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.

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.

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.

The value of procalcitonin for predicting urosepsis after mini-percutaneous nephrolithotomy or flexible ureteroscopy based on different organisms.

PURPOSE: To assess the value of procalcitonin (PCT) as an early biomarker for predicting urosepsis caused by Gram-negative (GN) bacteria, Gram-positive (GP) bacteria and fungi following mini-percutaneous nephrolithotomy (mPCNL) and flexible ureteroscopy (FURS). METHODS: A total number of 356 patients with positive preoperative UC (urine cultures) who underwent mPCNL and FURS between June 2017 and January 2021 were retrospectively analyzed. Univariable analysis and multivariable logistic regression analysis were conducted to compare the predictors for urosepsis caused by different organisms. Furthermore, the nomogram was established as a predicted model for urosepsis. RESULTS: Among 356 positive UC, 265 (74.4%) were positive for GN bacteria, 77 (21.4%) for GP bacteria and 14 (3.9%) for fungal pathogens. Escherichia coli (48.9%) were the predominant pathogens and Enterococcus (54/77) were the most common GP bacteria. Multivariate logistic regression analysis showed that positive nitrite (OR 3.31, 95% CI 1.20-9.14; P = 0.021), operative time > 90 min (OR 3.10, 95% CI 1.10-8.75, P = 0.033) and postoperative PCT > 0.1 ng/mL (OR 56.18, 95% CI 15.20-207.64, P < 0.001) were associated with postoperative urosepsis originated in GN infections, while urosepsis caused by GP bacteria and fungi was not associated with PCT > 0.1 ng/mL (P = 0.198), only stone burden > 800 mm2 (OR 3.69, 95% CI 1.01-13.53, P = 0.049) was an independent risk factor. CONCLUSIONS: For patients with positive preoperative UC, postoperative PCT > 0.1 ng/mL was an independent risk factor of post-PCNL and post-FURS urosepsis caused by GN bacteria rather than GP bacteria and fungi.

α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt-ß-catenin pathway.

Randall's plaques (RP) are well established as precursor lesions of idiopathic calcium oxalate (CaOx) stones, and the process of biomineralization driven by osteogenic-like cells has been highlighted in RP formation, but the mechanism is poorly understood. Given the inhibitory role of α-Klotho (KL), an aging suppressor protein with high expression in kidneys, in ectopic calcification and the close association between KL gene polymorphisms and urolithiasis susceptibility, we determined the potential role of KL in RP formation. This study found that both soluble KL (s-KL) and transmembrane KL (m-KL) were downregulated, and that s-KL but not m-KL was inversely correlated with upregulation of osteogenic markers in RP tissues. Additionally, s-KL expression was markedly suppressed in human renal interstitial fibroblasts (hRIFs) and slightly suppressed in HK-2 cells after osteogenic induction, intriguingly, which was echoed to the greater osteogenic capability of hRIFs than HK-2 cells. Further investigations showed the inhibitory effect of s-KL on hRIF osteogenic differentiation in vitro and in vivo. Moreover, coculture with recombinant human KL (r-KL) or HK-2 cells suppressed osteogenic differentiation of hRIFs, and this effect was abolished by coculture with KL-silenced HK-2 cells or the ß-catenin agonist SKL2001. Mechanistically, s-KL inactivated the Wnt-ß-catenin pathway by directly binding to Wnt2 and upregulating SFRP1. Further investigations identified activation of the Wnt-ß-catenin pathway and downregulation of SFRP1 and DKK1 in RP tissues. In summary, this study identified s-KL deficiency as a pathological feature of RP and revealed that s-KL released from HK-2 cells inhibited osteogenic differentiation of hRIFs by inactivating the Wnt-ß-catenin pathway, not only providing in-depth insight into the role of s-KL in renal interstitial biomineralization but also shedding new light on the interaction of renal tubular epithelial cells with interstitial cells to clarify RP formation.

Incidence and risk factors of venous thromboembolism after percutaneous nephrolithotomy: a single-center experience.

PURPOSE: To determine the incidence and risk factors of the venous thromboembolism (VTE) in patients undergoing percutaneous nephrolithotomy (PCNL). METHODS: We retrospectively reviewed the records of 896 consecutive cases receiving PCNL between July 2018 and August 2020 in our institution. Univariate analysis was performed to identify the risk factors of VTE, and multivariate logistic regression analysis was further performed to determine the independent risk factors. Furthermore, the corresponding nomogram was conducted to establish a predicted model for VTE. RESULTS: The overall incidence of VTE was 2.8%. The multivariate logistic regression analysis showed that discontinued anticoagulant or antiplatelet therapies (OR 4.505, 95% CI 1.410-14.401), increased postoperative 12-h D-dimer (OR 11.162, 95% CI 2.370-52.574), hydronephrosis (OR 3.303, 95% CI 1.303-8.375), higher Caprini risk assessment model (RAM) score (OR 3.233, 95% CI 1.207-8.659) and postoperative sepsis or septic shock (OR 3.784, 95% CI 1.163-12.306) were independent risk factors of VTE following PCNL. Moreover, the area under the curve of postoperative 12-h D-dimer, hydronephrosis and Caprini RAM score was 0.826, 0.621 and 0.660, respectively. Based on the identified independent risk factors, the well-calibrated nomogram showed a moderate discriminative ability with concordance index 0.731. CONCLUSIONS: 2.8% of patients developed VTE following PCNL. Regarding those patients who have independent risk factors in this study, due attention should be paid to the effective thromboprophylaxis and the early detection of VTE.

Correction to: Long non-coding RNA H19 promotes osteogenic differentiation of renal interstitial fibroblasts through Wnt-ß-catenin pathway.

