Inverse association of pre-pregnancy Systolic Blood Pressure and Live Birth Rate in normotensive women undergoing IVF/ICSI.

OBJECTIVE: To explore whether maternal baseline systolic and diastolic blood pressure (SBP and DBP) affect pregnancy outcomes particularly in normotensive women (SBP within 90-139 mmHg, DBP within 60-89 mmHg) but also hypertensive women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SUBJECTS: The study included 73,462 patients who underwent IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya between January 1, 2016, and November 30, 2020, selected based on pre-established criteria. Analysis was limited to the first transfer cycle of the first stimulation cycle. EXPOSURE: Baseline SBP and DBP. MAIN OUTCOME MEASURES: Primary outcome focused on the live birth rate (LBR), with secondary outcomes including clinical pregnancy rate, ectopic pregnancy rate, first trimester miscarriage rate, 2nd or 3rd trimester fetal loss, and delivery/neonatal/maternal outcomes. Analytical methods included Poisson regression, linear regression, linear mixed-effect model, and restricted cubic spline analysis as appropriate. RESULTS: For normotensive women, a 10mmHg increase in SBP was associated with an adjusted relative risk (aRR) of 0.988 (95% CI: 0.981-0.995, P=0.001) for live birth likelihood. DBP, however, was not significantly associated with LBR after adjustments. Secondary outcomes indicated that increases in SBP and DBP were associated with higher risks of first trimester miscarriage, gestational diabetes mellitus, and gestational hypertension in the normotensive subset. Sensitivity analyses confirmed these associations between SBP/DBP and LBR, consistent with the main findings even under stricter guidelines and after adjusting for multiple confounders. Subgroup analyses showed variation in the impact of blood pressure on LBR across different demographics and conditions. Consistent with earlier studies on blood pressure and birth outcomes, we found a 5.4% (aRR per 10mmHg =0.946, 95%CI: 0.907-0.986, P =0.009) reduction of LBR in the hypertensive subgroup. CONCLUSION: SBP impacted LBR outcomes in normotensive women undergoing IVF/ICSI, might suggest the need for reconsidering blood pressure management guidelines for reproductive-aged women, focusing on reproductive health in addition to cardiovascular risk.

Both partial inactivation as well as activation of NF-κB signaling lead to hypertension and chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of IL-6, TRAF-1, and NAF-1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by PAS-, Masson trichrome-, and Sirius-Red-staining as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine-ratio are markedly increased in NF-κB activated and inactivated mice compared to controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.

Associations of bisphenol A exposure with metabolic syndrome and its components: A systematic review and meta-analysis.

Mounting evidence shows that bisphenol A (BPA) is associated with metabolic risk factors. The aim of this study was to review related epidemiologic studies and conduct a meta-analysis to quantitatively estimate the association between BPA and metabolic syndrome. Four electronic databases were systematically searched to identify suitable articles. A total of 47 published studies were finally included. Two studies involved metabolic syndrome. Of the 17, 17, 14, and 13 studies on the relationship between BPA with abdominal obesity, blood pressure, fasting plasma glucose, and dyslipidemia, 10, 6, 3, and 4 studies were included in the meta-analysis, respectively. The results showed that the risk of abdominal obesity increased with the increase of BPA exposure, especially in the group with higher BPA exposure levels (Quartile 2 vs. Quartile 1, pooled OR = 1.16, 95%CI: 1.01, 1.33; Q3 vs. Q1, pooled OR = 1.31, 95%CI: 1.13, 1.51; Q4 vs. Q1, pooled OR = 1.40, 95%CI: 1.21, 1.61). However, there was no significant correlation between BPA exposure and metabolic syndrome components including hypertension, abnormal fasting plasma glucose, and dyslipidemia. The present study found that BPA exposure is significantly associated with a higher risk of abdominal obesity. However, the relationship between BPA with metabolic syndrome and its other components needs further longitudinal studies to verify.

Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies.

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

GSK343 modulates macrophage M2 polarization through the EZH2/MST1/YAP1 signaling axis to mitigate neurological damage induced by hypercalcemia in CKD mice.

Chronic kidney disease (CKD) often culminates in hypercalcemia, instigating severe neurological injuries that are not yet fully understood. This study unveils a mechanism, where GSK343 ameliorates CKD-induced neural damage in mice by modulating macrophage polarization through the EZH2/MST1/YAP1 signaling axis. Specifically, GSK343 downregulated the expression of histone methyltransferase EZH2 and upregulated MST1, which suppressed YAP1, promoting M2 macrophage polarization and thereby, alleviating neural injury in hypercalcemia arising from renal failure. This molecular pathway introduced herein not only sheds light on the cellular machinations behind CKD-induced neurological harm but also paves the way for potential therapeutic interventions targeting the identified axis, especially considering the M2 macrophage polarization as a potential strategy to mitigate hypercalcemia-induced neural injuries.

