) program was utilized to evaluate the association of individual PFAS exposure and metabolic disorders and further determined the joint effect of PFAS co-exposures. 13921 participants and five PFAS exposures(PFHxS, MPAH, PFDE, PFNA, and PFUA) were included for analysis. The association between individual PFAS and metabolic syndrome varied in the specific PFAS and the specific metabolic disorder examined. PFHxS was negatively associated with obesity(Q4; OR = 0.75; P < 0.001), but positively associated with hyperlipidemia (Q3; OR = 1.2; P = 0.013). PFUA was negatively associated with obesity (Q4; OR = 0.6; P < 0.001), hyperlipidemia (Q3; OR = 0.85; P = 0.03), and non-alcoholic fatty liver disease (NAFLD, Q4; OR = 0.64; P = 0.015), but positively associated with hyperglycemia(Q3; OR = 1.27; P = 0.004). Furthermore, PFAS co-exposures were negatively associated with obesity(OR = 0.63; P < 0.001) and NAFLD(OR = 0.85; P = 0.021), and positively associated with hyperlipidemia(OR = 1.05; P = 0.022), but not significantly associated with hyperglycemia or hypertension. Overall, there was a negative association between PFAS co-exposures and metabolic severity score(ß = -0.15; P < 0.001). Subgroup analysis stratified by gender and obesity consistently showed the negative association of PFAS co-exposures with metabolic severity score, and the positive association with hyperlipidemia. However, subgroup analysis showed a negative association with NAFLD in females but not in males, and a negative association with hyperglycemia in the obesity group, but not in the non-obesity group. Collectively, our study showed a negative association of PFAS co-exposures with metabolic syndrome severity score, but did not support a consistent association between PFAS co-exposures and individual components of metabolic syndrome. Additionally, there were gender-specific as well as BMI-specific differences in these associations. Further studies are needed to rule out the reverse causality and clarify the relationship of PFAS co-exposures with the specific metabolic disorder.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Association between tea consumption and risk of kidney stones: results from dose-response meta-analysis of prospective studies and Mendelian randomization analysis.

PURPOSE: The association between tea consumption and kidney stones is inconsistent in observational studies. Thus, we performed a dose-response meta-analysis of prospective cohort studies and a two-sample Mendelian randomization (MR) analysis to identify this association. METHODS: The prospective cohort studies reporting the relationship between tea consumption and kidney stones were searched from PubMed, the Cochrane Library, EMBASE, and Web of Science from inception to December 1, 2023. For MR analysis, the summary-level data for tea consumption and kidney stones were extracted from the UK Biobank available data and the 8th release of the FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was the primary analytical method. RESULTS: In our dose-response meta-analysis, four prospective cohort studies involving 1,263,008 participants were included, and tea consumption was found to have significant associations with kidney stones (RR: 0.80, 95% CI: 0.73-0.87). We also observed a substantially linear negative relationship between tea consumption and the risk of kidney stones. In MR analysis, the IVW method indicated that tea consumption was inversely associated with kidney stones (OR: 0.71, 95% CI: 0.53-0.94). CONCLUSION: Our study confirmed a causal relationship between tea consumption and kidney stones, and higher tea consumption may reduce the risk of kidney stones.

The association of dyslipidemia with kidney stone: result from the NHANES 2007-2020.

OBJECTIVE: To examine the association between dyslipidemia and kidney stone disease (KSD). METHODS: A cross-sectional study data from 2007 to 2020 National Health and Nutrition Examination Survey (NHANES) were analyzed. Multivariate logistic regression was conducted with serum lipid levels as the exposure and presence of KSD as the outcome, and included adjustment for confounders and subgroup analysis. RESULTS: A total of 38,617 participants were enrolled and classified into two groups according to whether they ever had (n = 3689) or did not have (n = 34,928) KSD. After multivariate logistic regression models, compared to quartile 1 (Q1) of lipid profile, the participants in Q3 (OR 0.8380; 95 CI 0.7380, 0.9515, P < 0.01) and Q4 (OR 0.7373; 95 CI 0.6377, 0.8525, P < 0.01) of high-density lipoprotein cholesterol (HDL) had a significantly lower risk of KSD in adjusted model 3. Results remained stable after stratified by age, gender, and body mass index (BMI) in subgroup analysis. No association was observed between low-density lipoprotein cholesterol (LDL), total cholesterol (TC) and triglycerides (TG) levels, and KSD. CONCLUSIONS: Low HDL was associated with a higher risk of kidney stones in the USA adult population.

Renal pedicle lymphatic ligation for non-parasitic chyluria via retroperitoneal laparoscopic surgery: a single-center 12-year experience.