In the original article, Fig. 2c was published incorrectly. The correct version of Fig. 2c is provided in this correction.

Long non-coding RNA H19 promotes osteogenic differentiation of renal interstitial fibroblasts through Wnt-ß-catenin pathway.

Randall's plaque (RP) serves as a nidus on which idiopathic calcium oxalate stones form. Renal interstitial mineralization may be the cause underlying RP, and recent studies demonstrated the similarities between the interstitial mineralization and ectopic calcification. The present study aimed to investigate whether human renal interstitial fibroblasts (hRIFs) could form calcification under osteogenic conditions, and whether long non-coding RNA H19 participated in regulating osteogenic differentiation of hRIFs through Wnt-ß-catenin pathway. HRIFs were isolated and induced for osteogenic differentiation under osteogenic conditions. Runx2, OCN, alkaline phosphatase (ALP) activity, and the mineralized nodule formation were used to assess the osteogenic phenotype. Molecule expressions were determined by qRT-PCR, immunofluorescence staining, and western blot. The mineralized nodules were assessed by Alizarin red staining. Compared to the normal renal papillary tissue, Runx2, OCN, and H19 were significantly upregulated in RP. After hRIFs were induced with osteogenic medium, osteogenic markers (Runx2, OCN and ALP), ß-catenin and H19 were significantly upregulated, and the mineralized nodules are formed. Additionally, overexpression of H19 promoted the osteogenic phenotype of hRIFs and increased the expression of ß-catenin, whereas knock-down of H19 or XAV939 (inhibitor of Wnt-ß-catenin signaling pathway) significantly repressed the osteogenic phenotype of hRIFs and decreased the ß-catenin. Moreover, XAV939 was shown to abolish the osteogenic differentiation of hRIFs promoted by H19. The study demonstrated that ectopic calcification partly participated in the formation of RP, and H19 promoted osteogenic differentiation of hRIFs by activating Wnt-ß-catenin pathway, which shed new light on the molecular mechanism of the RP formation.

The evaluation of early predictive factors for urosepsis in patients with negative preoperative urine culture following mini-percutaneous nephrolithotomy.

PURPOSE: To identify early predictive factors for urosepsis secondary to mini-percutaneous nephrolithotomy (MPCNL) in patients with negative preoperative urine culture (UC). METHODS: A total of 786 patients with baseline negative UC who underwent MPCNL between January 2017 and June 2019 were retrospectively analyzed. Urosepsis was defined according to the Sepsis-3 definition. Subsequently, perioperative potential risk factors were compared between non-urosepsis and urosepsis groups. RESULTS: Despite negative UC in all patients, the rate of positive stone culture (SC) was 16.0%; the rate of pelvic urine culture (PUC) was 7.5%; 23 cases (2.9%) developed urosepsis after MPCNL. Univariate analysis showed that urosepsis was associated with the female gender, BMI, stone burden, diabetes mellitus and preoperative urine test. Multivariate logistic regression analysis suggested that urine test with positive nitrite and white blood cells and leukocyte esterase (N+WBC+LE+) (OR 17.51, 95% CI 6.75-45.38, P < 0.001) and operative time > 120 min (OR 3.53, 95% CI 1.41-8.85, P = 0.007) were independent risk factors for urosepsis. Additionally, receiver operating characteristic curve analysis of N+WBC+LE+ showed that the area under the curve was 0.785 for predicting the occurrence of urosepsis. Further analysis showed that N+WBC+LE+ provided an efficient prediction of SC+/PUC+ (SC+ or PUC+) with 61.7% sensitivity and 97.3% specificity. CONCLUSIONS: In spite of the baseline negative preoperative UC, 2.9% of patients developed urosepsis after MPCNL. N+WBC+LE + was determined to be an early and efficient prediction of intraoperative bacterial status and urosepsis following MPCNL. Nevertheless, further studies are needed to confirm the results.

Comparison of suctioning and traditional ureteral access sheath during flexible ureteroscopy in the treatment of renal stones.

PURPOSE: To compare the efficiency and safety of suctioning ureteral access sheath (UAS) and traditional UAS during flexible ureteroscopy (FURS) for treatment of renal stones. METHODS: Between January 2015 and December 2017, 165 patients who had renal stones successfully underwent FURS with suctioning UAS created by connecting a channel on the tail of the suctioning UAS to a vacuum device. The outcomes of these patients were compared with those of 165 patients undergoing FURS with traditional UAS using a 1:1 scenario matched-pair analysis. The matching parameters were age, gender and stone burden. RESULTS: The baseline characteristics were homogeneous between the two groups. The suctioning UAS group had significantly higher SFR one day postoperatively (82.4% vs. 71.5%; P = 0.02), but SFR 1 month postoperatively was comparable in the two groups (P = 0.13). The incidence of overall complications was significantly higher in the traditional UAS group (24.8% vs 11.5%; P < 0.001). Regarding individual complications, the traditional UAS group was associated with a significantly higher incidence of fever (13.9% vs 5.5%; P = 0.009) and urosepsis requiring only additional antibiotics (6.7% vs 1.8%; P = 0.029). No significant difference was noted in the incidence of septic shock, hematuria, steinstrasse or ureteral stricture. The suctioning UAS group had significantly shorter operative time (49.7 + 16.3 min vs. 57.0 ± 14.0 min; P < 0.001). CONCLUSIONS: Compared to traditional UAS during FURS for treating renal stones, suctioning UAS had the advantages of higher SFR 1 day postoperatively, a lower incidence of infectious complications and a shorter operative time. Further well-designed studies are required to confirm the results.

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.

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.

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 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.

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.

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.

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.

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.