Endothelin receptor B-deficient mice are protected from high-fat diet-induced metabolic syndrome.

OBJECTIVE: Endothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB antagonism has been demonstrated to favorably influence insulin resistance. Our study explored the role of ETB in metabolic syndrome. METHODS: Wild type (etb+/+) and rescued ETB-deficient (etb-/-) mice were fed a high-fat diet, and energy, glucose, and insulin metabolism were analyzed, and hormones and lipids measured in serum and tissues. Cell culture experiments were performed in HepG2 cells. RESULTS: Compared to etb+/+ mice, etb-/- mice exhibited better glucose tolerance and insulin sensitivity, less WAT accumulation, lower serum triglycerides, and higher energy expenditure. Protection from metabolic syndrome was paralleled by higher hepatic production of fibroblast growth factor 21 (FGF21) and higher serum levels of free thyroxine (fT4), stimulators of energy expenditure. CONCLUSIONS: ETB deficiency confers protection from metabolic syndrome by counteracting glucose intolerance, dyslipidemia, and WAT accumulation due to enhanced energy expenditure, effects at least in part dependent on enhanced production of thyroid hormone/FGF21. ETB antagonism may therefore be a novel therapeutic approach in metabolic syndrome.

The Degree of Prepregnancy Vitamin D Deficiency Is Not Associated With Gestational Diabetes in Women Undergoing ART.

Context: Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly in women undergoing assisted reproductive technology (ART). An association of GDM with vitamin D in women conceiving naturally has been described; however, studies have yielded heterogeneous results. Objective: To analyze the association between prepregnancy total and free vitamin D and GDM incidence in women undergoing ART. Methods: Post hoc analysis of a prospective study at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China. Total and free vitamin D were measured 1 day before embryo transfer. The patients were screened for GDM using the oral glucose tolerance test. Results: A total of 1593 women were included in the study, among whom 256 (16.1%) developed GDM. According to international guidelines for total 25-hydroxyvitamin D [25(OH)D], 47 (2.9%) patients had sufficient (≥30 ng/mL) levels, while 696 (43.7%) were insufficient (20 to <30 ng/mL) and 850 (54.4%) were deficient (<20 ng/mL). Comparing GDM and non-GDM patients, there was no significant difference in total nor free vitamin D levels (P = .340 and .849). Similarly, analysis of GDM rates by quintiles of total and free 25(OH)D showed no significant association in one-way ANOVA (P = .831 and .799). Multivariate logistic regression, considering age, BMI, and fasting glucose, also did not show a significant influence of the 2 vitamin D forms on GDM incidence (P = .266 and .123 respectively). Conclusion: In this relatively vitamin D deficient/insufficient ART cohort, the degree of neither total nor free vitamin D deficiency before pregnancy was associated with the occurrence of GDM.

Exploring the efficacy and beneficial population of preimplantation genetic testing for aneuploidy start from the oocyte retrieval cycle: a real-world study.

BACKGROUND: Preimplantation genetic testing for aneuploidy (PGT-A) is widely used as an embryo selection technique in in vitro fertilization (IVF), but its effectiveness and potential beneficiary populations are unclear. METHODS: This retrospective cohort study included patients who underwent their first oocyte retrieval cycles at CITIC-Xiangya between January 2016 and November 2019, and the associated fresh and thawed embryo transfer cycles up to November 30, 2020. PGT-A (PGT-A group) and intracytoplasmic sperm injection (ICSI)/IVF (non-PGT-A group) cycles were included. The numbers of oocytes and embryos obtained were unrestricted. In total, 60,580 patients were enrolled, and baseline data were matched between groups using 1:3 propensity score matching. Sensitivity analyses, including propensity score stratification and traditional multivariate logistic regression, were performed on the original unmatched cohort to check the robustness of the overall results. Analyses were stratified by age, body mass index, ovarian reserve/responsiveness, and potential indications to explore benefits in subgroups. The primary outcome was cumulative live birth rate (CLBR). The other outcomes included live birth rate (LBR), pregnancy loss rate, clinical pregnancy rate, pregnancy complications, low birth weight rate, and neonatal malformation rate. RESULTS: In total, 4195 PGT-A users were matched with 10,140 non-PGT-A users. A significant reduction in CLBR was observed in women using PGT-A (27.5% vs. 31.1%; odds ratio (OR) = 0.84, 95% confidence interval (CI) 0.78-0.91; P < 0.001). However, women using PGT-A had higher first-transfer pregnancy (63.9% vs. 46.9%; OR = 2.01, 95% CI 1.81-2.23; P < 0.001) and LBR (52.6% vs. 34.2%, OR = 2.13, 95% CI 1.92-2.36; P < 0.001) rates and lower rates of early miscarriage (12.8% vs. 20.2%; OR = 0.58, 95% CI 0.48-0.70; P < 0.001), preterm birth (8.6% vs 17.3%; P < 0.001), and low birth weight (4.9% vs. 19.3%; P < 0.001). Moreover, subgroup analyses revealed that women aged ≥ 38 years, diagnosed with recurrent pregnancy loss or intrauterine adhesions benefited from PGT-A, with a significant increase in first-transfer LBR without a decrease in CLBR. CONCLUSION: PGT-A does not increase and decrease CLBR per oocyte retrieval cycle; nonetheless, it is effective in infertile populations with specific indications. PGT-A reduces complications associated with multiple gestations.

Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus.

BACKGROUND: Besides its established impact on bone and mineral metabolism, it was suggested that fibroblast growth factor 23 (FGF23) might play an important role in the pathogenesis of type 2 diabetes. The impact of FGF23 on gestational diabetes mellitus (GDM), however, is not well understood. iFGF23 ELISAs measure the intact FGF23 molecule, whereas cFGF23 assays measure intact FGF23 as well as degradation products of FGF23. OBJECTIVES: The aim of this study is to compare the association of maternal and foetal cFGF23 and iFGF23 with GDM in a German birth cohort. METHODS: cFGF23 and iFGF23 were analysed in 826 random mother/child pairs from the Berlin Birth Cohort. RESULTS: Mothers who developed GDM had higher concentrations of iFGF-23 compared to mothers who did not suffer from GDM (19.73 vs. 13.23 pg/mL, p < 0.0001), but not higher concentrations of cFGF-23. Multivariant regression analyses showed that gestational diabetes is associated with iFGF23 independently of confounding factors such as age, BMI, ethnic background, family history of diabetes, smoking during pregnancy, and recurrent pregnancy loss. This, however, was only seen when using an iFGF23 ELISA measuring just the full length FGF23 and not in addition FGF23 fragments. No differences in both iFGF23 and cFGF23 concentrations between the GDM and non-GDM groups were detected in cord blood samples of the offspring. CONCLUSIONS: This study of a representative German birth cohort showed that maternal but not foetal iFGF23 is independently associated with GDM.

Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench.

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.

Immune response of heterologous versus homologous prime-boost regimens with adenoviral vectored and mRNA COVID-19 vaccines in immunocompromised patients.

Due to rare but major adverse reactions to the AstraZeneca adenoviral ChAdOx1-S-nCoV-19 vaccine (ChAd), German health authorities recommended adults under 60 who received one dose of ChAd, to receive a second dose of the BioNTech mRNA BNT162b2 vaccine (BNT) as a booster. Studies in the general population suggest an enhanced efficacy of the heterologous (ChAd-BNT) compared to the homologous (BNT-BNT) vaccination regimen. However, an analysis of the efficacy in patient populations with a high risk of severe COVID-19 due to acquired immunodeficiency is still missing. We therefore compared both vaccination regimens in healthy controls, patients with gynecological tumors after chemotherapy, patients on dialysis and patients with rheumatic diseases concerning the humoral and cellular immune response. The humoral and cellular immune response differed substantially in healthy controls compared to patients with acquired immunodeficiency. Overall, the most significant differences between the two immunization regimens were found in neutralizing antibodies. These were always higher after a heterologous immunization. Healthy controls responded well to both vaccination regimens. However, the formation of neutralizing antibodies was more pronounced after a heterologous immunization. Dialysis patients, on the other hand, only developed an adequate humoral and particularly cellular immune response after a heterologous immunization. Tumor and rheumatic patients also - to a weaker extent compared to dialysis patients - benefited from a heterologous immunization. In conclusion, the heterologous COVID-19 vaccination regimens (ChAd-BNT) seem to have an advantage over the homologous vaccination regimens, especially in immunocompromised patients such as patients with end-stage kidney disease treated with hemodialysis.

Inverse correlation of intact PTH, oxidized PTH as well as non-oxidized PTH with 25-hydroxyvitamin D3 in kidney transplant recipients.