Background: Chyluria is a rare disease in which chylous is excreted in the urine. Currently, management of chyluria includes conservative treatments and surgical measures. This study aimed to report our experience in treating non-parasitic chyluria with retroperitoneal laparoscopic ligation of the renal lymphatic vessels. Methods: Data from 52 patients who underwent retroperitoneoscopic ligation of the renal lymphatic vessels for non-parasitic chyluria between December 2009 and May 2022 were reviewed. After general anesthesia, the patients were passively placed in the healthy lateral decubitus position and underwent three-port retroperitoneal laparoscopy. Detailed medical data, including demographic characteristics, intraoperative outcomes, postoperative data, and complications, were reviewed. Results: Fifty-two patients received surgery treatment at our institution. The mean disease course was 89.3 months. The mean age was 58.8 years, with females accounting for 57.7% (30/52); the majority of patients (33/52) had the laterality of chyluria on the left and 9 (17.3%) had a history of previous thoracic or abdominal surgery. Compared with the urine and blood data before the operation and on the first day after the operation, urinary protein, urinary tract infection, urinary red blood cells, hemoglobin, albumin, and serum total protein significantly improved 3 months after the operation. However, there were no significant differences in blood creatinine and blood urea nitrogen levels among the three groups. The mean surgery time was about 110.0 minutes, and the estimated total blood loss was 81.2 mL. The postoperative drainage volume was 229.9 mL. The average time to start a liquid diet and to be out of bed were 1.5 and 1.9 days, respectively. Transient postoperative gross hematuria occurred in eight patients, and complications occurred in five patients after surgery. The mean length of hospitalization was 6.6 days. The follow-up duration ranged from 3 to 152 months, and except for three patients who did not respond to treatment, the remaining patients had no recurrence and did not require reoperation. Conclusions: Our long-term follow-up results showed that renal pedicle lymphatic ligation via retroperitoneal laparoscopic surgery is an effective, safe, and reliable surgical option for patients with non-parasitic chyluria.

Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.

Background and objective: The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. Methods: We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. Results: The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). Conclusion: This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.

Risk factors for the comorbidity of osteoporosis/osteopenia and kidney stones: a cross-sectional study.

Low femoral neck bone mineral density (BMD) was associated with the increased risk of kidney stones. Low dietary magnesium intake and increased serum alkaline phosphatase were associated with the increased risk of low femoral neck BMD in kidney stone formers. PURPOSE: To evaluate whether low femoral neck bone mineral density (BMD) was associated with a higher risk of kidney stones, and identify risk factors for the comorbidity of osteoporosis/osteopenia and kidney stones. METHODS: We analyzed individuals aged ≥ 20 years from National Health and Nutrition Examination Survey 2007-2020 data. Osteoporosis/osteopenia is defined as any T-score < -1.0 of femoral neck, total femoral, and mean lumbar spine (L1-L4) BMD. Dietary intakes (sodium, potassium, magnesium, calcium, phosphorus, calcium/phosphorus, vitamin D (25OHD2+25OHD3)) and serum parameters (sodium, potassium, calcium, phosphorus, bicarbonate, vitamin D, alkaline phosphatase (ALP)) were screened for identifying risk factors for the comorbidity. RESULTS: The prevalence of comorbidity of osteoporosis/osteopenia and kidney stones was 4.82%. Femoral neck BMD T-score was negatively associated with the prevalence of kidney stones (n=11,864). Dietary magnesium intake, serum phosphorus, and bicarbonate were negatively associated with the comorbidity prevalence, and serum ALP was positively associated with the comorbidity prevalence (n=6978). Additionally, there remain significant associations of dietary magnesium intake, serum ALP, and bicarbonate with not only femoral neck BMD T-score (n=11331), but also the prevalence of kidney stones (n=23,111) in general population. Furthermore, dietary magnesium intake was positively correlated to femoral neck BMD T-score in stone formers (SFs), while serum ALP was negatively correlated to femoral neck BMD T-score in SFs (n=1163). CONCLUSION: Low femoral neck BMD was closely associated with an increased risk of kidney stones. Low magnesium intake and increased serum ALP were associated with the increased risk of the comorbidity, as well as indicative of low femoral neck BMD T-score in SFs, which offered a clue to further clarify the mechanism leading to paradoxical calcification of bone resorption and kidney stones, and had the potential to perform personalized diagnostic workup for low BMD in SFs.

Association of serum 25-hydroxyvitamin D concentrations with all-cause mortality among individuals with kidney stone disease: the NHANES database prospective cohort study.