Background: 25-hydroxyvitamin D (25(OH)D) and potentially also 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits the synthesis of parathyroid hormone (PTH) in the chief cells of the parathyroid gland. Clinical studies showing a negative correlation between (25(OH)D and PTH are in good agreement with these findings in basic science studies. However, PTH was measured in these studies with the currently clinically used 2nd or 3rd generation intact PTH (iPTH) assay systems. iPTH assays cannot distinguish between oxidized forms of PTH and non-oxidized PTH. Oxidized forms of PTH are the by far most abundant form of PTH in the circulation of patients with impaired kidney function. Oxidation of PTH causes a loss of function of PTH. Given that the clinical studies done so far were performed with an PTH assay systems that mainly detect oxidized forms of PTH, the real relationship between bioactive non-oxidized PTH and 25(OH)D as well as 1,25(OH)2D is still unknown. Methods: To address this topic, we compared for the first time the relationship between 25(OH)D as well as 1,25(OH)2D and iPTH, oxPTH as well as fully bioactive n-oxPTH in 531 stable kidney transplant recipients in the central clinical laboratories of the Charité. Samples were assessed either directly (iPTH) or after oxPTH (n-oxPTH) was removed using a column that used anti-human oxPTH monoclonal antibodies, a monoclonal rat/mouse parathyroid hormone antibody (MAB) was immobilized onto a column with 500 liters of plasma samples. Spearman correlation analysis and Multivariate linear regression were used to evaluate the correlations between the variables. Results: There was an inverse correlation between 25(OH)D and all forms of PTH, including oxPTH (iPTH: r=-0.197, p<0.0001; oxPTH: r=-0.203, p<0.0001; n-oxPTH: r=-0.146, p=0.001). No significant correlation was observed between 1,25(OH)2D and all forms of PTH. Multiple linear regression analysis considering age, PTH (iPTH, oxPTH and n-oxPTH), serum calcium, serum phosphor, serum creatinine, fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), albumin, and sclerostin as confounding factors confirmed these findings. Subgroup analysis showed that our results are not affected by sex and age. Conclusion: In our study, all forms of PTH are inversely correlated with 25-hydroxyvitamin D (25(OH)D). This finding would be in line with an inhibition of the synthesis of all forms of PTH (bioactive n-oxPTH and oxidized forms of PTH with minor or no bioactivity) in the chief cells of the parathyroid glad.

25(OH)D-but not 1,25(OH)2D-Is an independent risk factor predicting graft loss in stable kidney transplant recipients.

Background: Vitamin D deficiency (VDD) or vitamin D insufficiency is common in kidney transplant recipients (KTRs). The impact of VDD on clinical outcomes in KTRs remain poorly defined and the most suitable marker for assessing vitamin D nutritional status in KTRs is unknown so far. Methods: We conducted a prospective study including 600 stable KTRs (367 men, 233 women) and a meta-analysis to pool existing evidence to determine whether 25(OH)D or 1,25(OH)2D predicted graft failure and all-cause mortality in stable KTRs. Results: Compared with a higher 25(OH)D concentration, a low concentration of 25(OH)D was a risk factor for graft failure (HR 0.946, 95% CI 0.912-0.981, p = 0.003), whereas 1,25 (OH)2D was not associated with the study end-point graft loss (HR 0.993, 95% CI 0.977-1.009, p = 0.402). No association was found between either 25(OH)D or 1,25 (OH)2D and all-cause mortality. We furthermore conducted a meta-analysis including 8 studies regarding the association between 25(OH)D or 1,25(OH)2D and graft failure or mortality, including our study. The meta-analysis results were consistent with our study in finding that lower 25(OH)D levels were significantly associated with the risk of graft failure (OR = 1.04, 95% CI: 1.01-1.07), but not associated with mortality (OR = 1.00, 95% CI: 0.98-1.03). Lower 1,25(OH)2D levels were not associated with the risk of graft failure (OR = 1.01, 95% CI: 0.99-1.02) and mortality (OR = 1.01, 95% CI: 0.99-1.02). Conclusion: Baseline 25(OH)D concentrations but not 1,25(OH)2D concentrations were independently and inversely associated with graft loss in adult KTRs.

Correlation of Serum FGF23 and Chronic Kidney Disease-Mineral and Bone Abnormality Markers With Cardiac Structure Changes in Maintenance Hemodialysis Patients.