Background: The purpose of this study was to investigate the correlation between serum 25(OH)D concentrations and all-cause mortality in patients with kidney stone disease (KSD) as the effects of a deficiency in 25-hydroxyvitamin D on KSD patients are currently unclear. Methods: For our prospective cohort study, we included 2,916 participants from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. The National Death Index (NDI) was utilized to identify all causes of death and cause-specific mortality until December 31, 2018. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) using multivariate Cox regression models. Results: During the 18,859 person-years of follow-up, a total of 375 fatalities occurred, including 83 deaths from cardiovascular disease (CVD) and 79 deaths from cancer. At baseline, individuals with higher blood 25(OH)D concentrations had lower levels of glucose, glycohemoglobin, CRP, and insulin, as well as higher levels of HDL cholesterol (P < 0.01). In the fully adjusted model (Model 3), compared to the group with the lowest 25(OH)D concentrations, those with serum 25(OH)D concentrations ≥75 nmol/L had hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.48 (0.26, 0.87) for all-cause mortality (P=0.02, P for trend = 0.02). The association between serum 25(OH)D concentrations and all-cause mortality in KSD patients was found to be significantly non-linear. A 7% decrease in the risk of death from all causes was observed for each unit-nmol/L increase in serum 25(OH)D concentrations when the concentrations were below 27.7 nmol/L (P < 0.05). Conclusion: Based on the findings, KSD patients with insufficient serum 25(OH)D concentrations were at a higher risk of all-cause mortality. Therefore, it is crucial to maintain sufficient blood 25(OH)D concentrations and prevent 25(OH)D insufficiency in order to extend the lifespan of KSD patients.

Knockdown of lncRNA MALAT1 attenuates renal interstitial fibrosis through miR-124-3p/ITGB1 axis.

Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-ß1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-ß1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.

Causal relationship between kidney stones and gut microbiota contributes to the gut-kidney axis: a two-sample Mendelian randomization study.

Background: Gut microbiota, particularly Oxalobacter formigenes, has been previously reported to be associated with kidney stones. However, the conflicting results from both observational and intervention studies have created substantial uncertainty regarding the contribution of Oxalobacter formigenes to the formation of kidney stone. Methods: We employed a two-sample MR analysis to investigate the causal relationship between gut microbiota and kidney stones using GWASs summary statistics obtained from the MiBioGen and FinnGen consortia. Moreover, we conducted a reserve MR analysis to assess the direction of the causal associations between gut microbiota and kidney stones. The inverse variance weighted (IVW) approach represents the primary method of Mendelian Randomization (MR) analysis. Results: Our analyses do not yield supportive evidence for a causal link between the genus Oxalobacter (OR = 0.99, 95% CI: 0.90-1.09, p = 0.811) and the formation of kidney stones. The order Actinomycetales (OR = 0.79, 95% CI: 0.65-0.96, p = 0.020), family Actinomycetaceae (OR = 0.79, 95% CI: 0.65-0.96, p = 0.019), family Clostridiaceae 1 (OR = 0.80, 95% CI: 0.67-0.96, p = 0.015), genus Clostridiumsensustricto 1 (OR = 0.81, 95% CI: 0.67-0.98, p = 0.030) and genus Hungatella (OR = 0.86, 95% CI: 0.74-0.99, p = 0.040) had protective effects on kidney stones, and the genus Haemophilus (OR = 1.16, 95% CI: 1.01-1.33, p = 0.032), genus Ruminococcaceae (UCG010) (OR = 1.38, 95% CI: 1.04-1.84, p = 0.028), genus Subdoligranulum (OR = 1.27, 95% CI: 1.06-1.52, p = 0.009) were risk factors for kidney stones. Differential abundance analysis provide no evidence of a association between Oxalobacter formigenes and kidney stones, and showed genus Subdoligranulum were risk factors for kidney stones. Reverse MR analysis did not indicate any causal association of kidney stones on gut microbiota. No considerable heterogeneity of instrumental variables or horizontal pleiotropy was observed. Conclusion: Our two-sample MR study did not find any causal relationship between genus Oxalobacter and kidney stones. The association between gut microbiota and kidney stones does not solely depend on the presence of genus Oxalobacter/Oxalobacter formigenes. A more integrated approach using multiple omics platforms is needed to better understand the pathogenesis of kidney stones in the context of complex gene-environment interactions over time.

Comprehensive evaluation of serum cotinine on human health: Novel evidence for the systemic toxicity of tobacco smoke in the US general population.

BACKGROUND: Accumulating epidemiological studies have demonstrated that smoking caused damage to human health. However, these studies almost focused on the individual smoking pattern rather than the toxic ingredients of tobacco smoke. Despite the exact accuracy of cotinine as a smoking exposure biomarker, there were few studies investigating the association between serum cotinine and human health. This study aimed to provide novel evidence about the harmful effect of smoking on systemic health from the perspective of serum cotinine. METHODS: All used data was acquired from 9 survey cycles (2003-2020) of the National Health and Nutrition Examination Survey (NHANES) program. The mortality information of participants was derived from the National Death Index (NDI) website. The disease status of participants, including respiratory, cardiovascular, and musculoskeletal diseases, was obtained from questionnaire surveys. The metabolism-related index, including obesity, bone mineral density (BMD), and serum uric acid (SUA), was obtained from examination data. Multiple regression methods, smooth curve fitting, and threshold effect models were used for association analyses. RESULTS: With a total of 53,837 subjects included, we detected an L-shaped association between serum cotinine and obesity-related index, a negative association between serum cotinine and BMD, a positive association between serum cotinine and nephrolith and coronary heart disease (CHD), a threshold effect of serum cotinine on hyperuricemia (HUA), osteoarthritis (OA), chronic obstructive pulmonary disease (COPD), and stroke, as well as a positive saturate effect of serum cotinine on asthma, rheumatoid arthritis (RA), all-cause, cardiovascular disease (CVD)-cause, cancer-cause, and diabetes-cause mortality. CONCLUSIONS: In this study, we investigated the association between serum cotinine and multiple health outcomes, indicating the systematic toxicity of smoking exposure. These findings provided novel epidemiological evidence about how passive exposure to tobacco smoke affects the health condition of the general US population.

OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall's plaque formation.

BACKGROUND: Randall's plaques (RP) are identified as anchored sites for kidney calcium oxalate stones, but the mechanism remains unclear. Given the importance of osteogenic-like cells in RP formation and OCT4 in reprogramming differentiated cells to osteoblasts, the current study explored the potential role of OCT4 in RP formation. METHODS: OCT4 and biomineralization were evaluated in RP, and immunofluorescence co-staining was performed to identify these cells with alteration of OCT4 and osteogenic markers. Based on the analysis of tissue, we further investigated the mechanism of OCT4 in regulating osteogenic-like differentiation of primary human renal interstitial fibroblasts (hRIFs) in vitro and vivo. RESULTS: We identified the upregulated OCT4 in RP, with a positive correlation to osteogenic markers. Interestingly, fibroblast marker Vimentin was partially co-localized with upregulated OCT4 and osteogenic markers in RP. Further investigations revealed that OCT4 significantly enhanced the osteogenic-like phenotype of hRIFs in vitro and in vivo. Mechanically, OCT4 directly bound to BMP2 promoter and facilitated its CpG island demethylation to transcriptionally promote BMP2 expression. Furthermore, combination of RIP and RNA profiling uncovered that lncRNA OLMALINC physically interacted with OCT4 to promote its stabilization via disrupting the ubiquitination. Additionally, OLMALINC was upregulated in fibroblasts in RP visualized by FISH, and a positive correlation was revealed between OLMALINC and OCT4 in RP. CONCLUSIONS: The upregulation of OCT4 in hRIFs was a pathological feature of RP formation, and OLMALINC/OCT4/BMP2 axis facilitated hRIFs to acquire osteogenic-like phenotype under osteogenic conditions, through which the pathway might participate in RP formation. Our findings opened up a new avenue to better understand RP formation in which osteogenic-like process was partially triggered by lncRNAs and pluripotency maintenance related genes.

Increased risk of testosterone deficiency is associated with the systemic immune-inflammation index: a population-based cohort study.

Purpose: This study aimed to explore the relationship between serum testosterone levels and systemic immune-inflammation index (SII). Methods: Complete SII and serum testosterone data of men over 20 years of age were retrieved from the 2011-2016 National Health and Nutrition Examination Survey to conduct a prevalence survey. To calculate SII, the platelet count was multiplied by the neutrophil-to-lymphocyte count ratio. Isotope dilution liquid chromatography and tandem mass spectrometry were employed to measure serum testosterone concentration. Testosterone deficiency (TD) was defined as a serum testosterone level ≤ 300ng/dl. Weighted proportions and multivariable regression analyses were used to analyze the association between SII and TD. Results: Overall, the data of 7389 participants were analyzed, The SII ranged from 1.53 - 6297.60. Of the participants, 28.42% had a low serum testosterone level (≤ 300 ng/dl). In the fully adjusted multivariable logistic model, the second quartile (OR: 1.27, p = 0.0737), the third quartile (OR: 1.43, p = 0.0090), and the fourth quartile (OR:1.48, p = 0.0042) of SII significantly increased the TD incidence rate, with the lowest quartile of the SII as a reference. For subgroup analysis, statistically significant associations were observed in participants aged 20-40, obese, non-hypertensive, and non-diabetic. The interaction test revealed no significant effect on this connection. Conclusions: There was a positive relationship between a high SII and an increased prevalence of TD in a nationwide sample of adult men in the United States. Further prospective studies on a larger scale are warranted to confirm the causality between SII and TD.