Background: CKD-MBD is a mineral and bone metabolism syndrome caused by chronic kidney disease. FGF23 is an important factor regulating phosphorus and is the main influencer in the CKD-MBD process. In this study, we observed the correlation among serum FGF23 and calcium, phosphorus and parathyroid hormone, and the correlation between FGF23 levels and cardiac structural changes in MHD patients. Methods: We examined serum FGF23 concentrations in 107 cases of MHD patients using the ELISA method, recorded demographic information and biochemical data, and analyzed the correlation between serum FGF23 levels and blood calcium and blood phosphorus and PTH levels. All patients were evaluated by cardiac color ultrasound, and we finally analyzed the association between the FGF23 level and cardiac structural changes. Results: In 107 cases of MHD patients, serum FGF23 levels were linearly associated with serum calcium (r = 0.27 P < 0.01) and parathyroid hormone levels (r = 0.25, P < 0.05). FGF 23 was negatively correlated with age (r = -0.44, P < 0.01).Serum FGF23 levels were correlated with right atrial hypertrophy in HD patients (P < 0.05). No correlation was found among FGF23, left ventricular hypertrophy/enlargement, and valve calcification stenosis (P > 0.05). Conclusion: Serum FGF23 showed a positive correlation among blood calcium levels and PTH levels in hemodialysis patients, and FGF23 levels can affect the incidence of right atrial hypertrophy in MHD patients.

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

Association of BMAL1 clock gene polymorphisms with fasting glucose in children.

BACKGROUND: The brain and muscle Arnt-like protein-1 (BMAL1) gene is an important circadian clock gene and previous studies have found that certain polymorphisms are associated with type 2 diabetes in adults. However, it remains unknown if such polymorphisms can affect fasting glucose in children and if other factors modify the associations. METHODS: A school-based cross-sectional study with 947 Chinese children was conducted. A multivariable linear regression model was used to analyze the association between BMAL1 gene polymorphisms and fasting glucose level. RESULTS: After adjusting for age, sex, body mass index (BMI), physical activity, and unhealthy diet, GG genotype carriers of BMAL1 rs3789327 had higher fasting glucose than AA/GA genotype carriers (b = 0.101, SE = 0.050, P = 0.045). Adjusting for the same confounders, rs3816358 was shown to be significantly associated with fasting glucose (b = 0.060, SE = 0.028, P = 0.032). Furthermore, a significant interaction between rs3789327 and nutritional status on fasting glucose was identified (Pinteraction = 0.009); rs3789327 was associated with fasting glucose in the overweight/obese subgroup (b = 0.353, SE = 0.126, P = 0.006), but not in non-overweight/non-obese children. CONCLUSIONS: BMAL1 polymorphisms were significantly associated with the fasting glucose level in children. Additionally, the observed interaction between nutritional status and BMAL1 supports promoting an optimal BMI in children genetically predisposed to higher glucose level. IMPACT: Polymorphisms in the essential circadian clock gene BMAL1 were associated with fasting blood glucose levels in children. Additionally, there was a significant interaction between nutritional status and BMAL1 affecting fasting glucose levels. BMAL1 rs3789327 was associated with fasting glucose only in overweight/obese children. This finding could bring novel insights into mechanisms by which nutritional status influences fasting glucose in children.

Linagliptin treatment is associated with altered cobalamin (VitB12) homeostasis in mice and humans.

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320.

Urine metabolomics reveals biomarkers and the underlying pathogenesis of diabetic kidney disease.

PURPOSE: Diabetic kidney disease (DKD) is the most common complication of type 2 diabetes mellitus (T2DM), and its pathogenesis is not yet fully understood and lacks noninvasive and effective diagnostic biomarkers. In this study, we performed urine metabolomics to identify biomarkers for DKD and to clarify the potential mechanisms associated with disease progression. METHODS: We applied a liquid chromatography-mass spectrometry-based metabolomics method combined with bioinformatics analysis to investigate the urine metabolism characteristics of 79 participants, including healthy subjects (n = 20), T2DM patients (n = 20), 39 DKD patients that included 19 DKD with microalbuminuria (DKD + micro) and 20 DKD with macroalbuminuria (DKD + macro). RESULTS: Seventeen metabolites were identified between T2DM and DKD that were involved in amino acid, purine, nucleotide and primarily bile acid metabolism. Ultimately, a combined model consisting of 2 metabolites (tyramine and phenylalanylproline) was established, which had optimal diagnostic performance (area under the curve (AUC) = 0.94). We also identified 19 metabolites that were co-expressed within the DKD groups and 41 metabolites specifically expressed in the DKD + macro group. Ingenuity pathway analysis revealed three interaction networks of these 60 metabolites, involving the sirtuin signaling pathway and ferroptosis signaling pathway, as well as the downregulation of organic anion transporter 1, which may be important mechanisms that mediate the progression of DKD. CONCLUSIONS: This work reveals the metabolic alterations in T2DM and DKD, constructs a combined model to distinguish them and delivers a novel strategy for studying the underlying mechanism and treatment of DKD.